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Targeting Cancer Goes Virtual

Targeting Cancer Goes Virtual | Project Virtual Tumor Cancer in silico and Alternative Cancer Therapies |

By Glendon Mellow

Just like the original moonshot, the future of battling cancer may rely on precision targeting. And that’s going to require new ways of looking at each patient’s data.

While there are over 100 diseases labeled as human cancers, future treatments may be as individual as the people themselves – right down to individual microbiomes. Here are a couple of advancements that may guide oncological patient care in the near future.

Calibrating care with VR

Virtual reality (VR) is finding its way into a couple of important roles in cancer treatment: in diagnosis, and potentially in education for palliative care.

Soon, mapping mutations and reviewing related MRIs, pathology reports, patient history and a microbiome profile could be managed through VR platforms, such as one being developed at Weill Cornell Medicine. On their news page, they detail how in using VR, “seeing a protein or mutation lets researchers see how to design a drug to fit and treat the cancer.” In addition, they note the boon for collaboration, since other specialists who may have an insight on treatment can review the data and model. The potential is there to have a number of different reports, images and treatment options presented visually in a VR space, instead of switching between browser tabs.

High-fidelity simulations (HFS) have gained a recent footing in being used to help educate students and professionals in understanding the various roles HCPs play during palliative care, and new studies involving mannequins, prop, and simulated patient rooms are likely to reveal interesting insights, such as this one described at Virtual Hospice. The decreasing cost of virtual reality technology could create a new standard for this type of simulation, with multiple parameters being available for training sessions. Being able to set different cancer stages, treatments and conditions, as well as different patient personality profiles, may give students and HCPs a greater variety of experiences to learn from.

Palliative care for patients with cancer has shifted from being solely about caring for people at their end-of-life to, in some cases, managing symptoms. At ASCO earlier this year, Dr. Richard T. Lee and Neal J. Meropol suggested more research and standardization on palliative chemotherapy is needed. People are not always the same in how they react to caregivers, or in how their bodies respond to treatment. The ability to interact with different VR simulations, encompassing the variety of challenges found in long-term care could provide valuable insights.

Nanotechnology delivery capsules

While identifying vectors in VR may improve due to diagnosis and training, a variety of targeted approaches to kill tumours are being developed using nanotechnology, or nano-scale–sized particles.

Nanoparticles are typically used as a Trojan Horse against tumours, carrying chemotherapeutic drugs wrapped in a PEG (polyethylene glycol)-coated, liposome shell that allows the nanoparticle to slip by the bodies’ systems. Cancerous blood vessel walls have larger spaces between their cells than healthy blood vessels, which allows the tiny particle to slip between them to the targeted site. New research, by researchers at the Institute for Biomedical Sciences at Georgia State University, the Atlanta Veterans Affairs Medical Center and Wenzhou Medical University and Southwest University in China, reported on by, shows promise in developing vegetable-based nanoparticles by using liposomes derived from ginger. As reported, “Folic acid shows high-affinity binding to the folate receptors that are highly expressed on many tumors and almost undetectable on non-tumor cells.” The Trojan Horse nanoparticle should only release its chemical payload into cancerous tissue, and not bind to healthy tissue. It’s quite a remarkable molecular hack, and can potentially save patients some of the terrible side effects of chemotherapy.

Taking the precision targeting even further, MIT reports they may be able to deliver up to three drugs within the same nanoparticle, presumably to weaken the cancerous cells in different ways. These nanoparticles differ in that they’re not encapsulating the drugs; instead they are nanoparticles built, “from building blocks that already contain drug molecules.” In, researcher Jeremiah Johnson notes, “We can take any drug… and we can load it into our particles in exactly the ratio that we want, and have it release under exactly the conditions that we want it to… It’s very modular.”

Keeping the target in sight

It’s heartening to see that amidst the most advanced disease fighting technology being explored, there’s awareness among researchers to remember care for the people they are treating, and not just the disease they are fighting. From getting the full picture of the patients’ data in VR, to targeting aimed squarely at cancerous tissue, the cancer moonshot isn’t only about doing something big: it’s about doing something with inspiring precision.

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On glioblastoma and the search for a cure: where do we stand?

Bianco J, Bastiancich C, Jankovski A, des Rieux A, Préat V, Danhier F

Cell Mol Life Sci. 2017 Feb 17.

Although brain tumours have been documented and recorded since the nineteenth century, 2016 marked 90 years since Percival Bailey and Harvey Cushing coined the term "glioblastoma multiforme". Since that time, although extensive developments in diagnosis and treatment have been made, relatively little improvement on prognosis has been achieved. The resilience of GBM thus makes treating this tumour one of the biggest challenges currently faced by neuro-oncology. Aggressive and robust development, coupled with difficulties of complete resection, drug delivery and therapeutic resistance to treatment are some of the main issues that this nemesis presents today. Current treatments are far from satisfactory with poor prognosis, and focus on palliative management rather than curative intervention. However, therapeutic research leading to developments in novel treatment stratagems show promise in combating this disease. Here we present a review on GBM, looking at the history and advances which have shaped neurosurgery over the last century that cumulate to the present day management of GBM, while also exploring future perspectives in treatment options that could lead to new treatments on the road to a cure.

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Liquid biopsy offers a new way to target kidney cancer

By Denise Heady

City of Hope researchers and scientists constantly strive to find less invasive ways to help treat patients diagnosed with kidney cancer. Despite a wave of new targeted therapies being approved to treat the disease, many of those therapies have been challenging to use because of the difficulty in obtaining cancer tissue for genomic testing.

Now, researchers may have found a way to combat this problem: the liquid biopsy.

The liquid biopsy, using cell-free cancer DNA that is circulating in the patient’s blood, is an easy and less invasive method of accessing important genomic information in solid tumors, but had not yet been tested in patients with kidney tumors.

In a study led by City of Hope’s Sumanta K. Pal, M.D., assistant professor in the Department of Medical Oncology & Therapeutics Research and co-director of the Kidney Cancer Program at City of Hope, he and his team identified cancer-related DNA in about 80 percent of patients who had a liquid biopsy performed. A majority of the patients were found to have clinically relevant genomic alterations, including alterations in the TP53, VHL, EGFR, NF1 and ARID1A genes.

The results, based on data from Guardant Health, will be presented on Saturday, Feb. 18, at the 2017 Genitourinary Cancers Symposium, which is sponsored by the American Society of Clinical Oncology and the American Society for Radiation Oncology. The analysis of 224 patients diagnosed with metastatic renal cell carcinoma (mRCC) and tested with Guardant360 is the largest assessment of circulating tumor DNA in patients to date. Analysis of this large cohort demonstrated significant changes in circulating tumor DNA (ctDNA) profiles across patients’ clinical courses, which may have therapeutic implications.

“Until now, the only means of assessing kidney tumor DNA has been through biopsies of cancer tissue, a procedure which can be associated with risk of infection and bleeding,” said Pal. “The liquid biopsy circumvents this completely.”

Guardant360 has been used by more than 3,000 oncologists to identify somatic genomic alterations associated with targeted therapies in the tumor DNA of more than 30,000 patients with advanced cancer.

Many doctors rely on biopsies to create an individual treatment plan that is directed toward specific genomic changes in the patient’s tumor.

Because tumors evolve and develop resistance in response to treatment, the changes in ctDNA might provide key insights into how resistance to treatments for kidney cancer occurs. Pal and colleagues now aim to replicate this work in a larger study of patients to confirm the results.

This study also represents an example of City of Hope’s ongoing commitment to developing personalized medicine and targeted therapies. Personalized medicine, which offers physicians the ability to better diagnose, treat, cure and prevent diseases, depends on three factors: discovering the genetic causes of diseases, understanding why individuals respond to different therapies and translating this understanding into new diagnostic tests and therapies.

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New Type of PET Imaging Identifies Primary and Metastatic Prostate Cancer

New Type of PET Imaging Identifies Primary and Metastatic Prostate Cancer | Project Virtual Tumor Cancer in silico and Alternative Cancer Therapies |
In the featured article from the February 2017 issue of The Journal of Nuclear Medicine, researchers document the first-in-human application of a new imaging agent to help find prostate cancer in both early and advanced stages and plan treatment. The study indicates that the new agent—a PET radiotracer—is both safe and effective.

The new agent is a gallium-68 (Ga-68)-labeled peptide BBN-RGD agent that targets both gastrin-releasing peptide receptor (GRPR) and integrin αvβ3. Dual-receptor targeting provides advantages over single-receptor targeting by allowing tumor contrast when either or both receptor types are expressed, improving binding affinity and increasing the number of effective receptors.

Approximately one in seven men will be diagnosed with prostate cancer in his lifetime. In 2017, the American Cancer Society estimates that there will be more than 161,000 new prostate cancer cases in the United States and around 27,000 deaths from the disease. “Although treatable at the early stage, prostate cancer is prone to metastasis,” explain the team of authors, led by Xiaoyuan Chen, senior investigator, Laboratory of Molecular Imaging and Nanomedicine at the U.S. National Institute of Biomedical Imaging and Bioengineering. “An effective and specific imaging method of detecting both primary and metastatic lesions is thus of critical importance to manage patients with prostate cancer.”

This study included 13 patients with prostate cancer (four newly diagnosed and nine post-therapy) and five healthy volunteers. Ga-68-BBN-RGD PET/CT detected 20 bone lesions in seven patients either with primary prostate cancer or after radical prostatectomy. The patients with bone metastases did not necessarily have an elevated prostate specific antigen level. “This result is better than bone scanning with MDP,” Chen notes, referring to the most common radiotracer used today. “MDP bone scans are sensitive but lack specificity because localized skeletal accumulation of Tc-99m-MDP can also be observed in the case of trauma and infection.” No adverse side effects were found during the whole procedure and two-week follow-up, demonstrating the safety of Ga-68-BBN-RGD.

“Compounds capable of targeting more than one biomarker have the ability of binding to both early and metastatic stages of prostate cancer, creating the possibility for a more prompt and accurate diagnostic profile for both primary and the metastatic tumors,” explains Chen.

Looking ahead, Chen says, “Ga-68-BBN-RGD could play an additive role in staging and detecting prostate cancer and provide guidance for internal radiation therapy using the same peptide labeled with therapeutic radionuclides.” He points out that larger-scale clinical investigations are warranted.
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Immunotherapy May Need To Have Its Own Value Model

Immunotherapy May Need To Have Its Own Value Model | Project Virtual Tumor Cancer in silico and Alternative Cancer Therapies |

Immunotherapy has been a game changer for the oncology field, but typical models used to assess the value of cancer treatments don’t take into account the unique characteristics of this therapy, according to experts at the 2016 annual meeting of the Society for Immunotherapy of Cancer (SITC).

The average release price of a new therapeutic agent in oncology “is north of $10,000 a month,” Peter P. Yu, MD, the physician-in-chief of the Hartford HealthCare Cancer Institute, in Hartford, Conn., told attendees at the SITC meeting. There are multiple models to assess the value of a cancer treatment, including the American Society of Clinical Oncology’s Value Framework, the European Society of Medical Oncology’s Magnitude of Clinical Benefit Scale (ESMO-MCBS), the National Comprehensive Cancer Network Evidence Blocks, Memorial Sloan Kettering Cancer Center’s Drug Abacus, and the Institute for Clinical and Economic Review Value Assessment Framework, Dr. Yu said. While they all look at cost, effectiveness and population health impact, none are perfect to apply to immunotherapy or are really easy to use, he said. However, he noted that they could be used as a basis to develop a new value framework for immunotherapy.

These models, when applied to immunotherapy, tend to overestimate the impact of acute but reversible toxicities, as well as the costs of treatment, and underestimate the benefits of long-term survival and treatment-free survival, according to Michael B. Atkins, MD, the deputy director of Georgetown University Medical Center’s Lombardi Comprehensive Cancer Center, in Washington, D.C.

With respect to overestimating toxicity, Dr. Atkins said that while approximately 50% of patients getting the nivolumab-ipilimumab combination develop serious immune toxicities involving the skin liver, colon or endocrine organs, approximately 80% of adverse events resolve in four to six weeks with immune-modulating treatments such as steroids. In addition, he said, these side effects do not interfere with ultimate response to therapy.

The models also overestimate the costs of immunotherapy, according to Dr. Atkins. The costs, he argued, should be amortized over the longer horizons of benefit, taking into account the absence of the need for subsequent therapies in patients who achieve remission. In addition, many patients receiving immunotherapy are being overtreated, he said, noting that effective immunotherapy should do its job within a maximum of six to 12 months. “The benefits of activating the immune system persist long after the treatment stops, so we shouldn’t be so afraid of stopping treatment,” Dr. Atkins said. Any residual disease after a year of immunotherapy should be biopsied to see if it’s actually cancer, and resected. In addition, he noted, immunotherapy combinations may actually be less expensive than single agents if they work faster. Cost-cutting approaches include avoiding immunotherapy/nonimmunotherapy combinations that don’t clearly indicate which therapy is benefiting the patient or that don’t allow for cessation of treatment, and, whenever possible, using biomarkers to help select the right drug or combination therapy for the right patient.

The models also underestimate the benefits of immunotherapy not only for patients and their families but for society, he added. The annual benefit of curing just 1% more cancers is estimated to be $500 billion, he said.

The hallmark of immunotherapy, Dr. Atkins said, is the “tail of the [Kaplan-Meier survival] curve,” referring to long-term survival. In melanoma over the past few years, survival rates have increased from 10% to 20% with ipilimumab (Yervoy, Bristol-Myers Squibb) treatment, to 35% to 40% with anti–PD-1 [programmed cell death protein 1] agents, to potentially higher than 50% with combination ipilimumab/nivolumab (Opdivo, Bristol-Myers Squibb), Dr. Atkins noted. This “means melanoma—a disease that had a median survival of six to nine months in 2011—now has no median survival,” he said.

Immunotherapy, along with targeted therapy, also has helped transform the treatment of lung cancer over the past 10 to 15 years, said Roy S. Herbst, MD, PhD, a professor of medicine and chief of medical oncology at Yale Cancer Center, in New Haven, Conn. “Are we curing people?” he asked. “I think we’re getting pretty close.”

He described the findings of the KEYNOTE-024 trial presented at the ESMO 2016 Congress (N Engl J Med 2016 Oct 8. [Epub ahead of print], PMID: 27718847), which demonstrated significant progression-free and overall survival benefits for patients with advanced lung cancer and high programmed death ligand 1 (PD-L1), expression taking pembrolizumab (Keytruda, Merck) compared with those taking platinum chemotherapy. These findings have “changed the way we think about lung cancer,” Dr. Herbst said.

Anti–PD-1 agents are effective for several other cancers, Dr. Atkins said, noting, “We probably have had no single treatment that was so broadly relevant in oncology.”

In addition to incorporating the benefits shown via these positive clinical trial results, good value frameworks have to include patient-reported outcomes (PROs), according to Heather S. Jim, PhD, an associate member at Moffitt Cancer Center and Research Institute, in Tampa, Fla., and Adam P. Dicker, MD, PhD, a senior vice president and chair of radiation oncology, and a professor of radiation oncology, pharmacology and experimental therapeutics at Thomas Jefferson University, in Philadelphia, who also spoke at the SITC meeting. PROs can help show clinical benefit in reducing disease-related symptoms, provide more accurate estimates of toxicity, enhance value frameworks, help model treatment costs and help improve symptom management, they said. The National Cancer Institute has developed the PRO-Common Terminology Criteria for Adverse Events (PRO-CTCAE), offering a menu of symptoms such as rash, fatigue or itching to select clinical trials or targeted therapies that are more useful for immunotherapy than measures like the EQ-5D health-related quality of life questionnaire.

In the CheckMate 025 trial, a Phase III study of nivolumab versus everolimus (Afinitor, Novartis) in previously treated patients with advanced or metastatic renal cell carcinoma, investigators included a measure of kidney cancer–specific symptomatology, Dr. Jim said. Symptoms in patients taking nivolumab showed improvements as soon as four weeks into treatment, she said, and continued through two years of follow-up data, “showing that not only could nivolumab improve overall survival but could improve the quality of survival,” she said, noting that this information is “important not only for patients but also for regulatory agencies and payors.”

Using PROs in Assessing Cost of Toxicity

A study from Moffitt investigators, presented at the 2016 annual meeting of the American Society of Clinical Oncology, used PROs to model treatment toxicity costs. They looked at patients treated with ipilimumab, nivolumab and pembrolizumab and estimated patient toxicity from billing records. Then they searched public databases to estimate the added costs of these toxicities to the total cost of treatment, determining among other findings that colitis adds about $8,500 and fever adds $3,300, increasing the costs of ipilimumab by 6%, nivolumab by 18% and pembrolizumab by 16%. “These toxicities really do have costs, and it’s important to model those in the value frameworks so patients have an idea of how much out-of-pocket costs they might incur,” Dr. Jim said.

PROs also can help improve symptom management, which can help patients stay on treatment longer with potential survivor benefits, she added. In a recent clinical trial, 766 patients treated with chemotherapy for metastatic breast, genitourinary, gynecologic or lung cancer filled out tablet-based questionnaires about their symptoms (J Clin Oncol 2016;34[24]:2925-2934, PMID: 27247218). The program’s software triggered email alerts to nurses when patients reported severe or significantly worsening symptoms for common conditions in the PRO-CTCAE, and the nurses reached out to these patients to offer help in managing the symptoms. Of the patients receiving this intervention, 34% demonstrated improved quality of life compared with 18% of those receiving usual care; 21% of those in the intervention group had clinically significant improvements in quality of life compared with 11% in usual care. Patients receiving interventions also had fewer ER visits at one year and spent more median months on chemotherapy.

Technology such as smartphone applications or activity trackers may offer ways to better monitor PROs, Dr. Dicker said. “There’s a lot that happens between patient visits that’s not always being captured. We also appreciate white coat syndrome—patients may not want to report toxicities because they want to stay on therapy.”

—Karen Blum

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Non-Chromosomal DNA Drives Tumor Evolution

Non-Chromosomal DNA Drives Tumor Evolution | Project Virtual Tumor Cancer in silico and Alternative Cancer Therapies |

By Anna Azvolinsky

“This is the first comprehensive study of the frequency of extrachromosomal DNA found in diverse cancer types,” Charles Swanton, who studies cancer diversity at the Francis Crick Institute in the U.K., and who was not involved in the work, wrote in an email to The Scientist. “The results presented illustrate just how prevalent this process is and how important ecDNA is likely to be for altering cancer cell phenotypic behavior to adapt to selection pressures.”

“This study provides yet another layer of dimensionality to how tumors permute their genomic material to become more aggressive and adapt to [anti-cancer] therapy,” said Levi Garraway, head of global oncology development at Eli Lilly, who also was not involved in the work.

Oncogene-encoding ecDNA was thought to be rare and the role of this non-chromosomal DNA in tumor growth and evolution was not well understood. In a 2014 Science paper, Mischel and colleagues found that glioblastoma cells expressing a mutated EGFR gene could develop resistance to anti-EGFR drugs by eliminating mutated EGFR genes found in non-chromosomal DNA.

“EcDNA was thought to be a minor, weird thing that happens in some tumors,” Mischel told The Scientist. “After our 2014 paper, we thought about how important amplification of oncogenes can be in cancer and realized that there may be a hole in our knowledge of the role of ecDNA in tumors.”

One of the reasons for the knowledge gap, according to Mischel, is that next-generation sequencing can quantify the number of specific sequences but cannot always accurately map them to a location, particularly if that location is not on a chromosome.

Kristen Turner, a postdoctoral fellow in Mischel’s lab, first quantified the prevalence of ecDNA among 2,572 cells from 117 patient-derived tumor cell lines, eight non-cancerous human cell samples, and 10 immortalized but non-cancerous cell lines. The team developed imaging software to detect the ecDNA among metaphase spreads—when paired chromosomes and ecDNA can be easily distinguished—of each cell type. The ecDNA was almost never detected in normal cells, whereas 40 percent of a variety of cancer types and nearly 90 percent of patient-derived brain tumor xenograft models harbored ecDNA. Within a given tumor, the frequency of ecDNA varied greatly.

“It’s striking that the authors found that almost half of the different tumor cell lines they analyzed contained ecDNA,” noted Rameen Beroukhim, a cancer researcher at the Dana-Farber Cancer Institute in Boston who was not involved in the work.

To find which genes were found on the ecDNA, Mischel and colleagues performed whole-genome sequencing on the tumor cell lines and then used DNA FISH probes to localize the most commonly amplified oncogenes, finding that the ecDNA always harbored the most commonly amplified oncogenes associated with that tumor type.

“We saw that all of the oncogenes were amplified either entirely on ecDNA or on both ecDNA and on the chromosome but not at the gene’s normal chromosomal location, suggesting that these [oncogenic repeats] may be quite mobile,” said Mischel. The team showed that this is indeed the case using one example: the progeny of a glioblastoma cell expressing a high copy-number of a mutated EGFR gene had the EGFR genes move from circular ecDNA onto chromosomal regions.

Co-led by computer scientist Vineet Bafna, the team next created a model to simulate how ecDNA become segregated among daughter cells. Because the ecDNA doesn’t contain a centromere—needed for attachment to the metaphase spindle and equal segregation—the ecDNA are segregated randomly, resulting in some cells with many copies and some with none. The simulations suggested that unequal ecDNA segregation during cell division resulted in a range of cells containing low to high numbers of ecDNA fragments. The model showed that this wide range of distribution contributed to the heterogeneity of the cells that make up a tumor. “We found that if an oncogene was on ecDNA, it could far more rapidly reach high levels and that those high levels would be maintained much longer than if it were just on the chromosome,” explained Mischel.

“The implications are that these ecDNA fragments will be far less stable across tumor populations than chromosomal amplifications and contribute to intercellular diversity and evolution dramatically,” Swanton wrote.

The next questions are how ecDNA behaves within patient tumors, and how this correlates with clinical phenotypes. “Longitudinal studies of cancers through the disease course will be necessary to determine exactly how flexible this process might be,” noted Swanton.

“A question that this study raises is how ecDNA arise in tumors in the first place and how the biology of tumors with oncogene amplifications on ecDNA differs from oncogenes on chromosomal DNA,” said Beroukhim.

The team is now observing the dynamics of ecDNA maintenance throughout multiple cell divisions in culture, said Mischel. “We think this [ecDNA] is an important aspect of how cancers evolve.”

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Toward Killing Cancer with Bacteria

Toward Killing Cancer with Bacteria | Project Virtual Tumor Cancer in silico and Alternative Cancer Therapies |

By Ruth Williams

“I am super excited about applications for microbiota to eliminate cancer,” MIT’s Susan Erdman, who was not involved in the work, wrote in an email to The Scientist. “This work is part of a promising frontier in using bacteria or their products to stimulate beneficial host immune responses to inhibit and suppress cancer development and growth.”

The oxygen-starved and necrotic cores of tumors are attractive environments for anaerobic bacteria such as Salmonella, Clostridium, and Listeria, and an infection can lead to tumor colonization by these bugs. As the bacteria busily multiply, they can directly kill the cancer cells, but also attract the attention of the body’s immune system (which is generally suppressed within tumors), leading to further tumor destruction.

While this is the reasoning behind most bacterial cancer therapies, treating patients with this approach isn’t straightforward. There are safety issues, explained Saurabh Saha, president and chief executive officer of the San Francisco–based biotechnology company Delinia, who was not involved in the work. For example, said Saha, recounting a recent experimental Clostridium treatment, although the patient’s tumor was dramatically diminished by a single dose of the bacteria, the effect “was so potent that the patient needed to get hydration, needed antibiotics—because we needed to contain the reaction.”

On the other hand, in a recent trial, in which researchers injected attenuated Salmonella into patients, the bacteria “were shown to be safe, but . . . they weren’t as effective at creating a strong response,” Saha said, adding: “We have a long way to go to get to some happy medium.”

To improve the chances of developing a successful bacterial treatment for cancer, Jung-Joon Min of the Chonnam National University in Korea and colleagues are trying to first perfect the approach in mice. The team had previously shown that an attenuated Salmonella strain could colonize tumors and activate immunity in mice, but it was “not perfect” at killing cancers, Min wrote in an email to The Scientist, “because 70-80 percent of [the] cancers recur.”

To boost the potency of the Salmonella, Min’s team engineered the bacteria to overexpress a protein proven to induce a strong immune response—flagellin B (a component of the tail-like swimming appendage of some bacteria).

Intravenous injections of the flagellin-expressing Salmonella eradicated the experimental tumors in 55 percent of mice, which then remained healthy until the end of the four-month observation period, the researchers reported. Without overexpression of flagellin, the Salmonella initially shrank tumors in the mice, but the tumors tended to regrow.

The researchers observed that, following Salmonella colonization of the animals’ tumors, local macrophages—cells of the innate immune system—switched from an immunosuppressive to a pro-inflammatory phenotype. Furthermore, genetic knock-out experiments revealed that Toll-like receptor 4 (TLR4)—a host protein that stimulates the innate immune response—was essential for the Salmonella-induced anti-cancer activity.

One of the problems with developing bacterial cancer treatments, said Saha, has been that “these bacteria are almost a black box.” They promote cancer destruction, but no one is exactly sure how. The present study “extends our understanding of bacterial-based cancer therapy at a molecular level,” he said.

Although there has been a recent flurry of investigations into the use of bacteria as cancer-killing agents, it is actually the second wave for such research, said Robert Hoffman, president and chief executive offers of Anticancer, a San Diego–based preclinical contract research organization.

In the late 1800s, bone surgeon William Coley pioneered the use of bacteria as a cancer treatment after discovering that a cancer patient who suffered a bacterial infection survived longer than expected. Back then, before radiation and chemotherapies prevailed, bacteria injection “was a first line therapy,” said Hoffman.

Today’s renaissance of bacterial therapies, he added, is “very, very promising.”

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Bacteria May Help Battle Cancer, Study Suggests

By Robert Preidt

Bacteria may offer a new way to treat cancer, a small, preliminary study suggests.

Researchers injected a weakened strain of Clostridium novyi-NT bacteria spores into tumors in six patients. The bacteria grew in the tumors and killed cancer cells, the investigators reported.

C. novyi-NT, which lives in soil, is a close relative of the bacteria that causes botulism. Before injecting C. novyi-NT into the patients, the researchers weakened it by removing its dangerous toxin.

Five of the six patients are still alive, while one died from unrelated causes several months after receiving the bacteria injection, according to the study to be presented Saturday at the annual Symposium on Clinical Interventional Oncology in Hollywood, Fla.

Research presented at medical meetings should be viewed as preliminary until published in a peer-reviewed journal.

"When tumors reach a certain size, parts of them do not receive oxygen, which makes them resistant to conventional therapies such as radiation and chemotherapy," study author Dr. Ravi Murthy, a professor of interventional radiology at M.D. Anderson Cancer Center in Houston, said in a symposium news release.

"C. novyi-NT thrives under these conditions, hones in on the low-oxygen areas and destroys tumors from the inside while sparing normal tissue," Murthy explained.

C. novyi-NT also triggers an immune response to cancer.

"Essentially, C. novyi-NT causes a potent cancer-killing infection in the tumor," study principal investigator Dr. Filip Janku, an associate professor in the department of investigation therapeutics at M.D. Anderson Cancer Center, said in the news release.

The new findings are very preliminary and much additional research into the potential therapy is needed.

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Better scaffolds help scientists study cancer

Better scaffolds help scientists study cancer | Project Virtual Tumor Cancer in silico and Alternative Cancer Therapies |

By Mike Williams

Testing treatments for bone cancer tumors may get easier with new enhancements to sophisticated support structures that mimic their biological environment, according to Rice University scientists.

A team led by Rice bioengineer Antonios Mikos has enhanced its three-dimensional printed scaffold to see how Ewing’s sarcoma (bone cancer) cells respond to stimuli, especially shear stress, the force experienced by tumors as viscous fluid such as blood flows through bone. The researchers determined the structure of a scaffold, natural or not, has a very real effect on how cells express signaling proteins that help cancer grow.
Sarcoma (bone cancer) cells proliferate on the surface of a 3-D printed scaffold created at Rice University. Experiments at Rice showed that the size of pores in the scaffold, which mimics the extracellular matrix in bone, and the pores' orientation make a difference in how cells proliferate in the presence of a flowing fluid, like blood.

Sarcoma (bone cancer) cells proliferate on the surface of a 3-D printed scaffold created at Rice University. Experiments at Rice showed that the size of pores in the scaffold, which mimics the extracellular matrix in bone, and the pores’ orientation make a difference in how cells proliferate in the presence of a flowing fluid, like blood. Courtesy of the Mikos Research Group

The size and shape of pores and scaffold porosity — the percent of empty space in a structure created by pores — can impact cell attachment, alter the permeability of media and nutrients and facilitate cell migration, according to the researchers. The scientists said 3-D printing allows them to get closer than ever to mimicking the architecture of real bone.

The research is detailed in the American Chemical Society journal ACS Biomaterials Science and Engineering.

The scaffold itself is special, according to Mikos. The bone-like printed polymer contains pores of varying sizes to constrain fluids that flow through and apply varying degrees of shear stress to the tumor cells, depending on the scaffold’s orientation in relation to the flow.

“We aim to develop tumor models that can capture the complexity of tumors in vitro and can be used for drug testing, thus providing a platform for drug development while reducing the associated cost,” Mikos said. He noted that by varying the scaffold architecture, they can change the mechanical environment through which fluids flow and the magnitude of shear stress exerted on tumor cells.

Flat sections of scaffold were printed with pores in one of three sizes: 0.2, 0.6 and 1 millimeter. Three layers of each were stacked to make each 3-D scaffold, and these were seeded with tumor cells and placed in a flow perfusion reactor that mimics the push and pull of fluids and tissues in a biological environment. This makes simulations much more realistic than growing cells in a flat petri dish, Mikos said.
Rice University researchers combined experiments with computational modeling to find that the structure of a scaffold, natural or not, has a very real effect on how cells express signaling proteins that help cancer grow.

Rice researchers combined experiments with computational modeling to find that the structure of a scaffold, natural or not, has a very real effect on how cells express signaling proteins that help cancer grow. Click on the image for a larger version. Courtesy of the Mikos Research Group

The researchers found that cells proliferated far better under flow than in conditions with no fluid flow. When the fluid began to flow, layers with the smallest pores, which restrict permeability, showed significantly more proliferation. They also found that under flow, cells increased their production of insulin-like growth factor protein (IGF-1), a ligand on the surface of sarcoma cells and part of the signaling pathway that plays a critical role in resistance to chemotherapy. Additionally, the orientation of the 0.2, 0.6 and 1 millimeter pore sizes played a role in how much IGF-1 the cells produced.

They suspected that the combination of shear stress and scaffold orientation prompted different levels of protein production.

The researchers now plan to refine their scaffold-printing process to study metastasis and test tumors’ response to drugs.

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An Innovative New Cancer Therapy Hijacks Bacteria to Fight Tumors

An Innovative New Cancer Therapy Hijacks Bacteria to Fight Tumors | Project Virtual Tumor Cancer in silico and Alternative Cancer Therapies |

By George Dvorsky

Researchers from South Korea have engineered a strain of bacteria that infiltrates tumors and fools the body’s immune system into attacking cancer cells. In experiments, the modified bacteria worked to reduce cancer in mice, raising hope for human trials.

In a study published today in Science Translational Medicine, a research team led by biologists Joon Haeng Rhee and Jung-Joon Min from Chonnam National University in South Korea describe a new immunotherapy in which a bioengineered strain of Salmonella is converted into a biological version of the fabled Trojan Horse. Once inside an unsuspecting tumor, the modified bacteria transmits a signal that triggers nearby immune cells into launching an attack on the malignant cells.

In preliminary tests, the technique shrunk tumors in more than half of the mice who received injections of the commandeered bacteria. It’s preliminary, but the researchers are hopeful that this form of immunotherapy will be both safe and effective in humans.

Bacterial cancer therapy dates back to 1893 when surgeon William B. Coley noticed that recurrent tumors of connective tissue, called sarcoma tumors, disappeared after patients became infected with Erysipelas bacterium. This led him to develop a therapy, now called “Coley’s toxins,” that utilizes various bacterial strains to fight cancer. This line of cancer research went into hibernation, however, once surgical and chemical therapies emerged.

But since 2008, bacterial cancer therapy has been going through a bit of a renaissance. Some success in this area has been reported, particularly when scientists use modified Salmonella to deliver various therapeutic agents to the body, such as genes and anti-cancer medicines. Bacteria have a natural ability to home in on tumors, making them excellent cargo ships. Unfortunately, all pre-existing bacterial cancer therapies require multiple injections of the microbes, and relapses are common.

In an effort to develop a better method, Rhee and Min took a strain of Salmonella typhimurium and made it 10,000 times less toxic than normal, while retaining the bacterium’s ability to stay alive and carry therapeutic cargo. And unlike previous efforts, the modified bacteria weren’t designed to deliver medicines per se; instead, they were engineered to deliver an important message to nearby immune cells—a message that says, “Attack this tumor!”

Specifically, the Salmonella bacteria is genetically modified to secrete a foreign protein known as flagellin (FlaB). This protein, found in an aquatic microbe called Vibrio vulnificus, is the building block of flagellum—the lash-like appendage that allows microorganisms to swim around. Since vertebrate animals, including humans, don’t have a flagellum, this protein is foreign to our cells. When voracious white blood cells known as macrophages detect the presence of these foreign proteins, they immediately sense danger and spring into action.

Macrophages are like microscopic Roombas, vacuuming anything that doesn’t look like it’s supposed to be there, including bits of cellular debris, unfamiliar substances, viruses, unwanted bacteria, and importantly, cancer cells. But macrophages don’t always see tumors as a threat, owing to the presence of identifiable markers, such familiar proteins associated with healthy cells. The modified bacteria, parked inside a tumor with its alien cargo, basically tricks the immune cells into launching an attack (i.e. triggering an immune response). The macrophages then happily go about devouring the malignant cells.

The researchers tested their Trojan Horse bacteria in mice with colon cancer. Three days after the injections, the bacteria inside the tumors were 10,000 times more abundant than those found in the mice’s vital organs. The macrophages then quickly went to work, causing the tumors to shrink below detectable limits in more than half of the mice.

“We [documented the] total eradication of tumors in approximately 60 percent of treated subjects,” explained Rhee and Min in an interview with Gizmodo “The remaining 20 percent of the animals remained stable,” meaning they didn’t die, “though tumors were reduced in size.”

Importantly, the modified FlaB-expressing bacteria was shown to be non-toxic, and it didn’t invade non-cancerous tissues in the rodents. Instead, Salmonella, armed with FlaB, shrank the tumors, prolonged the survival of the mice, and prevented new growths from re-appearing in mouse models of human colon cancer.

“We did not use any extra medication or chemotherapy,” said Rhee and Min, adding that their bacterial therapy could be combined with other anti-cancer techniques, such as radiation or chemotherapy.

Should this form of immunotherapy reach the clinical stage (and that’s still a big if—mice studies can be notoriously unreliable), the researchers don’t see regular injections as being appropriate.

“The bacteria could be injected repeatedly if required,” noted the researchers. “But we do not encourage multiple repeated therapies since the human immune system will build up an antibacterial immune response after repeated administration of the same bacteria.”An antibacterial response would prevent Salmonella from proliferating at the tumor site, meaning the tumor would no longer be marked for destruction.

To cope with this problem, the researchers are planning to use different strains with distinct biological markers should repeated injections be required in some instances.

It’s too early to tell if this treatment will be effective and safe in humans, but these early results are encouraging. Rhee and Min say their technique should work for other cancers, including breast cancer, glioma, melanoma, and lung cancer. “This is more like proof of concept study,” said the researchers.

“We are planning comprehensive preclinical tests in nearest future. If we find right partners that grant reasonable funding, clinical trials could hopefully be started very soon.”

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Tiny exports signal big shifts in cancer tissue, researchers find

Tiny exports signal big shifts in cancer tissue, researchers find | Project Virtual Tumor Cancer in silico and Alternative Cancer Therapies |

Performed with rat and human cancer tissue, the study looked at five changes seen in a tumor’s environment as it develops, grows and spreads. There are techniques to study each of these separately, but all involve disturbing the cellular environment with chemical dyes, fluorescent probes or genetic manipulation, for example. The Illinois group used finely tuned wavelengths of light to see the structural and molecular makeup of tissue in its natural state. The researchers isolate the signals from specific cancer processes by focusing on distinct wavelengths and combine the images to see how the processes interact.

“We’re starting to connect the dots here. This is the first time all of these pieces have been looked at together. No one’s been able to visualize the tissue this way and see the changes dynamically,” said Dr. Stephen Boppart, the leader of the study, published in the journal Science Advances. Boppart is an Illinois professor of electrical and computer engineering and of bioengineering, and also is a medical doctor.

The researchers were particularly interested in vesicles, the tiny packages that cells use to transport things in and out of the cell. Cancer cells pump out vesicles at an increased rate. Many cancer researchers believe this to be a response to the stress from molecular changes in the tissue.

Because the Illinois imaging technique doesn’t disturb the cells and thus can watch them over time, the researchers saw that a wave of vesicles came before the larger tissue-scale changes like new blood vessels or recruitment of neighboring cells. Together with changes in metabolism, increased vesicle production could be a cause of the larger-scale changes in cancer tissue rather than an effect, the researchers say.

“This paper is important because it connects the microscopic scale — the molecular and vesicle scale — with the larger-scale events in the tissue,” said Haohua Tu, a research scientist at the Beckman Institute for Advanced Science and Technology at Illinois and the first author of the paper. “Also, this is the first time we’ve compared changes in metabolism and vesicle production, and we found that they are linked. Both are microscopic events, but their concurrence leads to a lot of large-scale changes associated with tumor progression. The conclusion is that the combination of these two signals early cancer development and should be a focus of cancer therapy, rather than only focusing on larger-scale events later.”

The study also provides evidence that vesicles from cancer cells may play a role in spreading the cancer to other tissues in addition to changing a tumor’s local environment, the researchers said.

“Often, when there is a tumor in one tissue, cells elsewhere have undergone changes because of that tumor,” Boppart said. “Are all these changes happening because there was some sort of environmental carcinogen that caused tumors at different points? Or did the tumor give off vesicles that changed the microenvironment to prepare it for those later cells that metastasize?”

Boppart hopes that the findings on vesicles and the role they play in signaling cancer progression will open new avenues of exploration for cancer detection, progression and treatment. The researchers have developed a portable version of the imaging device for use in operating rooms and biopsy suites, and are now testing whether it can identify increased vesicle production in cancer patients and assess how aggressive a tumor is. They also are conducting further studies into the vesicles to see what they contain.

“We also know from other studies that these vesicles carry a lot of information about where they came from and where they’re going,” Boppart said. “Imaging is great, but you have to know where to look. There’s no way we can look at the whole body on the cellular level. But if we can take a drop of blood, scan it for cancer-related vesicles and know where they came from, then we know where to look for the tumor.”

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Technique for Blocking Capillaries to Starve and Suffocate Tumors

Technique for Blocking Capillaries to Starve and Suffocate Tumors | Project Virtual Tumor Cancer in silico and Alternative Cancer Therapies |
Researchers from Shanghai Institute of Ceramics of the Chinese Academy of Sciences and the East China Normal University have reported in journal Nature Nanotechnology on a new technique of blocking cappilaries that feed oxygen and nutrients to tumors, essentially suffocating and starving them at the same time. The researchers developed nanoparticles made of polymer-modified magnesium silicide (Mg2Si). When these find themselves within the acidity of tumors, they react and the magnesium silicide produces silane. Silane is a deoxygenation agent, an oxygen scavenger that reacts with oxygen in blood and tissues to produce clumps of silicon oxide. These clumps get large enough and tough enough to block capillaries, blocking a tumor’s access to what it needs to survive.

This has only been tested in a laboratory environment, but the idea sounds novel and promising, and we look forward to seeing it develop along a path toward clinical trials.
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Designer vaccine nanodiscs for personalized cancer immunotherapy

Designer vaccine nanodiscs for personalized cancer immunotherapy | Project Virtual Tumor Cancer in silico and Alternative Cancer Therapies |

Rui Kuai, Lukasz J. Ochyl, Keith S. Bahjat, Anna Schwendeman, James J. Moon

Nature Materials (2016)

Despite the tremendous potential of peptide-based cancer vaccines, their efficacy has been limited in humans. Recent innovations in tumour exome sequencing have signalled the new era of personalized immunotherapy with patient-specific neoantigens, but a general methodology for stimulating strong CD8α+ cytotoxic T-lymphocyte (CTL) responses remains lacking. Here we demonstrate that high-density lipoprotein-mimicking nanodiscs coupled with antigen (Ag) peptides and adjuvants can markedly improve Ag/adjuvant co-delivery to lymphoid organs and sustain Ag presentation on dendritic cells. Strikingly, nanodiscs elicited up to 47-fold greater frequencies of neoantigen-specific CTLs than soluble vaccines and even 31-fold greater than perhaps the strongest adjuvant in clinical trials (that is, CpG in Montanide). Moreover, multi-epitope vaccination generated broad-spectrum T-cell responses that potently inhibited tumour growth. Nanodiscs eliminated established MC-38 and B16F10 tumours when combined with anti-PD-1 and anti-CTLA-4 therapy. These findings represent a new powerful approach for cancer immunotherapy and suggest a general strategy for personalized nanomedicine.

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Is Artificial Intelligence the Answer to Finding a Cure for Cancer?

Is Artificial Intelligence the Answer to Finding a Cure for Cancer? | Project Virtual Tumor Cancer in silico and Alternative Cancer Therapies |
Cancer is a devastating disease and statistics now suggest that nearly one in every two people worldwide will develop cancer at some point in their lives.
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With Immunotherapy, Glimmers of Progress against Glioblastoma

With Immunotherapy, Glimmers of Progress against Glioblastoma | Project Virtual Tumor Cancer in silico and Alternative Cancer Therapies |
Treatment advances for patients with glioblastoma, an aggressive form of brain cancer, have been rare. But recent studies have raised hopes that immunotherapy, which has recently established itself as a proven therapy for several types of cancer, may be able to reverse this trend.

Patients diagnosed with glioblastoma, the most common malignant brain tumor in adults, typically survive fewer than 15 months after diagnosis. Despite continued efforts to develop and test new therapies for glioblastoma, none have improved survival appreciably.

However, in early-stage clinical trials, several different immunotherapies have shown promise against glioblastoma, including some that have produced long-lasting responses in patients with advanced disease. And now at least three immunotherapies are in phase III clinical trials, the results of which may form the basis for Food and Drug Administration (FDA) approvals.

But just because a therapy looks promising in early-stage trials does not mean that it will succeed in larger randomized trials. Even so, researchers who specialize in brain cancer are genuinely, if cautiously, optimistic about immunotherapy’s prospects.

“Just the fact that we have some phase III trials in glioblastoma, where for years we had a hard time getting past phase II trials, is an encouraging sign,” said Michael Lim, M.D., who directs the brain tumor immunotherapy program at the Johns Hopkins Kimmel Comprehensive Cancer Center. “So, for the first time in a long time, there’s some real excitement.”
Breaking Down Barriers

When it comes to the brain, immune-based treatments face some substantial obstacles before they can even reach a tumor.

The most significant challenge is the blood–brain barrier, a layer of tightly packed, specialized endothelial cells that form the blood vessels in the brain and contractile cells called pericytes. While this barrier protects the brain from threats that may be circulating in the bloodstream, like viruses or toxins, it can also impede the delivery cancer treatments.

In addition, the immune response to brain tumors is generally weak, “because tumors are very effective at blunting it,” explained Mark Gilbert, M.D., director of NCI’s Neuro-Oncology Branch.

Nevertheless, studies have now shown that the immune system has sentries that can react to foreign threats in the brain and that immune cells from other parts of the body can travel there, Dr. Gilbert continued, “although the mechanisms that allow that to happen aren’t very clear.”

These are formidable obstacles for immune-based treatments to overcome in treating brain cancers, acknowledged John Sampson, M.D., Ph.D., chair of the Department of Neurosurgery at Duke University Medical Center and director of Duke’s Brain Tumor Immunotherapy Program.

“But I don’t think they limit most of the immunotherapy approaches being studied,” he said.
Therapeutic Vaccines on Board

Among the immunotherapies being studied for the treatment of glioblastoma are several therapeutic vaccines, including a so-called peptide vaccine, rindopepimut. The central component of rindopepimut is a fragment, or peptide, of a mutated form of the epidermal growth factor receptor (EGFR) protein called EGFRvIII.

Approximately 20 to 30 percent of patients with glioblastoma have tumors that express EGFRvIII. Because EGFRvIII is expressed almost exclusively by glioblastoma cells and is not found on healthy brain cells, it is an attractive target around which to develop immune-based treatments, explained Dr. Sampson, who initially developed rindopepimut.

Initial findings from a small randomized trial of rindopepimut showed an improvement in both median overall survival and 6-month progression-free survival in glioblastoma patients who received the vaccine and bevacziumab (Avastin®) compared with patients who received a placebo vaccine.

According to longer-term data, at 2 years of follow-up, 25 percent of patients treated with rindopepimut were still alive, compared with no patients in the control arm. These findings were reported in November 2015 at the Society for Neuro-Oncology annual meeting by the trial's lead investigator, David Reardon, M.D., of the Dana-Farber Cancer Institute.

The vaccine’s manufacturer, Celldex Therapeutics, has completed enrollment in a phase III trial testing rindopepimut in patients with newly diagnosed EGFRvIII-positive glioblastoma who have undergone surgery to have their tumors removed. [UPDATE: On March 7, 2016, Celldex announced that it was halting this phase III trial. The decision was based on findings from an interim data analysis which showed that patients receiving rindopepimut were unlikely to have an improvement in overall survival compared with patients in the control arm.]

Vaccines composed primarily of immune cells known as dendritic cells are also being studied as potential therapies for glioblastoma.

Because dendritic cells primarily orchestrate immune responses, they are often called the generals of the immune system, Dr. Lim explained. “So it makes sense to use the general,” he said.

These vaccines are typically patient specific. Their production entails a complex manufacturing process that involves collecting immature immune cells from each patient, coaxing them to develop into dendritic cells, and engineering them to produce a tumor-specific immune response when they’re administered back to the patient.

One of the dendritic cell vaccines that is furthest along in testing for glioblastoma is DCVax-L®. In a small phase I/II trial testing DCVax-L in patients with operable glioblastoma, the median survival was approximately 31 months. Northwest Biotherapeutics, which manufactures the vaccine, is currently enrolling patients with operable, newly diagnosed glioblastoma in a phase III trial.

Dr. Sampson’s team at Duke has developed a dendritic cell vaccine that is engineered to target cells that express proteins, or antigens, induced by infection with cytomegalovirus (CMV)—a highly common virus that up to 80 percent of adults aged 40 and older have been infected with. For reasons that are still unclear, glioblastoma cells, but not healthy brain cells, tend to express these CMV antigens, Dr. Sampson said.

Earlier this year, the researchers reported promising results from a 12-patient clinical trial of the vaccine. Patients who received the dendritic cell vaccine in combination with the tetanus and diphtheria (Td) vaccine—given to further strengthen the immune response—had a median survival of more than 3 years, compared with approximately 18 months in patients who received the dendritic cell vaccine alone.

Much of the data from the vaccine trials that have been conducted to date are preliminary and need to be replicated in larger randomized trials, Dr. Sampson acknowledged.

But they are all pointing in the right direction, he continued. “There’s clearly something going on here, and I’m encouraged by it.”
Supercharged T Cells

Another type of immune-based treatment, called CAR T-cell therapy, is also being tested against glioblastoma. This approach—which, like some of the vaccines being tested, typically requires engineering cells collected from patients and then returning them to the patient—has already demonstrated success in early-stage clinical trials in patients with advanced cancers, including melanoma and leukemia.

Researchers from NCI’s Center for Cancer Research and several large cancer centers have launched trials testing CAR T-cell therapy in patients with glioblastoma.

At the Baylor College of Medicine, investigators have developed “bi-specific” CAR T cells. The therapy relies on T cells collected from the patient that have a strong affinity for CMV-infected cells. And, because approximately 80 percent of glioblastoma cells overexpress a receptor that binds to the HER2 protein (perhaps best known for its role in breast cancer), the T cells are also engineered to express a receptor that binds to HER2.

This approach is very much in the early testing stages. In November 2015, at the Society for Immunotherapy of Cancer annual meeting, Nabil Ahmed, M.D., of Baylor reported preliminary findingsExit Disclaimer from a small trial testing bi-specific CAR T cells in pediatric and adult patients with advanced glioblastoma. Only one patient experienced enough tumor shrinkage to qualify as a partial response (at least 30 percent reduction in tumor size), but five patients have had a stabilization in their disease that has lasted for more than 10 weeks.

“From a scientific standpoint and from a creativity standpoint, CAR T cells are a very interesting approach for glioblastoma,” Dr. Gilbert said.

These early trials should help answer important questions, he added, including “how well the T cells are tracking to tumors.”
Checkpoint Inhibitors Check In

Several immunotherapy drugs known as checkpoint inhibitors are also advancing to late-stage clinical trials in patients with glioblastoma. Checkpoint inhibitors interfere with signals from tumor cells to T cells that, in effect, direct the T cells to stand down.

Two checkpoint inhibitors, ipilimumab (Yervoy®) and nivolumab (Opdivo®), have been approved by the FDA for the treatment of advanced melanoma and lung cancer, and promising results have been reported for these and other drugs in this class in several other cancer types.

There’s solid evidence to support testing checkpoint inhibitors against glioblastoma, Dr. Lim explained. In some patients with advanced melanoma, treatment with ipilimumab, which targets the CTLA-4 checkpoint protein on T cells, has shrunk brain metastases. And in some animal model studies, checkpoint inhibitors have eradicated glioblastoma tumors.

A phase III clinical trial comparing nivolumab, which targets the checkpoint protein PD-1, against bevacizumab in patients with glioblastoma that has returned after prior treatment is currently enrolling patients. Embedded within this trial is a phase I trial testing nivolumab in combination with ipilimumab.

The Neuro-Oncology Branch has launched an early-stage trial that is testing PD-1 and CTLA-4 inhibitors, either alone or in combination, along with the chemotherapy drug temozolomide, in patients with newly diagnosed glioblastoma. Because of slight differences in how these two therapies work, Dr. Gilbert explained, there may be a benefit to combining the treatments.

Eventually, he said, a large trial testing them alone and in combination will be needed to determine their optimal use in patients with glioblastoma.

Dr. Lim and his colleagues, meanwhile, are studying whether administering localized radiation therapy to a brain tumor can not only help shrink it, but also kick start an immune response that could be strengthened further by a checkpoint inhibitor or other immunotherapy—a response referred to as the “abscopal effect.”

Based in part on findings from a recently published animal model study, they are launching an early-phase trial testing this treatment approach in patients with advanced melanoma that has spread to the brain.

Ultimately, Dr. Lim believes, combination approaches, consisting of either immune-based therapies or immune and traditional therapies, may offer the most promise.

“We need to keep studying our options and find the best combinations that are the most effective and least toxic for our patients,” he said.
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Hypoxia-induced angiotensin II by the lactate-chymase-dependent mechanism mediates radioresistance of hypoxic tumor cells

Hypoxia-induced angiotensin II by the lactate-chymase-dependent mechanism mediates radioresistance of hypoxic tumor cells | Project Virtual Tumor Cancer in silico and Alternative Cancer Therapies |

Guozhu Xie, Ying Liu, Qiwei Yao, Rong Zheng, Lanfang Zhang, Jie Lin, Zhaoze Guo, Shasha Du, Chen Ren, Quan Yuan, Yawei Yuan

Scientific Reports 7, Article number: 42396 (2017)

The renin-angiotensin system (RAS) is a principal determinant of arterial blood pressure and fluid and electrolyte balance. RAS component dysregulation was recently found in some malignancies and correlated with poor patient outcomes. However, the exact mechanism of local RAS activation in tumors is still unclear. Here, we find that the local angiotensin II predominantly exists in the hypoxic regions of tumor formed by nasopharyngeal carcinoma CNE2 cells and breast cancer MDA-MB-231 cells, where these tumor cells autocrinely produce angiotensin II by a chymase-dependent rather than an angiotensin converting enzyme-dependent mechanism. We further demonstrate in nasopharyngeal carcinoma CNE2 and 5–8F cells that this chymase-dependent effect is mediated by increased levels of lactate, a by-product of glycolytic metabolism. Finally, we show that the enhanced angiotensin II plays an important role in the intracellular accumulation of HIF-1α of hypoxic nasopharyngeal carcinoma cells and mediates the radiation-resistant phenotype of these nasopharyngeal carcinoma cells. Thus, our findings reveal the critical role of hypoxia in producing local angiotensin II by a lactate-chymase-dependent mechanism and highlight the importance of local angiotensin II in regulating radioresistance of hypoxic tumor cells.

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Cedars-Sinai, UCLA Scientists Use New ‘Blood Biopsies’ With Experimental Device to Speed Cancer Diagnosis and Predict Disease Spread

Cedars-Sinai, UCLA Scientists Use New ‘Blood Biopsies’ With Experimental Device to Speed Cancer Diagnosis and Predict Disease Spread | Project Virtual Tumor Cancer in silico and Alternative Cancer Therapies |
The investigators are conducting “liquid biopsies” by running blood through a postage-stamp-sized chip with nanowires 1,000 times thinner than a human hair and coated with antibodies, or proteins, that recognize circulating tumor cells. The device, the NanoVelcro Chip, works by “grabbing” circulating tumor cells, which break away from tumors and travel through the bloodstream, looking for places in the body to spread.

Use of the chip in liquid biopsies could allow doctors to regularly and easily monitor cancer-related changes in patients, such as how well they’re responding to treatment. The research earned the lead investigators a place on the U.S. Cancer Moonshot program, an initiative led by former Vice President Joe Biden to make available more therapies to more patients and to prevent cancer.

“It’s far better to draw a tube of blood once a month to monitor cancer than to make patients undergo repeated surgical procedures,” said Edwin Posadas, MD, medical director of the Urologic Oncology Program at Cedars-Sinai’s Samuel Oschin Comprehensive Cancer Institute and one of the lead investigators. “The power of this technology lies in its capacity to provide information that is equal to or even superior to traditional tumor sampling by invasive procedures.”

Although some forms of prostate cancer are so slow-growing that they pose little risk to patients, other forms of the disease are lethal. Identifying which patients have which type of disease has become a crucial area of study because prostate cancer is one of the leading causes of cancer death among men in the U.S. Nearly 27,000 U.S. men are expected to die from the disease in 2017, according to the American Cancer Society.

The research team has determined that in certain cancer cells, the nucleus is smaller than in other, more typical, cancer cells. Patients with the most advanced cases of aggressive prostate cancer have cells with these very small nuclei.

The investigators’ teamwork also revealed that very small nuclei are associated with metastasis, or cancer spread, to the liver and lung in patients with advanced cases of prostate cancer. Those nuclei developed before the metastases were detected. Identifying very small nuclei early in the disease progression may help pinpoint which patients have high risk of developing cancer that can spread and be fatal.

Hsian-Rong Tseng, PhD, professor, Department of Molecular and Medical Pharmacology in the David Geffen School of Medicine at UCLA and the other lead investigator, said that his work with Posadas is focused on improving the quality of life for cancer patients.

“We’re on a mission to dramatically change patients’ everyday lives and their long-term outcomes,” Tseng said. “We now have powerful new tools to accomplish that.”

Posadas and Tseng join an elite cadre of academicians, technology leaders and pharmaceutical experts as partners in the Blood Profiling Atlas in Cancer (BloodPAC) Project, a Moonshot program. Participants will collect and share data gathered from circulating tumor cells. Posadas and Tseng expect to contribute microscopic images from 1,000 circulating tumor cells that have not yet been analyzed, as well as additional data and cells they have cataloged.

For the past five years, Posadas and Tseng have collected blood samples from cancer patients to profile and analyze the circulating tumor cells and other components. That process has helped them understand how prostate and other cancers evolve. The two investigators and their teams hope their findings will contribute to developing effective, targeted treatments for many types of cancer.

“Minimally invasive methods to both diagnose and follow cancer, through simple blood tests, offer a unique and novel approach that can lead to earlier diagnosis and treatment, leading to more cures,” said Robert A. Figlin, MD, director of the Division of Hematology Oncology and deputy director of the Samuel Oschin Comprehensive Cancer Institute at Cedars- Sinai.
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Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity

Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity | Project Virtual Tumor Cancer in silico and Alternative Cancer Therapies |

Kristen M. Turner, Viraj Deshpande, Doruk Beyter, Tomoyuki Koga, Jessica Rusert, Catherine Lee, Bin Li, Karen Arden, Bing Ren, David A. Nathanson, Harley I. Kornblum, Michael D. Taylor, Sharmeela Kaushal, Webster K. Cavenee, Robert Wechsler-Reya, Frank B. Furnari, Scott R. Vandenberg, P. Nagesh Rao, Geoffrey M. Wahl, Vineet Bafna, Paul S. Mischel

Nature (2017)

Human cells have twenty-three pairs of chromosomes. In cancer, however, genes can be amplified in chromosomes or in circular extrachromosomal DNA (ecDNA), although the frequency and functional importance of ecDNA are not understood1, 2, 3, 4. We performed whole-genome sequencing, structural modelling and cytogenetic analyses of 17 different cancer types, including analysis of the structure and function of chromosomes during metaphase of 2,572 dividing cells, and developed a software package called ECdetect to conduct unbiased, integrated ecDNA detection and analysis. Here we show that ecDNA was found in nearly half of human cancers; its frequency varied by tumour type, but it was almost never found in normal cells. Driver oncogenes were amplified most commonly in ecDNA, thereby increasing transcript level. Mathematical modelling predicted that ecDNA amplification would increase oncogene copy number and intratumoural heterogeneity more effectively than chromosomal amplification. We validated these predictions by quantitative analyses of cancer samples. The results presented here suggest that ecDNA contributes to accelerated evolution in cancer.

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Two-step enhanced cancer immunotherapy with engineered Salmonella typhimurium secreting heterologous flagellin

Jin Hai Zheng, Vu H. Nguyen, Sheng-Nan Jiang, Seung-Hwan Park, Wenzhi Tan, Seol Hee Hong, Myung Geun Shin, Ik-Joo Chung, Yeongjin Hong, Hee-Seung Bom, Hyon E. Choy, Shee Eun Lee, Joon Haeng Rhee, Jung-Joon Min

Science Translational Medicine 08 Feb 2017:
Vol. 9, Issue 376,

We report a method of cancer immunotherapy using an attenuated Salmonella typhimurium strain engineered to secrete Vibrio vulnificus flagellin B (FlaB) in tumor tissues. Engineered FlaB-secreting bacteria effectively suppressed tumor growth and metastasis in mouse models and prolonged survival. By using Toll-like receptor 5 (TLR5)–negative colon cancer cell lines, we provided evidence that the FlaB-mediated tumor suppression upon bacterial colonization is associated with TLR5-mediated host reactions in the tumor microenvironment. These therapeutic effects were completely abrogated in TLR4 and MyD88 knockout mice, and partly in TLR5 knockout mice, indicating that TLR4 signaling is a requisite for tumor suppression mediated by FlaB-secreting bacteria, whereas TLR5 signaling augmented tumor-suppressive host reactions. Tumor microenvironment colonization by engineered Salmonella appeared to induce the infiltration of abundant immune cells such as monocytes/macrophages and neutrophils via TLR4 signaling. Subsequent secretion of FlaB from colonizing Salmonella resulted in phenotypic and functional activation of intratumoral macrophages with M1 phenotypes and a reciprocal reduction in M2-like suppressive activities. Together, these findings provide evidence that nonvirulent tumor-targeting bacteria releasing multiple TLR ligands can be used as cancer immunotherapeutics.

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Mathematical modeling of intraperitoneal drug delivery: simulation of drug distribution in a single tumor nodule

Steuperaert M, Falvo D'Urso Labate G, Debbaut C, De Wever O, Vanhove C, Ceelen W, Segers P

Drug Deliv. 2017 Nov;24(1):491-501.

The intraperitoneal (IP) administration of chemotherapy is an alternative treatment for peritoneal carcinomatosis, allowing for higher intratumor concentrations of the cytotoxic agent compared to intravenous administration. Nevertheless, drug penetration depths are still limited to a few millimeters. It is thus necessary to better understand the limiting factors behind this poor penetration in order to improve IP chemotherapy delivery. By developing a three-dimensional computational fluid dynamics (CFD) model for drug penetration in a tumor nodule, we investigated the impact of a number of key parameters on the drug transport and penetration depth during IP chemotherapy. Overall, smaller tumors showed better penetration than larger ones, which could be attributed to the lower IFP in smaller tumors. Furthermore, the model demonstrated large improvements in penetration depth by subjecting the tumor nodules to vascular normalization therapy, and illustrated the importance of the drug that is used for therapy. Explicitly modeling the necrotic core had a limited effect on the simulated penetration. Similarly, the penetration depth remained virtually constant when the Darcy permeability of the tissue changed. Our findings illustrate that the developed parametrical CFD model is a powerful tool providing more insight in the drug transport and penetration during IP chemotherapy.

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Improved multiparametric MRI discrimination between low-risk prostate cancer and benign tissues in a small cohort of 5α-reductase inhibitor treated individuals as compared with an untreated cohort

Starobinets O, Kurhanewicz J, Noworolski SM. 

NMR Biomed. 2017 Feb 6.

The purpose of this study was to determine whether 5α-reductase inhibitors (5-ARIs) affect the discrimination between low-grade prostate cancer and benign tissues on multiparametric MRI (mpMRI). Twenty men with biopsy-proven Gleason 3 + 3 prostate cancer and 3 T mpMRI were studied. Ten patients (Tx) had been receiving 5-ARIs for at least a year at scan time. Ten untreated patients (Un) were matched to the treated cohort. For each subject two regions of interest representing cancerous and benign tissues were drawn within the peripheral zone of each prostate, MR measures evaluated, and cancer contrast versus benign (contrast = (MRTumor - MRHealthy )/MRHealthy ) calculated. Decreased cancer contrast was noted on T2 -weighted images: 0.4 (Un) versus 0.3 (Tx). However, for functional MR measures, a better separation of cancerous and benign tissues was observed in the treated group. Cancer contrast on high-b diffusion-weighted imaging (DWI) was 0.61 (Un) versus 0.99 (Tx). Logistic regression analysis yielded higher AUC (area under the curve) values for distinguishing cancerous from benign regions in treated subjects on high-b DWI (0.71 (Un), 0.94 (Tx)), maximal enhancement slope (0.95 (Un), 1 (Tx)), peak enhancement (0.84 (Un), 0.93 (Tx)), washout slope (0.78 (Un), 0.99 (Tx)), Ktrans (0.9 (Un), 1 (Tx)), and combined measures (0.86 (Un), 0.99 (Tx)). Coefficients of variation for MR measures were lower in benign and cancerous tissues in the treated group compared with the untreated group. This study's results suggest an increase in homogeneity of benign and malignant peripheral zone prostatic tissues with 5-ARI exposure, observed as reduced variability of MR measures after treatment. Cancer discrimination was lower with T2 -weighted imaging, but was higher with functional MR measures in a 5-ARI-treated cohort compared with controls.

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An alternative theory on how aspirin may thwart cancer

Studies abound that point to a role for plain old aspirin in keeping deadly cancers at bay. While aspirin is not yet part of mainstream treatment for any cancer, it is recommended by the U.S. Preventive Services Task Force for certain adults to help prevent colorectal cancer.

But researchers have puzzled over how exactly the "wonder drug" works to ward off cancer. Most think it has to do with the drug's inflammation-lowering effects.

Now Veterans Affairs (VA) scientists and colleagues in Texas have a new theory, tested successfully in mice and cell cultures. It has to do with aspirin's effects on platelets–blood cells that form clots to stop bleeding.

The findings appear in the February 2017 issue of Cancer Prevention Research.

Along with clotting, platelets also play a role in forming new blood vessels. That action is normally beneficial, such as when a new clot forms after a wound, and new vessels are needed to redirect blood flow. But the same action can help tumors grow. It's this process that aspirin can interrupt, say the researchers. Their lab tests showed how aspirin blocked the interaction between platelets and cancer cells by shutting down the enzyme COX-1, thereby curbing the number of circulating platelets and their level of activity.

Some of the experiments used regular aspirin from a local drug store. In another phase, the researchers used a special preparation of aspirin combined with phosphatidylcholine, a type of lipid, or fat molecule. The molecule is a main ingredient in soy lecithin. The product, known as Aspirin-PC/PL2200, now in development by Houston-based PLx Pharma, Inc., is designed to ease the gastrointestinal risk associated with standard aspirin.

The enhanced aspirin complex was even stronger against cancer than the regular aspirin. Summarizing their findings, the researchers wrote: "These results suggest that aspirin's chemopreventive effects may be due, in part, to the drug blocking the proneoplastic [supporting new, abnormal growth, as in cancer] action of platelets and [they support] the potential use of Aspirin-PC/PL2200 as an effective and safer chemopreventive agent for colorectal cancer and possibly other cancers."

Dr. Lenard Lichtenberger, who led the research, has a financial stake in PLx Pharma, the company developing the new lipid-based aspirin under the brand name Aspertec. None of the other authors reported potential conflicts of interest. Lichtenberger is a professor of integrative biology and pharmacology at the University of Texas Health Sciences Center.

The VA leader in the group was Dr. Vinod Vijayan, a research health scientist at the DeBakey VAMC and an expert in platelet biology. He is with the site's Center for Translational Research on Inflammatory Diseases. Vijayan is also an associate professor at Baylor College of Medicine.

The group says they plan to test the lipid-aspirin complex for safety and efficacy in people at high risk for colorectal cancer in a collaboration with researchers at MD Anderson Cancer Center in Houston. Meanwhile, they say their results so far "support the use of low-dose aspirin for chemoprevention." They add that Aspirin-PC/PL2200 has "similar chemopreventive actions to low-dose aspirin and may be more effective."
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Targeting Cancer Stem Cells with Exosome-Based Therapy

Targeting Cancer Stem Cells with Exosome-Based Therapy | Project Virtual Tumor Cancer in silico and Alternative Cancer Therapies |
Drug resistance, difficulty in specific targeting and self-renewal properties of cancer stem cells (CSCs) all contribute to cancer treatment failure and relapse. CSCs have been suggested as both the seeds of the primary cancer, and the roots of chemo- and radio-therapy resistance. The ability to precisely deliver drugs to target CSCs is an urgent need for cancer therapy, with nanotechnology-based drug delivery system being one of the most promising tools to achieve this in the clinic. Exosomes are cell-derived natural nanometric vesicles that are widely distributed in body fluids and involved in multiple disease processes, including tumorigenesis. Exosome-based nanometric vehicles have a number of advantages: they are non-toxic, non-immunogenic, and can be engineered to have robust delivery capacity and targeting specificity. This enables exosomes as a powerful nanocarrier to deliver anti-cancer drugs and genes for CSC targeting therapy. Here, the authors explore exosome-based delivery system in cancer therapy, with particular focus on several exosomal engineering approaches that have improved their efficiency and specificity for CSC targeting.
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Magnesium silicide nanoparticles as a deoxygenation agent for cancer starvation therapy

Magnesium silicide nanoparticles as a deoxygenation agent for cancer starvation therapy | Project Virtual Tumor Cancer in silico and Alternative Cancer Therapies |

Chen Zhang, Dalong Ni, Yanyan Liu, Heliang Yao, Wenbo Bu, Jianlin Shi

Nature Nanotechnology (2017)

A material that rapidly absorbs molecular oxygen (known as an oxygen scavenger or deoxygenation agent (DOA)) has various industrial applications, such as in food preservation, anticorrosion of metal and coal deoxidation. Given that oxygen is vital to cancer growth, to starve tumours through the consumption of intratumoral oxygen is a potentially useful strategy in fighting cancer. Here we show that an injectable polymer-modified magnesium silicide (Mg2Si) nanoparticle can act as a DOA by scavenging oxygen in tumours and form by-products that block tumour capillaries from being reoxygenated. The nanoparticles are prepared by a self-propagating high-temperature synthesis strategy. In the acidic tumour microenvironment, the Mg2Si releases silane, which efficiently reacts with both tissue-dissolved and haemoglobin-bound oxygen to form silicon oxide (SiO2) aggregates. This in situ formation of SiO2 blocks the tumour blood capillaries and prevents tumours from receiving new supplies of oxygen and nutrients.

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Scientists discover new way to inhibit growth of glioblastoma

Scientists have found a way to inhibit the growth of glioblastoma, a type of brain cancer with low survival rates, by targeting a protein that drives growth of brain tumors, according to research from the Peter O'Donnell Jr. Brain Institute and Harold C. Simmons Comprehensive Cancer Center.

"These findings change our fundamental understanding of the molecular basis of glioblastoma, and how to treat it," said co-senior author Dr. Robert Bachoo, Associate Professor of Neurology and Neurotherapeutics, Internal Medicine, and with the Annette G. Strauss Center for Neuro-Oncology at UT Southwestern Medical Center. "We may have identified a set of critical genes we can target with drugs that are shared across nearly all glioblastomas."

The study, published in Cell Reports, represents research from UT Southwestern's precision medicine campaign in neuro-oncology.

For the past decade, patients diagnosed with glioblastoma have been treated with the current standard of care regimen: surgery followed by chemotherapy and radiation. This regimen improves median survival by an average of four to six months, followed by recurrence of the tumor. There are currently no successful therapies available to treat glioblastoma patients when the tumor recurs. Five-year survival rates are around 5 percent.

Faced with these prospects, the brain tumor research and clinical communities turned to genetic studies to guide possible treatment strategies.

"Our work shows that the gene mutations which the pharmaceutical industry and clinicians have been focusing on are essential only for starting tumor growth. Once the tumor has advanced to the stage where patients seek treatment, these mutations are no longer required for continued tumor growth; they are in effect redundant," said Dr. Bachoo, a member of the Simmons Cancer Center and O'Donnell Brain Institute, who holds the Miller Family Professorship in Neuro‐Oncology.

Previously, proteins called receptor tyrosine kinase were considered the drivers of glioblastoma; however, drugs that inhibit these proteins have not been effective in treating this type of cancer.

"We learned that, instead, it is neurodevelopmental transcription factors (master proteins that regulate the activity of hundreds of genes during normal brain development), which are reactivated to drive the growth of glioblastoma. We can inhibit these transcription factors and prevent further tumor growth with the chemotherapy drug mithramycin, a drug that has not been in clinical use for years due to its side effects," said co-senior author Dr. Ralf Kittler, Assistant Professor of Pharmacology in the Eugene McDermott Center for Human Growth and Development. "Our discovery has the potential for the development of a new therapy that may increase survival time for glioblastoma patients."

Dr. Kittler, a member of the Simmons Cancer Center and the Cecil H. and Ida Green Center for Reproductive Biology Sciences, is a Cancer Prevention and Research Institute of Texas (CPRIT) Scholar in Cancer Research and John L. Roach Scholar in Biomedical Research.

The researchers caution that repurposing mithramycin, which is known to cause liver toxicity in some patients, with safer and more effective treatments for brain tumor patients may take years.

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Designer vaccine nanodiscs treat tumours

Designer vaccine nanodiscs treat tumours | Project Virtual Tumor Cancer in silico and Alternative Cancer Therapies |

Researchers at the University of Michigan in the US have designed novel vaccine nanodiscs that could be used to treat cancer. The lipoprotein-mimicking nanostructures coupled with antigen peptides and adjuvants efficiently deliver vaccine components to lymphoid tissues and so are significantly better than conventional vaccines in this context. They could herald a new era of personalized cancer immunotherapy if used with patient-specific tumour antigens (Nature Materials doi: 10.1038/nmat4822).

Although peptide-based cancer vaccines showed great promise, they have proved disappointing when it comes to treating tumours in clinical trials. The main reason for their failure? Their inability to efficiently deliver antigen peptides and adjuvants to lymphoid tissues, which means that only weak immune responses are seen.

Now, a team led by James Moon and Anna Schwendehman has developed an alternative strategy in which pre-formed non-toxic nanocarriers are mixed with adjuvants and antigen peptides, including tumour-specific mutant neo-epitopes, to produce personalized cancer vaccines. The researchers have designed high-density lipoprotein (HDL) nanodiscs made from simple phospholipids and apolipoprotein A1-mimetic peptides.

Nanodiscs don't trigger autoimmunity

"Thanks to their ultrasmall size (around 10 nm in diameter), the nanodiscs efficiently drain through lymphatic vessels after being injected into the body," explains Schwendeman, "thereby significantly improving delivery of antigen peptides and adjuvants to lymphoid tissues." And that is not all: compared with other HDLs (produced from purified human plasma, for example), the new HDLs do not trigger autoimmunity.

The nanodiscs can be used to deliver antigens to draining lymph nodes in the body and stimulate the activity of anti-tumour T-cells that significantly inhibit tumour growth. "They can also eradicate established tumours when combined with so-called immune checkpoint inhibitors (that work by removing the 'brakes' in immunosuppressed T-cells)," Moon tells our sister site "And in experiments on mice, they even protect the animals from tumour recurrence.

EVOQ Therapeutics

"We have also shown that we can achieve potent personalized antitumor immune responses targeted to unique tumour mutations (or neo-antigens), which, in the majority of somatic mutations in cancer cells, are specific to each patient," says Moon. "Coupled with recent innovations in tumour DNA/RNA sequencing, such a strategy may usher in a new era of personalized cancer immunotherapy if used with patient-specific antigens."

The researchers have created a new start-up EVOQ Therapeutics to translate their results to the clinic.

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