Melanoma BRAF Inhibitors Review
45.4K views | +7 today
Follow
 
Scooped by Krishan Maggon
onto Melanoma BRAF Inhibitors Review
Scoop.it!

Targeting the IL-6/JAK/STAT3 signalling axis in cancer

Targeting the IL-6/JAK/STAT3 signalling axis in cancer | Melanoma BRAF Inhibitors Review | Scoop.it

Review


The IL-6/JAK/STAT3 pathway is aberrantly hyperactivated in many types of cancer, and such hyperactivation is generally associated with a poor clinical prognosis. In the tumour microenvironment, IL-6/JAK/STAT3 signalling acts to drive the proliferation, survival, invasiveness, and metastasis of tumour cells, while strongly suppressing the antitumour immune response. Thus, treatments that target the IL-6/JAK/STAT3 pathway in patients with cancer are poised to provide therapeutic benefit by directly inhibiting tumour cell growth and by stimulating antitumour immunity. Agents targeting IL-6, the IL-6 receptor, or JAKs have already received FDA approval for the treatment of inflammatory conditions or myeloproliferative neoplasms and for the management of certain adverse effects of chimeric antigen receptor T cells, and are being further evaluated in patients with haematopoietic malignancies and in those with solid tumours. Novel inhibitors of the IL-6/JAK/STAT3 pathway, including STAT3-selective inhibitors, are currently in development. Herein, we review the role of IL-6/JAK/STAT3 signalling in the tumour microenvironment and the status of preclinical and clinical investigations of agents targeting this pathway. We also discuss the potential of combining IL-6/JAK/STAT3 inhibitors with currently approved therapeutic agents directed against immune-checkpoint inhibitors.

more...
No comment yet.
Melanoma BRAF Inhibitors Review
Zelboraf (vemurafenib, Roche) and Tafinlar (dabrafenib, GSK) get FDA and EMA approval for advanced metastatic melanoma. Several follow up BRAF inhibitors are in clinical development by rival pharma  companies  (Novartis, BMS, J&J, Teva) to get a share of expanding melanoma market and improve complete response rates and overcome resistance. Nexavar (sorafenib, Bayer) for for liver (HCC) and renal (RCC) cancer was the first approved and marketed BRAF inhibitor.
Curated by Krishan Maggon
Your new post is loading...
Your new post is loading...
Scooped by Krishan Maggon
Scoop.it!

Metastatic Melanoma Cells: Image Details - NCI Visuals Online

Metastatic Melanoma Cells: Image Details - NCI Visuals Online | Melanoma BRAF Inhibitors Review | Scoop.it
Image information and view/download options.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Immune to cancer’s return? The day could be coming | LLUH News

Immune to cancer’s return? The day could be coming | LLUH News | Melanoma BRAF Inhibitors Review | Scoop.it
In melanoma, this possibility is already becoming reality; immunotherapy has raised five-year survival rates for patients with a non-operable recurrence from 10 percent or less to 80 percent or above, says Frank Howard IV, MD, PhD, who specializes at the Cancer Center in melanoma and unusual tumors.  
more...
No comment yet.
Rescooped by Krishan Maggon from Immunology and Biotherapies
Scoop.it!

Immune Checkpoint Inhibitors: Anti-NKG2A Antibodies on Board

Immune Checkpoint Inhibitors: Anti-NKG2A Antibodies on Board | Melanoma BRAF Inhibitors Review | Scoop.it
Antibodies directed towards checkpoint inhibitors have unveiled extraordinary potential
in cancer therapy. An article by the Vivier group (Cell 2018;175:1731–1743) shows
that blocking the HLA-E-specific NKG2A inhibitory receptor, expressed by NK and inducible
in T cells, results in benefits against poor prognosis tumors. Moreover, NKG2A and
PD-1/PD-L1 mAb combinations unleash tumor-specific T cell proliferation and memory.

Via Gilbert C FAURE
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Melanoma study: are two immunotherapies better than one?

Melanoma study: are two immunotherapies better than one? | Melanoma BRAF Inhibitors Review | Scoop.it
January 2019 Earle A. Chiles Research Institute, a division of Providence Cancer Institute in the Robert W. Franz Cancer Center, is currently conducting more than 120 research studies, including clinical trials of targeted therapies and novel immunotherapy approaches. Melanoma study: are two immunotherapies better than one? A newly opened Phase 3 study at Providence Cancer Institute will compare the benefits of two immunotherapies, nivolumab and NKTR-214 , against nivolumab alone for patients with advanced melanoma. Nivolumab (Opdivo), an FDA-approved treatment, has already been shown to offer a survival benefit for metastatic melanoma. Early research into combining nivolumab with the investigational immunotherapy NKTR-214 have revealed promising antitumor activity. All current open studies: Find additional studies for many types of cancer in Multiple Tumor Types . New studies are posted frequently - please check our  website  for a complete list of our current studies. For more information, call 503-215-2614. See All Open Studies
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Experts Forecast Cancer Research and Treatment Advances in 2019 –

Experts Forecast Cancer Research and Treatment Advances in 2019 – | Melanoma BRAF Inhibitors Review | Scoop.it
Experts Forecast Cancer Research and Treatment Advances in 2019...
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

An update on immunotherapy for melanoma

An update on immunotherapy for melanoma | Melanoma BRAF Inhibitors Review | Scoop.it
IDO inhibitors have recently emerged as a new and exciting class of anticancer drugs. Learn more about this and other immunotherapy treatments in this article.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Sustained SREBP-1-dependent lipogenesis as a key mediator of resistance to BRAF-targeted therapy

Sustained SREBP-1-dependent lipogenesis as a key mediator of resistance to BRAF-targeted therapy | Melanoma BRAF Inhibitors Review | Scoop.it
Abstract
Whereas significant anti-tumor responses are observed in most BRAFV600E-mutant melanoma patients exposed to MAPK-targeting agents, resistance almost invariably develops. Here, we show that in therapy-responsive cells BRAF inhibition induces downregulation of the processing of Sterol Regulator Element Binding (SREBP-1) and thereby lipogenesis. Irrespective of the escape mechanism, therapy-resistant cells invariably restore this process to promote lipid saturation and protect melanoma from ROS-induced damage and lipid peroxidation. Importantly, pharmacological SREBP-1 inhibition sensitizes BRAFV600E-mutant therapy-resistant melanoma to BRAFV600E inhibitors both in vitro and in a pre-clinical PDX in vivo model. Together, these data indicate that targeting SREBP-1-induced lipogenesis may offer a new avenue to overcome acquisition of resistance to BRAF-targeted therapy. This work also provides evidence that targeting vulnerabilities downstream of oncogenic signaling offers new possibilities in overcoming resistance to targeted therapies.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma - ScienceDirect

Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma - ScienceDirect | Melanoma BRAF Inhibitors Review | Scoop.it
Highlights

Single-cell RNA-seq reveals distinct CD45+ cells associated with clinical outcome


The balance between two CD8+ T cell states is linked with tumor regression


TCF7+CD8+ T cell frequency in tumor tissue predicts response and better survival


Dual blockade of CD39 with different checkpoint proteins enhances immunity
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Vulvar malignant melanoma: Pathogenesis, clinical behavior and management: Review of the literature

Vulvar malignant melanoma: Pathogenesis, clinical behavior and management: Review of the literature | Melanoma BRAF Inhibitors Review | Scoop.it
Highlights
•Vulvar malignant melanoma (VMM) is a distinct entity of mucosal melanoma with an unfavourable prognosis.
•Surgery is the cornerstone of treatment for VMM.
•There is no indication for lymph node dissection whilst the role of sentinel node biopsy is being studied.
•There is an urgent need for new and better treatment strategies in VMM of which in particular immunotherapy is of high interest.
Abstract
Vulvar malignant melanoma (VMM) is a rare disease, accounting for 5% of all vulvar malignancies and is characterized by low survival and high recurrence rates. It is considered as a distinct entity of mucosal melanoma. Prognostic factors are higher age, advanced Breslow thickness, and lymph node involvement whilst central localization and ulceration status are still under debate. Surgery is the cornerstone for the treatment of primary VMM, however, it can be mutilating due to the anatomical location of the disease. Elective lymph node dissection is not part of standard care. The value of sentinel lymph node biopsy in VMM is still being studied. Radiation therapy and chemotherapy as adjuvant treatment do not benefit survival. Immunotherapy in cutaneous melanoma has shown promising results but clinical studies in VMM are scarce. In metastatic VMM, checkpoint inhibitors and in case of BRAF or KIT mutated metastatic VMM targeted therapy have shown clinical efficacy.

In this review, we present an overview of clinical aspects, clinicopathological characteristics and its prognostic value and the latest view on (adjuvant) therapy and follow-up.

Keywords:
vulvar malignant melanoma, mucosal melanoma, prognostic factors, immunotherapy
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

JCI - Lactate inhibits ATP6V0d2 expression in tumor-associated macrophages to promote HIF-2α–mediated tumor progression

JCI - Lactate inhibits ATP6V0d2 expression in tumor-associated macrophages to promote HIF-2α–mediated tumor progression | Melanoma BRAF Inhibitors Review | Scoop.it
Macrophages perform key functions in tissue homeostasis that are influenced by the local tissue environment. Within the tumor microenvironment, tumor-associated macrophages can be altered to acquire properties that enhance tumor growth. Here, we found that lactate, a metabolite found in high concentration within the anaerobic tumor environment, activated mTORC1 that subsequently suppressed TFEB-mediated expression of the macrophage-specific vacuolar ATPase subunit ATP6V0d2. Atp6v0d2–/– mice were more susceptible to tumor growth, with enhanced HIF-2α–mediated VEGF production in macrophages that display a more protumoral phenotype. We found that ATP6V0d2 targeted HIF-2α but not HIF-1α for lysosome-mediated degradation. Blockade of HIF-2α transcriptional activity reversed the susceptibility of Atp6v0d2–/– mice to tumor development. Furthermore, in a cohort of patients with lung adenocarcinoma, expression of ATP6V0d2 and HIF-2α was positively and negatively correlated with survival, respectively, suggesting a critical role of the macrophage lactate/ATP6V0d2/HIF-2α axis in maintaining tumor growth in human patients. Together, our results highlight the ability of tumor cells to modify the function of tumor-infiltrating macrophages to optimize the microenvironment for tumor growth.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Checkpoint inhibitors go viral

Checkpoint inhibitors go viral | Melanoma BRAF Inhibitors Review | Scoop.it
As clinical evidence mounts demonstrating the power of combining oncolytic viruses and checkpoint inhibitors, companies are scrambling to get in on the action.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

 FDA Approves tagraxofusp-erzs (Elzonris, Stemline Therapeutics) infusion for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN)

 FDA Approves tagraxofusp-erzs (Elzonris, Stemline Therapeutics) infusion for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) | Melanoma BRAF Inhibitors Review | Scoop.it
The FDA has approved tagraxofusp-erzs (Elzonris, Stemline Therapeutics) infusion for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in adults and in pediatric patients, aged 2 years and older.

 

The efficacy of Elzonris was studied in 2 cohorts of patients in a single-arm clinical trial. The first trial cohort enrolled 13 patients with untreated BPDCN, and 7 of those patients achieved complete remission (CR) or CR with a skin abnormality not indicative of active disease (CRc). The second cohort included 15 patients with relapsed or refractory BPDCN. One patient achieved CR and 1 patient achieved CRc.

Common adverse effects reported by patients in clinical trials were capillary leak syndrome, nausea, fatigue, swelling of legs and hands, fever, chills and weight increase. Most common laboratory abnormalities were decreases in lymphocytes, albumin, platelets, hemoglobin, and calcium, and increases in glucose and liver enzymes (ALT and AST). According to the FDA, health care providers are advised to monitor liver enzyme levels and for signs of intolerance to the infusion. Women who are pregnant or breastfeeding should not take Elzonris because it may cause harm to a developing fetus or newborn baby.

 

The labeling for Elzonris contains a Boxed Warning to alert health care professionals and patients about the increased risk of capillary leak syndrome which may be life-threatening or fatal to patients in treatment.

Krishan Maggon 's insight:

Stemline's application for tagraxofusp-erzs was granted Breakthrough Therapy and Priority Review designations by the FDA. The product also received Orphan Drug designation.

more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Application of 3D tumoroid systems to define immune and cytotoxic therapeutic responses based on tumoroid and tissue slice culture molecular signatures

Application of 3D tumoroid systems to define immune and cytotoxic therapeutic responses based on tumoroid and tissue slice culture molecular signatures | Melanoma BRAF Inhibitors Review | Scoop.it
We have developed 3D-tumoroids and tumor slice in vitro culture systems from surgical tumor specimens derived from patients with colorectal cancer (CRC) or lung cancer to evaluate immune cell populations infiltrating cultured tissues.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

JCI - Type I IFN blockade uncouples immunotherapy-induced antitumor immunity and autoimmune toxicity

JCI - Type I IFN blockade uncouples immunotherapy-induced antitumor immunity and autoimmune toxicity | Melanoma BRAF Inhibitors Review | Scoop.it
Despite its success in treating melanoma and hematological malignancies, adoptive cell therapy (ACT) has had only limited effects in solid tumors. This is due in part to a lack of specific antigen targets, poor trafficking and infiltration, and immunosuppression in the tumor microenvironment. In this study, we combined ACT with oncolytic virus vaccines (OVVs) to drive expansion and tumor infiltration of transferred antigen-specific T cells and demonstrated that the combination is highly potent for the eradication of established solid tumors. Consistent with other successful immunotherapies, this approach elicited severe autoimmune consequences when the antigen targeted was a self-protein. However, modulation of IFN-α/-β signaling, either by functional blockade or rational selection of an OVV backbone, ameliorated autoimmune side effects without compromising antitumor efficacy. Our study uncovers a pathogenic role for IFN-α/-β in facilitating autoimmune toxicity during cancer immunotherapy and presents a safe and powerful combinatorial regimen with immediate translational applications.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Targeting NKG2A to elucidate natural killer cell ontogenesis and to develop novel immune‐therapeutic strategies in cancer therapy - Zaghi - - Journal of Leukocyte Biology - Wiley Online Library

Journal of Leukocyte Biology considers manuscripts of original investigations focusing on the origins, developmental biology, biochemistry and functions of granulocytes, lymphocytes, mononuclear phagocytes, and other cells involved in host defense.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

CTLA-4 Prevents Long-Term Immune Responses

CTLA-4 Prevents Long-Term Immune Responses | Melanoma BRAF Inhibitors Review | Scoop.it
Cytotoxic T-Lymphocyte-associated Antigen 4 (CTLA-4) is a checkpoint receptor that modulates long-term immunity.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Radiotherapy and immune response: the systemic effects of a local treatment

Radiotherapy and immune response: the systemic effects of a local treatment | Melanoma BRAF Inhibitors Review | Scoop.it
Technological developments have allowed improvements in radiotherapy delivery, with higher precision and better sparing of normal tissue. For many years, it has been well known that ionizing radiation has not only local action but also systemic effects ...
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Unraveling the genetic causes of skin cancer

Unraveling the genetic causes of skin cancer | Melanoma BRAF Inhibitors Review | Scoop.it
Skin cancer is on the rise in the United States.Squamous cell carcinoma, the second most common form of cancer in the U.S., has the highest mortality...
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Cytokines, Chemokines, and Other Biomarkers of Response for Checkpoint Inhibitor Therapy in Skin Cancer

Cytokines, Chemokines, and Other Biomarkers of Response for Checkpoint Inhibitor Therapy in Skin Cancer | Melanoma BRAF Inhibitors Review | Scoop.it
Immunotherapy for skin malignancies has ushered in a new era for cancer treatments by demonstrating unprecedented durable responses in the setting of metastatic Melanoma. Consequently, checkpoint inhibitors are now the first-line treatment of metastati
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Novel Immunotherapeutic Approaches for Neuroblastoma and Malignant Melanoma

Novel Immunotherapeutic Approaches for Neuroblastoma and Malignant Melanoma | Melanoma BRAF Inhibitors Review | Scoop.it
Abstract
Neuroblastoma (NB) and malignant melanoma (MM), tumors of pediatric age and adulthood, respectively, share a common origin, both of them deriving from the neural crest cells. Although NB and MM have a different behavior, in respect to age of onset, primary tissue involvement and metastatic spread, the prognosis for high stage-affected patients is still poor, in spite of aggressive treatment strategies and the huge amount of new discovered biological knowledge. For these reasons researchers are continuously attempting to find out new treatment options, which in a near future could be translated to the clinical practice. In the last two decades, a strong effort has been spent in the field of translational research of immunotherapy which led to satisfactory results. Indeed, several immunotherapeutic clinical trials have been performed and some of them also resulted beneficial. Here, we summarize preclinical studies based on immunotherapeutic approaches applied in models of both NB and MM.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Intratumoral Tcf1+PD-1+CD8+ T Cells with Stem-like Properties Promote Tumor Control in Response to Vaccination and Checkpoint Blockade Immunotherapy

Since chronic activation promotes terminal T cell differentiation (exhaustion), it
has remained unclear how checkpoint blockade mediates a proliferative response of
tumor-infiltrating T cells. Siddiqui et al.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Interventional therapy combined with immune checkpoint inhibitors: Emerging opportunities for cancer treatment in the era of immunotherapy

Interventional therapy combined with immune checkpoint inhibitors: Emerging opportunities for cancer treatment in the era of immunotherapy | Melanoma BRAF Inhibitors Review | Scoop.it
Highlights
•Interventional therapy can induce an immunosuppressive microenvironment.
•Immune checkpoint inhibitors can increase T cell activity directed against tumor cells.
•Interventional therapy combined with immune checkpoint inhibitors might lead to a synergistic activity.
Abstract
Immune checkpoint inhibitors-based immunotherapy offers a new effective modality in the treatment of advanced malignancies. Considering the remarkable efficacy of immune checkpoint inhibitors in clinical trials, the FDA has approved a variety of immune checkpoint inhibitors for the treatment of advanced tumors. However, only limited patients with certain cancers can benefit from monotherapy of immune checkpoint inhibitors. Interventional therapy for cancer can not only destroy the primary tumors, but also regulate the immune system through different mechanisms, which provides a potential possibility for the combination of immune checkpoint inhibitors and interventional modalities in cancer treatment. This article reviews the possible synergistic mechanisms of interventional therapy combined with immune checkpoint inhibitors and summarizes the research progress of the combined therapy in cancer treatment.

Keywords:
Interventional oncology, Immune checkpoint inhibitor, Immunotherapy, Synergistic effect
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

JCI - Lactate inhibits ATP6V0d2 expression in tumor-associated macrophages to promote HIF-2α–mediated tumor progression

JCI - Lactate inhibits ATP6V0d2 expression in tumor-associated macrophages to promote HIF-2α–mediated tumor progression | Melanoma BRAF Inhibitors Review | Scoop.it
Macrophages perform key functions in tissue homeostasis that are influenced by the local tissue environment. Within the tumor microenvironment, tumor-associated macrophages can be altered to acquire properties that enhance tumor growth. Here, we found that lactate, a metabolite found in high concentration within the anaerobic tumor environment, activated mTORC1 that subsequently suppressed TFEB-mediated expression of the macrophage-specific vacuolar ATPase subunit ATP6V0d2. Atp6v0d2–/– mice were more susceptible to tumor growth, with enhanced HIF-2α–mediated VEGF production in macrophages that display a more protumoral phenotype. We found that ATP6V0d2 targeted HIF-2α but not HIF-1α for lysosome-mediated degradation. Blockade of HIF-2α transcriptional activity reversed the susceptibility of Atp6v0d2–/– mice to tumor development. Furthermore, in a cohort of patients with lung adenocarcinoma, expression of ATP6V0d2 and HIF-2α was positively and negatively correlated with survival, respectively, suggesting a critical role of the macrophage lactate/ATP6V0d2/HIF-2α axis in maintaining tumor growth in human patients. Together, our results highlight the ability of tumor cells to modify the function of tumor-infiltrating macrophages to optimize the microenvironment for tumor growth.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

How Immunotherapy Became the Next Big Thing - U Magazine - UCLA Health - Los Angeles, CA

How Immunotherapy Became the Next Big Thing - U Magazine - UCLA Health - Los Angeles, CA | Melanoma BRAF Inhibitors Review | Scoop.it
Features How Immunotherapy Became the Next Big Thing Once a stepchild of cancer research, immunotherapy is taking a leading role with new approaches to attack and kill tumors. By Lyndon Stambler | Illustration by Mark McGinnis The story of today’s hottest science in the battle against cancer was, up until fairly recently, one of “failure and futility.” “Immunotherapy was considered to be a backwater of cancer research,” says John A. Glaspy, MD ’79 (RES ’82, FEL ’83), Estelle, Abe, and Marjorie Sanders Endowed Chair in Cancer Research at UCLA’s Jonsson Comprehensive Cancer Center. “It was not prime time.” For some four decades, researchers who dedicated their lives to finding the key to unlock the immune system to battle cancer toiled in obscurity and struggled to get funding for their work as other scientists dismissed their efforts. Even though early animal studies showed some promising results, translating those findings to human trials was painstakingly slow. At oncology conferences, the sessions on immunotherapy usually were an afterthought, and few people bothered to attend. “All of cancer research was focused on figuring out what was the difference between cancer cells and the tissues within which cancer arose and developing targeted treatments for those differences,” Dr. Glaspy says. “So we focused on the cancer’s biology and not on the biology of the host tissues.” That has changed. Today, the evidence is indisputable: The immune system can battle cancer. Sometimes, it just needs a little help. We can see videos, for example, that show a dark red T cell attacking and destroying a blue cancer cell, setting its membrane ablaze with poisonous proteins. With Food and Drug Administration (FDA)-approved treatments for 17 different cancers and more than 1,000 new clinical trials, immunotherapy has emerged as the most promising area of cancer research in many, many years — a tribute to persistent scientific and medical investigation. It has come so far, in fact, that on October 1, 2018, two cancer researchers — James P. Allison, PhD, of MD Anderson Cancer Center in Houston, Texas, and Tasuku Honjo, MD, PhD, of Japan’s Kyoto University — won the Nobel Prize in Physiology or Medicine for their work in immunotherapy. Getting to such a landmark was not easy. Antoni Ribas, MD (FEL ’98, ’01), PhD, director of the Tumor Immunology Program at UCLA’s Jonsson Comprehensive Cancer Center, has been a leader in the drive to alter the direction of immunotherapy research. “Changing minds to get to this point has depended on understanding the biology,” he says. Dr. Ribas always felt drawn to immunotherapy rather than chemotherapy. “The immune system was always puzzling to me, and it seemed promising,” says Dr. Ribas, who won the 2018 Lloyd J. Old Award in Cancer Immunology from the American Association for Cancer Research as a scientist whose “innovative research in cancer immunology has had a far-reaching impact on the cancer field.” In addition, Dr. Ribas is director of the Parker Institute for Cancer Immunotherapy (PICI) Center at UCLA, which is part of a consortium of 11 of the nation’s leading cancer centers that is focused on advancing new immunotherapies to turn cancer into a curable disease. His explorations began in the early 1990s, when he spent three months in a San Diego lab researching tumor vaccines and immunotherapy. That led to his PhD dissertation on tumor immunology. In 1996, he came to UCLA, which was receptive to research in immunotherapy. Yet, in the early days, when he sat on a grant-review panel for the National Cancer Institute, colleagues routinely rejected applications for immunotherapy research. “They’d say, ‘It just doesn’t work,’” he says, with a hint of lingering sadness still in his voice. SCIENTISTS, AT LEAST SINCE THE LATE 19TH CENTURY, HAVE EXPLORED WAYS TO BOOST THE IMMUNE SYSTEM to fight cancer. In the 1890s, a New York surgeon named William Coley injected patients with sarcomas with the Streptococcus bacteria, called “Coley’s Toxins,” to stimulate an immune reaction. Sometimes it worked; often it did not. Throughout most of the 20th century, surgery, radiation and chemotherapy dominated cancer treatments. That started to change in the 1970s, when bone marrow transplantation, which boosted T cells, was used to treat leukemia. In the 1980s, recombinant DNA technology enabled researchers to clone proteins such as interferon and interleukin-2, which mimic stimulants in the immune system. Interferon had success in treating hairy cell leukemia and kidney cancer. High-dose interleukin-2 had a modest impact in treating melanoma and kidney cancer, but it also had severe side effects. The few patients who did respond, however, had durable remissions, a positive sign. “In those days, some benefit was the best we’d ever seen,” Dr. Glaspy says. The FDA approved the first monoclonal antibody, rituximab, in 1997, and UCLA has employed it since to treat lymphomas. But scientists had yet to realize that there were natural suppressors to turn off the immune system. “We were focusing everything on making the immune system stronger. What we did not really appreciate was this whole area of the defenses that the cancer cells were using, the immune checkpoints, the brakes on the immune system,” says John M. Timmerman, MD, professor of medicine in the UCLA Division of Hematology & Oncology. “We were stepping our foot on the gas; however, as you know, you can step your foot on the gas all you want, but if the brake is on, the car won’t move.” By the beginning of the 21st century, armed with powerful scientific tools, researchers gained a better understanding of how the immune system is regulated. Researchers came to understand that the immune system has accelerators and inhibitors, or “checkpoints,” to prevent it from attacking normal tissue. And cancer cells can take advantage by expressing proteins that activate those checkpoints. The first breakthrough was the discovery, by a scientist then at UC Berkeley, of the immune checkpoint effect of a protein called CTLA-4. That led to the development of the first checkpoint inhibitor, a monoclonal antibody called ipilimumab, which blocks the CTLA-4 receptor. Blocking CTLA-4 allowed the immune system to respond to cancers. Drs. Glaspy and Ribas were involved in clinical trials of ipilimumab beginning in 2001. After trials involving 5,000 patients, the FDA approved the drug in 2011, which led to a 10 percent response rate in melanoma. More important, it encouraged investigators to look for additional checkpoints. Soon, scientists identified an even more potent checkpoint, the protein PD-1 and its ligand PD-L1, resulting in the development of several new monoclonal antibodies, including pembrolizumab and nivolumab, for treating advanced melanoma. Treating melanoma was Dr. Ribas’s life’s work, but it had been a heartbreaking endeavor. “For many years, the majority of patients I treated would die within weeks to months because none of the therapies were working. We were just observing the cancer win the battle every time,” he says. But in 2011, Dr. Ribas began clinical trials of pembrolizumab, and he immediately experienced a rare aha! moment. “We treated the first seven patients. These were patients with metastatic melanoma, melanoma spread throughout their bodies and multiple organs, some of them in the brain, liver, the bones, the lungs. These were patients who would have weeks to months of life expectancy.” After treatment, “six of the seven patients had positive responses!” The FDA approved pembrolizumab in 2014 for treatment of melanoma. With the addition of several hundred other patients, it became clear that the response rate for melanoma — 40 percent — turned out to be a significant improvement. But it still left 60 percent of patients who didn’t respond. Dr. Ribas now is focusing on devising treatments, using several immunotherapy approaches for those patients. The ability of cancer cells to resist assault mounted by the immune system remains an ongoing challenge. “Cancer cells are stupid, but they grow fast and they’re very strong,” Dr. Timmerman says. “Just like Darwinian selection, a few cancer cells will survive these treatments. It only takes one cell for the whole cancer to come back.” WHY I GIVE In 2016, entrepreneur and philanthropist Sean Parker and The Parker Foundation founded the Parker Institute for Cancer Immunotherapy with a $250 million grant that was the largest contribution ever made to the field of cancer immunotherapy. The Parker Institute for Cancer Immunotherapy (PICI) Center at UCLA is among 11 leading centers nationwide brought together under the Parker umbrella to maximize the potential of cancer immunotherapy research. “We are at an inflection point in cancer research, and now is the time to maximize immunotherapy’s unique potential to transform all cancers into manageable diseases, saving millions of lives. We believe that the creation of a new funding and research model can overcome many of the obstacles that currently prevent research breakthroughs.” — Sean Parker. THE DEVELOPMENT OF CHECKPOINT INHIBITORS REPRESENTED A PAYOFF AFTER DECADES OF FRUSTRATION. Unlike targeted treatments that work in one tumor type, the checkpoint inhibitors have proven effective in a broad array of cancers: lymphoma, lung, bladder, kidney, stomach, head and neck and some types of colon and endometrial cancers. “It is a more global potential solution,” Dr. Glaspy says. Dr. Timmerman led the first trial of nivolumab, another anti-PD-1 antibody, in lymphoma in 2015, and he was astounded by the 87 percent response rate in Hodgkin’s lymphoma. “It was the most exciting thing I’ve seen in my career,” he says. “Tumors were just melting away. There were almost no side effects. For those patients with Hodgkin’s lymphoma, it has been a complete lifesaver.” In 2012, Dr. Ribas approached Edward B. Garon, MD (FEL ’06), director of thoracic oncology at UCLA’s Jonsson Comprehensive Cancer Center, with the idea of testing pembrolizumab in patients with non-small-cell lung cancer, which represents 85 percent of lung cancer cases. Twelve patients out of an initial cohort of 38 were enrolled at UCLA. The initial response rate was between 20-to-25 percent in patients whose disease had worsened after multiple prior therapies, which, Dr. Garon says, “was obviously not what we were used to seeing in this disease.” When this trial was expanded to include a total of 550 patients with lung cancer, approximately 100 were treated at UCLA, requiring UCLA to overhaul its lung cancer clinical research team to run the study. Dr. Garon was the lead author when the findings were published in the New England Journal of Medicine in 2015. The study showed an approximately 20 percent response rate overall, and patients with a high expression of the protein PD-L1 had about a 40 percent response rate and lived much longer than other patients. More recently, he was part of a group that published a report in the New England Journal of Medicine in 2018 that showed the benefits of adding pembrolizumab to frontline chemotherapy in treating lung cancer. Today, patients with lung cancer who have a high-level of PD-L1 often receive pembrolizumab rather than chemotherapy, and those without a high-level of PD-L1 generally receive a combination of chemotherapy and pembrolizumab. This experience has served as a proof of concept that the management of a common malignancy such as lung cancer can be overhauled by immunotherapy, Dr. Garon says. When she was completing her fellowship training at UCLA, Deborah Wong, MD (RES ’09, FEL ’13), PhD, got a firsthand look at Dr. Ribas’s research while working in his lab during the phase-1 studies of pembrolizumab. “I got to see the field of immunotherapy unfold,” says Dr. Wong, now an assistant professor of medicine with a specialty in head and neck cancers. “It’s really revolutionized treatments for patients with incurable cancer.” Among Dr. Wong’s patients with head and neck cancers, the response rate to checkpoint inhibitor therapy is about 15 percent. But for those patients who do respond, the results are enduring, lasting two to three years, or more. “We know our immune system has memory, which is why the saying goes, ‘You never get the same cold twice,’” Dr. Wong says. “It’s this idea that, perhaps, the immune system can remember this particular cancer that the patient has is foreign and continue responding to kill off this cancer.” THE REVOLUTION OF CHECKPOINT INHIBITORS ALSO HAS PAVED THE WAY for other immunotherapy treatments. CAR T-cell therapy (CAR stands for chimeric antigen receptor) received FDA approval in 2017 for treatment for two forms of blood cancers: acute lymphoblastic leukemia and diffuse large B-cell lymphoma. UCLA, which was involved in the CAR T-cell clinical trials, is one of the few centers in the country capable of administering CAR T-cell therapy, which involves genetically modifying a patient’s T cells to add claw-like receptors that seek out and destroy the CD19 protein in those two blood cancers. “Once the CAR T cells are infused back into the patient’s veins, they migrate around the body, and whenever they encounter a cell that expresses CD19, it ignites an inflammatory reaction inside the cancer cells, eradicating them,” explains Joshua P. Sasine, MD (RES ’13, FEL ’17), clinical director of UCLA’s CAR T-cell program. “It is like a GPS to find cancer cells,” Dr. Ribas says. Dr. Sasine notes that about one-third to two-thirds of the patients who receive the innovative new therapy are having durable remissions. “There are patients who had large volumes of tumors all over their bodies who are now, as far as we can tell, free of cancer,” he says. But it is not a perfect cure. While side effects most often mimic flu-like symptoms such as fever, mild nausea or malaise, Dr. Sasine does note that a significant percentage of patients — 10-to-30 percent — do experience serious and potentially life-threatening inflammation. Last fall, UCLA treated a 40-year-old patient with a high-risk lymphoma that did not respond to chemotherapy. “We knew he was in trouble right away,” Dr. Sasine says. Initiating CAR T-cell therapy, physicians extracted millions of white blood cells from the patient, which were sent to be genetically engineered and grown to a sufficient number to be infused back into the patient. In March 2018, he received the treatment. Although he experienced treatable inflammation, the patient’s cancer was in remission within a month following therapy. “The precision of CAR T-cell therapy really is limited only by the proteins that are expressed on the surface of the target cells. While that does impose more of a limit than we would like, it still is a degree of precision that we’ve never had before,” Dr. Sasine says. “The ability to genetically engineer a cell to kill any other cell that expresses protein X, Y or Z is new. We’ve never had that degree of flexible accuracy.” To which Dr. Timmerman adds: “We’ve turned the body’s natural killers into something that’s going to target the patient’s lymphoma or leukemia. When these cells are given back to the body, they are a living therapy; they circulate through the body and hunt down these tumors and attack them wherever they are.” Such successes have made it impossible for the medical community to ignore immunotherapy. “One can no longer say immunotherapy is not going to have a role,” Dr. Glaspy says. “It does have a role. And it is not an insignificant role. Whether or not it will be 20 percent or 80 percent of the ultimate solution — stay tuned.” While there are many obstacles that still need to be overcome — immunotherapy can lead to inflammation in the lungs, liver, kidneys, colon, brain, and even the heart — the benefits of treating the cancer with immunotherapy most often outweigh the risks of the autoimmune toxicity. “Our hope, obviously, is that with continued understanding at the basic science level, and additional clinical testing, we will have more effective immunotherapies — ideally without a significant increase in toxicity,” Dr. Garon says. “We’ve been fortunate at UCLA to have a wealth of investigators who put seminal work into this area that hopefully will continue to expand even further over the coming years.” A patient’s dendritic cells (DCs) are stimulated to develop from their own blood cells and then strengthened with CCL21, which attract other cancer-fighting immune cells. The enhanced DCs are injected into the tumor, alerting the immune system to find and fight the cancer cells. Graphic: Courtesy of Dr. Steven M. Dubinett On the Horizon Beyond CAR T cells and checkpoint inhibitors to turn the body’s own immune system against cancer, UCLA is working to bolster the arsenal of weapons in the fight, testing combinations of drugs, studying tumor biopsies and pioneering new treatments. Dr. Antoni Ribas, for example, received a $20 million grant from the California Institute for Regenerative Medicine (CIRM) to use stem cells to treat cancer. His team will genetically modify a patient’s bloodforming, or hematopoietic, stem cells and T cells and add receptors to redirect them to biomarkers for melanoma and other forms of resistance-prone cancers. Dr. Ribas recently treated the first patient with this new approach; he says he will have a better idea of its potency after treating six or seven patients. Steven M. Dubinett, MD (RES ’84), director of the UCLA Lung Cancer Research Program at the UCLA Jonsson Comprehensive Cancer Center, has long studied inflammation and immunology in lung cancer. He is experimenting with a novel treatment by genetically modifying a person’s own dendritic cells — the most potent antigen presenting cells — and injecting them back into a patient’s tumor. The goal of the clinical trial, which is supported by a $12 million grant from CIRM, is to more effectively present a patient’s own tumor antigens to their immune system. A checkpoint inhibitor also will be given in an effort to enhance the power of the immune system to destroy the tumor. And Sherie L. Morrison, PhD, Distinguished Research Professor of Microbiology, Immunology and Molecular Genetics, together with Dr. John M. Timmerman, is studying antibody-interferon fusion proteins, which can target interferon to tumors to help shrink tumors and sensitize them to the effects of checkpoint inhibitors and CAR T cells. — Lyndon Stambler FOR ALL THE PROMISE OF IMMUNOTHERAPY, cost of treatment remains a not-inconsequential issue. The price tag for CAR T-cell therapy to treat lymphoma is about $373,000, and it is $475,000 to treat leukemia. That doesn’t include hospitalization, follow-up care and autoimmune toxicity management. Checkpoint inhibitors, which require infusions every three weeks, cost about $20,000 per dose. In a practical sense, “It is going to have to morph into something that is a lot cheaper and more accessible for the broader population,” Dr. Glaspy says. Still, “It is hard to put a price on keeping people alive and getting people to live normal lives after having had a metastatic cancer,” Dr. Ribas says. The science of immunotherapy is fascinating, but the evolution of this revolutionary treatment modality from fringe to mainstream medicine is all about helping patients. One of the many beneficiaries of the new immunotherapy era is Wayne Parker, 61, a retired electronics technician with the U.S. Postal Service, who found a mole on the back of his neck in October 2017. The Salem, Oregon, resident was diagnosed with Stage IV metastatic melanoma. Tumors had spread to his liver and lymph nodes. His prognosis was dire. Oncologists in Oregon recommended surgery on his liver and lymph nodes. Instead, Parker (no relation to Sean Parker, founder of the Parker Institute for Cancer Immunotherapy) sought a second opinion, from Dr. Ribas. In November 2017, Dr. Ribas told Parker that surgery would be futile. Instead, he enrolled Parker in a clinical trial combining pembrolizumab with an immune-activating molecule injected into his lymph nodes. In January 2018, Parker began treatments every three weeks, driving his motor home more than 900 miles south, to Los Angeles, to get injections, 30-minute infusions and biopsies. Initially, he experienced side effects: 24 hours of nausea, sudden diarrhea and intense shivering. The side effects subsided, and within a few weeks, his tumors started to shrink. By August, a CT scan revealed that Parker’s tumors had all but disappeared. “When Dr. Ribas said, ‘You’re in remission,’ that was like a million bucks right there,” Parker says. Such treatments were unimaginable just a few decades ago. No longer. “We are using a host of approaches to attack cancers from many different angles,” Dr. Timmerman says. “Momentum is growing faster and faster toward finding cures for so many different kinds of cancers.” Lyndon Stambler is a freelance writer and associate professor of journalism at Santa Monica College. “Pembrolizumab for the Treatment of Non-Small-Cell Lung Cancer,” New England Journal of Medicine, May 2015 “Pembrolizumab Plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer,” New England Journal of Medicine, May 2018   Previous The Pluripotent-ialist: Expanded Interview with Dr. Kathrin Plath Next The Prize
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

STING Pathway Activators | Cyclic dinucleotides (CDNs) | Aduro Biotech

STING Pathway Activators | Cyclic dinucleotides (CDNs) | Aduro Biotech | Melanoma BRAF Inhibitors Review | Scoop.it
Aduro’s proprietary CDNs have shown promising therapeutic activity in preclinical testing. Aduro is a clinical-stage cancer immunotherapy company.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

An errant editing enzyme promotes tumor suppressor loss and leukemia propagation | Science Codex

An errant editing enzyme promotes tumor suppressor loss and leukemia propagation | Science Codex | Melanoma BRAF Inhibitors Review | Scoop.it
Writing in the January 3 issue of Cancer Cell, researchers at University of California San Diego School of Medicine report that detection of "copy editing" by a stem cell enzyme called ADAR1, which is active in more than 20 tumor types, may provide a kind of molecular radar for early detection of malignancies and represent a new therapeutic target for preventing cancer cell resistance to chemotherapy and radiation. Adenosine deaminases are a family of three enzymes encoded by the ADAR genes, which stand for adenosine deaminase acting on RNA. They regulate gene expression by modifying nucleotides within double stranded RNA molecules, serving as fundamental editors in the development of new stem cells. The enzyme, however, is also activated in cancers as diverse as liver, breast and leukemia. A research team led by senior author Catriona Jamieson, MD, PhD, deputy director of the Sanford Stem Cell Clinical Center and deputy director of the UC San Diego Moores Cancer Center, found that the normal functions of the ADAR1 enzyme are hijacked by pre-malignant cells, leading to a cascade of molecular consequences that promote malignant transformation, dormant cancer stem cell generation and resistance to treatment. "We were able to illuminate the abilities of ADAR1 to 'hyper-mutate' tumor suppressor RNAs in leukemia and, at the same time, edit the microRNA aimed at targeting the tumor suppressor RNA. This enzyme turns on cancer resistance via a domino effect on RNA instead of DNA," said first author Qingfei Jiang, PhD, assistant project scientist in Jamieson's lab. Jamieson characterized RNA editing as tweaking basic genetic blueprints, not fundamentally rewriting them. Nonetheless, the results might be dramatic. "One result of detection of malignant RNA editing could be exposing dormant cancer stem cells that often escape therapies that target dividing cells, which leads to therapeutic resistance and disease relapse, and also highlight ADAR as a potentially tractable target for cancer stem cell elimination," said Jamieson.
more...
No comment yet.