Cancer Immunotherapy Review and Collection
171.1K views | +125 today
Follow
 
Scooped by Krishan Maggon
onto Cancer Immunotherapy Review and Collection
Scoop.it!

Safety and efficacy of anti-programmed death 1 antibodies in patients with cancer and pre-existing autoimmune or inflammatory disease

Safety and efficacy of anti-programmed death 1 antibodies in patients with cancer and pre-existing autoimmune or inflammatory disease | Cancer Immunotherapy Review and Collection | Scoop.it



Highlights •In patients treated with anti-PD-1 antibodies, the presence of a pre-existing auto-immune or inflammatory disease is associated with a higher risk of immune-related adverse events. •Immunotherapies provide similar levels of effectiveness (overall survival) in patients with and without pre-existing auto-immune or inflammatory disease. •Half of these immune-related adverse events are flares or manifestations of the pre-existing autoimmune or inflammatory disease. •Anti-PD-1 antibodies can be maintained in 75% of the patients despite the immune-related adverse events.

more...
No comment yet.
Cancer Immunotherapy Review and Collection
A magic life saving cure for advanced metastatic melanoma.  
Curated by Krishan Maggon
Your new post is loading...
Your new post is loading...
Scooped by Krishan Maggon
Scoop.it!

Ipilimumab (BMS) Review: A Cancer Breakthrough? - un knol de Krishan Maggon

Ipilimumab (BMS) Review: A Cancer Breakthrough? - un knol de Krishan Maggon | Cancer Immunotherapy Review and Collection | Scoop.it
FDA has approved Yervoy (ipilimumab, BMS) under REMS for the treatment of metastatic melanoma. The European expert panel CHMP...
more...
rosywills's comment, September 22, 2017 9:07 AM
Cancer Immunotherapy Market is expected to reach USD 119.39 Billion by 2021
Download Free Brochure @ http://bit.ly/2cHlrFH
Scooped by Krishan Maggon
Scoop.it!

Cell-Based Cancer Immunotherapies - Commercial Outlook (Blue Matter)

Cell-Based Cancer Immunotherapies - Commercial Outlook (Blue Matter) | Cancer Immunotherapy Review and Collection | Scoop.it
In Part One of this series, we provided an overview of how the immune system can fight cancer, as well as the reasons it can sometimes fail in the effort.  In addition, we explored an extremely interesting class of therapies that show great promise in initiating or boosting the immune system’s ability to eradicate cancer cells: cell-based immunotherapies.  Specifically, we outlined the key types of cell-based immunotherapies and provided some insights into how they work.

Part Two of this series explores the commercial opportunities and challenges facing these therapies.  It also provides a brief outlook as how the commercial landscape is likely to evolve.
more...
No comment yet.
Rescooped by Krishan Maggon from Immunology and Biotherapies
Scoop.it!

Checkpoint Blockade Immunotherapy Induces Dynamic Changes in PD-1−CD8+ Tumor-Infiltrating T Cells - ScienceDirect

Checkpoint Blockade Immunotherapy Induces Dynamic Changes in PD-1−CD8+ Tumor-Infiltrating T Cells - ScienceDirect | Cancer Immunotherapy Review and Collection | Scoop.it
An improved understanding of the anti-tumor CD8+ T cell response after checkpoint blockade would enable more informed and effective therapeutic strate…

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

Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): a multicentre, open-label, randomised, non-comparative, phase 2 trial

Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): a multicentre, open-label, randomised, non-comparative, phase 2 trial | Cancer Immunotherapy Review and Collection | Scoop.it
Anti-PD-1 nivolumab monotherapy or nivolumab plus anti-CTLA-4 ipilimumab combination therapy both showed promising activity in relapsed patients with malignant pleural mesothelioma, without unexpected toxicity. These regimens require confirmation in larger clinical trials.
Funding
French Cooperative Thoracic Intergroup.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Checkpoint inhibitors in mesothelioma: hope for the future?

Checkpoint inhibitors in mesothelioma: hope for the future? | Cancer Immunotherapy Review and Collection | Scoop.it
Malignant pleural mesothelioma is an aggressive, asbestos-related tumour of the thoracic
cavity, with increasing global incidence.1 Prognosis is poor and treatment options
are scarce. Pemetrexed and platinum doublet chemotherapy has been the standard first-line therapy for non-resectable malignant...
more...
No comment yet.
Rescooped by Krishan Maggon from Immunology and Biotherapies
Scoop.it!

Regulation and potential drug targets of tumor-associated Tregs

Regulation and potential drug targets of tumor-associated Tregs | Cancer Immunotherapy Review and Collection | Scoop.it
According to estimates from the World Health Organization (WHO), there will be 18.1 million new cases and 9.6 million cancer deaths worldwide in 2018. Cancer is a serious disease that affects people all over the world.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Steering CAR T Cells into Solid Tumors | NEJM

Steering CAR T Cells into Solid Tumors | NEJM | Cancer Immunotherapy Review and Collection | Scoop.it
The CAR T cell is a recent and impressive addition to the armamentarium of medicines to treat hematologic cancers. A recent study of a mouse model of glioblastoma suggests that an engineering tweak to the CAR T cell may equip it to infiltrate and kill cells of solid tumors as well.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Patient-reported outcomes of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib (CheckMate 214): a randomised, phase 3 trial

Nivolumab plus ipilimumab leads to fewer symptoms and better HRQoL than sunitinib
in patients at intermediate or poor risk with advanced renal cell carcinoma. These results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib comes with the additional benefit of improved...
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Holy grail in oncology – Deep Science Ventures

Holy grail in oncology – Deep Science Ventures | Cancer Immunotherapy Review and Collection | Scoop.it
Just over 30 years since the initial experiments, Immuno-oncology has reached the clinic and demonstrated remarkable results and the recognition of a Nobel Prize. The feeling is that this can’t come soon enough given that current mainstay therapies of chemotherapy, radiation and surgery have a high therapeutic burden and often only work in the short term with estimates of over 2/3rds of spending providing zero patient benefit. Vast amounts of investment have been poured into immuno-oncology ventures, over $9.3bn last year, and even biotech press is almost lavish in its praise. All this gives the impression that we have reached the holy-grail. Unfortunately, this is far from the case. Immuno-oncology is still largely only suitable for a minority of patients, only available for 1/3rd of cancers and only effective in around 20% of cases. Moreover autologous treatments, where a patient’s own immune cells are used is incredibly difficult to fit into current healthcare regimes, and even allogeneic treatments which use ‘off the shelf’ cells are logistically troublesome. In our opinion the most impactful approaches are less likely to be found in the proliferation of tweaks to make chimeric antigen receptor (CAR) approaches work, and more likely to involve smarter ways of fully taking into account the integrated complexity of the cancer and immune system. Here we take a brief look at areas where new ventures could create significant impact over the next few years.   Immune mediated clearance Adoptive cell transfer involves the growth of immune cells outside the patient’s body, their activation against cancers and dosing of the patient. Currently two therapies are approved, Yescarta and Kymriah, which both take cytotoxic T-cells, derived from the patient. These are genetically modified to express a CAR which enables them to ‘specifically’ target cancerous blood cells. In practice this is labour intensive, the cells are difficult to grow and there have been some severe reactions against the therapies which cost up to $475,000. As with many early breakthroughs, CAR-Ts are a blunt instrument. CAR-Ts are matured against an antigen presented on the surface of cancer cells, antigens which are highly heterogeneous within and between cancers and remodel in the face of resistance to treatment. Given that most cancer mutations involve non-surface proteins, it’s clear that any holy-grail will need to target intracellular proteins. There are early players in this field such as Immunocore which uses a T-cell receptor mimic (ImmTAC) to bind intracellular antigens presented on the surface of cells by the HLA complex and recruit T-cell effectors. Whilst this has impressed investors, this strategy is unlikely to represent a broadly applicable solution due to the fact that up to 90% of cancers demonstrate HLA downregulation, leaving ImmTACs little or nothing to bind. Our immune system is an incredibly complex system consisting of multiple cell types and a huge range of dynamics across receptors and signaling molecules. We are right at the start of understanding how to work with these systems but early work suggests that approaches such as using other cell types such as natural killer (co.) and mesenchymal stromal cells may overcome many of the challenges of sourcing, scaling and patient specificity. Ultimately we’re likely to see a shift deploying multiple cell types in combinations alongside multiple immunomodulatory compounds (see below), to stimulate a more balanced and durable response.     Disrupting the defensive tumour microenvironment One area of huge progress over the last couple of years has been checkpoint inhibitors. This approach increases the efficacy of immuno-oncology therapies by reducing the immunosuppressant properties of solid-tumor cancers. Tumors mediate this immunosuppressant environment by adapting to highly express PD-1, a receptor that shuts down the cytotoxic T-cell response, and inhibition of this ‘checkpoint’ using a PD-1 binding antibody reverses this effect. The leader in this field is Keytruda, Merck’s latest blockbuster. Sometimes this works really well, but sadly often not: This is because there are a multitude of other checkpoints and different strategies that tumours use to evade immune activity: Checkpoint inhibition only takes the cancer one step back along a long road to immune evasion. Targeting two checkpoints simultaneously can be beneficial as emerging combination strategies will be, but other factors such as regulatory T cells and macrophages, downregulation of MHC (again) and production of immunosuppressive cytokines all contribute to the resistance of cancers to checkpoint inhibition. What’s needed is approaches that fully consider this as an adaptive system as opposed to point solutions. Beyond approaches that more fully consider the adaptive complexity of the system, the physical structure around a solid tumour (which are notably difficult to treat) is the key element that maintains this hostile environment. Whilst it sounds like a step back from the elegance of cell based approaches, it might be essential to combine immuno-oncology based approaches with more physical disruption that is capable of temporarily breaking down the extracellular matrix. Either through digestion, chemical modulation or even physical disruption.   Maybe cell based therapies aren’t that great after all? As solid tumours are naturally resistant to immune cell attack, therapies employing cells might in and of themselves be fighting an unnecessary uphill battle. Antibody drug conjugates (ADC), whilst slightly out of favour, could provide similar specificity without the biological unpredictability. The reason for their falling out of favour is due to specificity challenges. If the very toxic payload is even slightly misdirected to other tissues consequences are serious (e.g. the fatal exfoliation events caused by bivatuzumab mertansine). There is clearly potential for a strategy which employs a triple safety lock, where ADCs are locally delivered, specifically cleaved and specifically active would limit off-targeting and dose limiting toxicities without impinging on efficacy. Unfortunately, again, most emerging companies are concentrating on one aspect. For instance, ADC therapeutics and ImmunoGen are exploring new payloads, while CytomX looks at ‘probodies’ that only bind to antigens in tumour environments (interestingly Pfizer have recently dumped their collaboration). Whilst this might provide an improvement it is frustrating that there isn’t a more joined up approach to addressing this complexity.   The stratification and targeting dichotomy The major problem with targeting cancers is that they’re heterogeneous both within the cancer and across patients. In an ideal world it would be possible to very specifically target each cancer cell, in practice this is challenging as it requires developing therapeutics (and all the costs associated with that) for smaller and smaller patient groups. Fairly quickly the economics don’t work. For instance the use bispecific targeting, where two antigens are required for therapeutic activity can decrease off-targeting. However this presents challenges as only a sub-population of the cancer cells will have both these markers and if clearance isn’t swift and complete it is inviting the emergence of resistance. We expect to see a divergence of strategies in stratification, firstly further work on identifying unified targets and better clinical support tools to quantify the effectiveness of combinations. In terms of unified targeting we think it’s fair to say that we don’t yet fully understand the generalised characteristics of cancer across all levels from genotype to phenotype expression and there may well be very conserved features that can act as a ubiquitous target. It’s unlikely that there is one magic bullet given the level of heterogeneity but there’s certainly room for better targets beyond the small sample of surface antigens currently in play.     Finally, as the landscape of therapeutics and patient stratification becomes increasingly complex we expect to see some of the biggest impact coming not from biotech but software that helps clinicians and patients make sense of the options available. Something that we’re looking to solve with ConcR (stealth). We’re just at the beginning of this paradigm shift, but concentrating on building more general therapies and using them in tailor-made combinations for individuals (as opposed to highly targeted monotherapy) may be the most effective path towards cost-effective and fully efficacious treatment – a true holy grail.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

VISTA Molecule a Target for Pancreatic Cancer Immunotherapy | Articles | ClinicalOMICs

VISTA Molecule a Target for Pancreatic Cancer Immunotherapy | Articles | ClinicalOMICs | Cancer Immunotherapy Review and Collection | Scoop.it
While current immune checkpoint inhibitor therapies are largely ineffective against pancreatic cancer, scientists in the U.S. have now identified an immune checkpoint molecule that could represent a promising immunotherapeutic target for this tumor type. The University of Texas MD Anderson Cancer Center-led team found that V-domain immunoglobulin suppressor of T cell activation (VISTA) is preferentially expressed at high levels in pancreatic cancer, when compared with melanoma tumors. The researchers’ studies also provided a detailed analysis of immune infiltration in primary and metastatic pancreatic cancers, in comparison with melanoma, which could further help to direct immunotherapy strategies against pancreatic cancer treatment.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

What, Why, Where, and When: Bringing Timing to Immuno-Oncology

What, Why, Where, and When: Bringing Timing to Immuno-Oncology | Cancer Immunotherapy Review and Collection | Scoop.it
Highlights
The temporal progression of response to infection and the order of events in the cancer–immune cycle indicate the existence of an endogenous temporal program for the immune system.
A growing number of examples illustrate that choice of dose schedule can either eliminate or synergistically amplify the therapeutic benefit of immunotherapeutic agents.
Treatment schedule design should take into account both duration and sequencing of combination immunotherapy agents.
New biomarkers such as circulating tumor DNA and cell counts derived from the blood can help align preclinical and clinical immunological timescales for clinical translation.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Inflammatory T cells maintain a healing disposition

Inflammatory T cells maintain a healing disposition | Cancer Immunotherapy Review and Collection | Scoop.it
Commensal-specific T cells dually possess type-2 and type-17 effector potential, allowing plasticity in orchestrating tissue immunity.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Anti-regulatory T cell vaccines in immunotherapy: focusing on FoxP3 as target: Human Vaccines & Immunotherapeutics: Vol 0, No ja

Anti-regulatory T cell vaccines in immunotherapy: focusing on FoxP3 as target: Human Vaccines & Immunotherapeutics: Vol 0, No ja | Cancer Immunotherapy Review and Collection | Scoop.it
ABSTRACT
Anti- tumor vaccination elicits imperfect immune responses against tumor cells; that is related to the presence of suppressive obstacles in the tumor microenvironment. The main members of suppressive milieu of tumor are heteroogenous groups of immune cells in which regulatory T cell is a substantial component. Tregs express different immunomodulatory molecules such as FoxP3. Transcription factor, FoxP3, is a specific intracellular marker of Treg and crucial for Treg development. Therefore it is an attractive target for cancer treatment. This article reviews some recent anti-Treg vaccine focusing on FoxP3 to ameliorate anti-tumor immune responses. Among them, fusion vaccine of FoxP3-Fc(IgG) recombinant DNA vaccine and its accordant protein vaccine represents effective results.

Keywords: Treg, FoxP3, immunotherapy, Anti-Treg, vaccine
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Immuno-Oncology

Immuno-Oncology | Cancer Immunotherapy Review and Collection | Scoop.it
What is Immuno-Oncology? “Immuno” in Immuno-Oncology (I-O) refers to your immune system. I-O uses drugs known as immunotherapies that target your body’s immune system to help fight cancer. Immuno-oncology is an important pillar in cancer therapy. The Immune system The immune system is a network of organs, cells and molecules throughout the whole body. The role of the immune system is to protect the body from harmful things like germs, viruses, and diseases like cancer. After first finding a foreign substance (such as germs, viruses, or cancer cells), the immune system takes action. Immune responses are the way the body works to find and destroy abnormal cells, including cancer cells. The principle of Immuno-Oncology Most treatment options available for cancer are directed against a tumour or against cancer cells. The tumour can be treated locally (surgery, radiotherapy) or with medication (chemotherapy, targeted therapies). On the other hand, immuno-oncology focuses on strengthening the body's own defence mechanism and can thus offer a different treatment option in the fight against various types of cancer. Cancer and the Immune Response Cancerous cells are actually quite common in the body. When cancerous cells form in the body, the immune system works to find and fight the cancer by activating an immune response. The immune response involves several types of cells, including a kind of white blood cell called a T cell. These cells work to find and destroy the abnormal cancer cells. Normally, the immune response works like it is supposed to by finding and destroying cancerous cells. Sometimes though, cancer cells can undergo changes in order to escape the body’s ability to attack them, allowing cancerous cells to grow and spread. Immuno-Oncology research is looking at how to work with the immune system so that immune responses can work as they should. As a results, the immune response, including T cells, may be able to do its job of destroying cancerous cells. How Immuno-Oncology treatment activates the body's own tumour defence Immuno-oncology therapies can support the immune system to re-activate its own anti-cancer cell immune response. The natural killer cells and T cells are thereby enabled again to actively fight cancer cells. Immuno-oncology therapies try to support the body's immune system so that the cancer cells can no longer escape the attack of T cells. The body’s own anti-cancer cell immune response is reactivated.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Translation control of the immune checkpoint in cancer and its therapeutic targeting

Translation control of the immune checkpoint in cancer and its therapeutic targeting | Cancer Immunotherapy Review and Collection | Scoop.it
Abstract
Cancer cells develop mechanisms to escape immunosurveillance, among which modulating the expression of immune suppressive messenger RNAs is most well-documented. However, how this is molecularly achieved remains largely unresolved. Here, we develop an in vivo mouse model of liver cancer to study oncogene cooperation in immunosurveillance. We show that MYC overexpression (MYCTg) synergizes with KRASG12D to induce an aggressive liver tumor leading to metastasis formation and reduced mouse survival compared with KRASG12D alone. Genome-wide ribosomal footprinting of MYCTg;KRASG12 tumors compared with KRASG12D revealed potential alterations in translation of mRNAs, including programmed-death-ligand 1 (PD-L1). Further analysis revealed that PD-L1 translation is repressed in KRASG12D tumors by functional, non-canonical upstream open reading frames in its 5′ untranslated region, which is bypassed in MYCTg;KRASG12D tumors to evade immune attack. We show that this mechanism of PD-L1 translational upregulation was effectively targeted by a potent, clinical compound that inhibits eIF4E phosphorylation, eFT508, which reverses the aggressive and metastatic characteristics of MYCTg;KRASG12D tumors. Together, these studies reveal how immune-checkpoint proteins are manipulated by distinct oncogenes at the level of mRNA translation, which can be exploited for new immunotherapies.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Ipilimumab and nivolumab in the treatment of recurrent malignant pleural mesothelioma (INITIATE): results of a prospective, single-arm, phase 2 trial

Ipilimumab and nivolumab in the treatment of recurrent malignant pleural mesothelioma (INITIATE): results of a prospective, single-arm, phase 2 trial | Cancer Immunotherapy Review and Collection | Scoop.it
In this single-centre phase 2 trial, the combination of nivolumab plus ipilimumab showed marked efficacy in patients with recurrent malignant pleural mesothelioma. The safety profile was consistent with known data on the combination regimen. Our results warrant further investigation of this combination in a phase 3 trial.
Funding
Bristol-Myers Squibb.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

FBXO38 Drives PD-1 to Destruction

FBXO38 Drives PD-1 to Destruction | Cancer Immunotherapy Review and Collection | Scoop.it
Aberrant expression of T cell-resident programmed cell death protein-1 (PD-1) is known to promote tumor progression. A recent study ( Nature 2018;564:130–135) has now identified the E3 ubiquitin ligase FBXO38 as a crucial regulator of PD-1 protein turnover in T cells, providing a novel mechanism for potential use in cancer immunotherapy.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Immunotherapy Showcase Session Chair: Kimberly Blackwell, Lilly Oncology

Immunotherapy Showcase Session Chair: Kimberly Blackwell, Lilly Oncology | Cancer Immunotherapy Review and Collection | Scoop.it
Biography Kimberly Blackwell is the Vice President of Early Phase Development and Immuno-oncology at Lilly Oncology. A graduate of Mayo Clinic Medical School, Dr. Blackwell was Professor of Medicine and Assistant Professor of Radiation Oncology at Duke University Medical Center. She has played a major role in developing therapies that represent revolutionary non-chemotherapy based approaches for treating breast cancer. Her clinical and research interests include various topics in breast cancer including endocrine therapy, novel HER2 therapies, breast cancer vaccines, and other experimental therapeutics. She has studied and served as the principal investigator on studies that led to regulatory approval of four cancer agents, including the first biosimilar treatment for cancer in the United States. Due to her leadership, she has received numerous awards, including the Duke University Distinguished Alumni in 2015 and TIME Magazine’s 100 Most Influential People in the World in 2013. Additionally, Dr. Blackwell is a recipient of the Young Investigator Award in breast cancer from the National Cancer Institute Specialized Program of Research Excellence and the Joseph Greenfield Award for Mentorship of Clinical Research.
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

Abstract
Natural Killer (NK) cells are innate immune cells with a primary role in the immune surveillance against non‐self‐cells. NK cell recognition of “self” relies on the surface expression on autologous cells of MHC class I (MHC‐I) molecules. Either the absence or the down‐modulation of MHC‐I on target cells “license” NK cells to kill threatening tumor‐transformed or virally infected cells. This phenomenon is controlled by a limited repertoire of activating and inhibitory NK receptors (aNKRs and iNKRs) that tunes NK cell activation and effector functions. Hence, the calibration of NK cell alloreactivity depends on the ability of iNKRs to bind MHC‐I complex and these interactions are key in regulating both NK cell differentiation and effector functions. Indeed, the presence of iNKRs specific for self‐MHC haplotypes (i) plays a role in the “licensing/education” process that controls the responsiveness of mature NK cells and prevents their activation against the “self” and (ii) is exploited by tumor cells to escape from NK cell cytotoxicity. Herein, we review our current knowledge on function and clinical application of NKG2A, a C‐type lectin iNKR that binds specific haplotypes of human leukocyte antigens early during the NK cell maturation process, thus contributing to modulate the terminal maturation of NK cells as potent effectors against cancers cells. These NKG2A‐mediated mechanisms are currently being exploited for developing promising immune‐therapeutic strategies to improve the prognosis of solid and blood tumors and to ameliorate the clinical outcome of patients undergone allogeneic hematopoietic stem cell transplantation to treat high‐risk hematologic malignancies.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Merck And The Future of Immuno-Oncology: A Chat With Roger Perlmutter

Merck And The Future of Immuno-Oncology: A Chat With Roger Perlmutter | Cancer Immunotherapy Review and Collection | Scoop.it
Cancer immunotherapy is, in a word, tantalizing. It might save the life of someone at death’s door and keep the cancer at bay for years.Or it might not...
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Regulatory T cells mediate specific suppression by depleting peptide–MHC class II from dendritic cells

Regulatory T cells mediate specific suppression by depleting peptide–MHC class II from dendritic cells | Cancer Immunotherapy Review and Collection | Scoop.it
Regulatory T cells suppress target cells through diverse mechanisms. Shevach and colleagues demonstrate that regulatory T cells in vivo strip complexes of cognate peptide and major histocompatibility complex class II from dendritic cells and thereby help to maintain immune homeostasis.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Use of a Single CAR T Cell and Several Bispecific Adapters Facilitates Eradication of Multiple Antigenically Different Solid Tumors

Use of a Single CAR T Cell and Several Bispecific Adapters Facilitates Eradication of Multiple Antigenically Different Solid Tumors | Cancer Immunotherapy Review and Collection | Scoop.it
Most solid tumors are comprised of multiple clones that express orthogonal antigens, suggesting that novel strategies must be developed in order to adapt chimeric antigen receptor (CAR) T-cell therapies to treat heterogeneous solid tumors.
more...
No comment yet.
Rescooped by Krishan Maggon from Immunology and Biotherapies
Scoop.it!

Frontiers | Expanding the Therapeutic Window for CAR T Cell Therapy in Solid Tumors: The Knowns and Unknowns of CAR T Cell Biology | Immunology

Frontiers | Expanding the Therapeutic Window for CAR T Cell Therapy in Solid Tumors: The Knowns and Unknowns of CAR T Cell Biology | Immunology | Cancer Immunotherapy Review and Collection | Scoop.it
A major obstacle for chimeric antigen receptor (CAR) T cell therapy in solid tumors is the lack of truly tumor-specific target antigens, which translates to the targeting of tumor-associated antigens (TAAs) overexpressed on tumors but shared with normal organs, raising safety concerns. In addition, expression of TAAs in solid tumors is particularly heterogeneous. In this regard, it is critical to deeply understand the sensitivity of CAR T cells, especially against low-density targets and the possible therapeutic window of antigen density targeted by CAR T cells. In this review, we discuss the recent findings of mechanisms of antigen recognition through CAR, including immunological synapse formation, and the impact of target antigen density for induction of distinct T cell functions. We also discuss rational strategies to adjust and expand the therapeutic window for effective and safe targeting of solid tumors by CAR T cell platforms.

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

The Emergence of Natural Killer Cells as a Major Target in Cancer Immunotherapy

The Emergence of Natural Killer Cells as a Major Target in Cancer Immunotherapy | Cancer Immunotherapy Review and Collection | Scoop.it
NK cells possess the innate ability to detect transformed cells, and thus, are key to cancer immunosurveillance and antitumor immunity, particularly in hematological cancers and the control of metastatic dissemination.
Immune checkpoint inhibitors that function by enhancing cytotoxic immune responses of tumor-infiltrating lymphocytes have revolutionized the cancer therapy landscape.
Seminal discoveries in NK cell biology have culminated in recent breakthroughs with the identification of potent ‘checkpoints’ for NK cell activation, several of which may be shared with T cells.
Given the ability of NK cells to detect and destroy a range of cancerous tissues, mechanistic insight into how cancer cells regulate NK cell checkpoints and the pharmacological modulation of these checkpoints represents an unmet need for immunotherapy development.
Immune ‘checkpoint’ inhibitors can increase the activity
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Neoantigen Directed T-Cell Therapies – Adaptive Biotechnologies

Neoantigen Directed T-Cell Therapies – Adaptive Biotechnologies | Cancer Immunotherapy Review and Collection | Scoop.it
Adaptive has partnered* with Genentech, a member of the Roche Group, to develop, manufacture, and commercialize novel neoantigen directed T-cell therapies for the treatment of a broad range of cancers. We are building a transformational new treatment paradigm to tailor cellular therapy for each patient’s individual cancer. In this partnership, Adaptive will screen and identify in real-time the best T-cell receptors (TCRs) targeting a patient’s specific neoantigens. Genentech will use these patient-specific TCRs to engineer and manufacture a personalized cellular medicine and deliver it to each patient. The goal is to harness the vast majority of therapeutically relevant, patient-specific neoantigens and advance the next generation of cellular therapies in oncology. The collaboration will also support the clinical development of “off-the-shelf” TCR-based cellular therapies, where Adaptive will use its investigational TruTCR platform to screen and identify TCRs against shared cancer antigens from blood of healthy donors. Genentech will use these TCRs to develop and manufacture “off-the shelf” cell therapy products.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

A Race Well Underway: CAR-Ts Overtake ASH – OBR

A Race Well Underway: CAR-Ts Overtake ASH – OBR | Cancer Immunotherapy Review and Collection | Scoop.it
January 2019 Edition Vol.11, Issue 1 A Race Well Underway: CAR-Ts Overtake ASH By Neil Canavan To cover a lot of ground quickly, you need a car. To spill a lot of ink quickly, cover just a fraction of the CAR-T cell presentations at ASH 2018. To that end, and discussed herein, there is: longer-term follow-up data for chimeric antigen receptor (CAR) T cell products currently approved; approaches to optimize patient care and access to CARs; tweaks to optimize CAR-T cell efficacy with combinations and genetic tweaks to the CARs themselves; and the potential for universal adoptive cell therapy. ELIANA Trial: Longer-term, follow-up pediatric patients with relapse/refractory ALL In brief, the ELIANA study looked at pediatric patients with relapse/refractory (R/R) ALL treated with tisagenlecleucel (Kymriah, N=79). The data presented at ASH 2018 by Stephan Grupp, University of Pennsylvania, were an update to the registration trial and represented an additional 11 months of follow-up from previous reports. Investigators wanted to see how patients who initially responded were doing over time. Turns out, they are doing well—of the 82% of critically ill patients that went into remission initially, 66% remain in complete remission at 12 and 18 months. “That longer-term follow up indicates that there are groups of patients for whom this therapy has the potential for long term disease control,” said Grupp. Further, overall survival at 18 months for all infused patients was 70% – which is an extraordinary finding for patients who had months, or even weeks to live at study entry (Figure 1).   JULIET Trial Update: Diffuse large B-cell lymphoma Richard Maziarz, Oregon Health & Science Knight Cancer Institute, Portland, gave an update on the phase II JULIET investigation. First reported at ASH 2017, the data represent a median follow-up of 19 months. “The reason this is important is … as you move into 19 months, now you are looking at the natural history of this disease.” JULIET focused on adult patients with R/R DLBCL. Primary endpoints were overall response rate (ORR), complete response (CR), partial response (PR), and as a secondary endpoint, overall survival (OS). The ORR for JULIET was initially 54% for the entire cohort (this was a single arm study), with 40% of patients achieving CR. The update had more of the same, but “54% of patients who had a PR converted to CR, so the drug continues to work over time,” said Maziarz. This encouraging phenomenon is the exact opposite of how chemo or targeted cancer therapy works. For all patients, regardless of response, the OS was 11.1 months. More impressively though, the median OS for patients in CR has yet to be reached (Figure 2).   Regarding safety, the incidence of cytokine release syndrome (CRS)—a hallmark of CAR-T therapy—was less in this disease setting than in ALL. “This is the beginning of the end,” said Maziarz, meaning—it works—genetically engineered T cells, a living drug, works. “What we are doing now is investigating ways we can build on the first-generation T cell therapies.” CAR Tune Ups There are three distinct ways of improving on CAR-T therapy: expanding access/efficacy through patient selection; adding other drugs to work in combination with CARs; and expanding on the original CAR-T cell design. Rawan Faramand, a clinician at Moffitt Cancer Center, where a new service has been established to treat CAR-T patients, observed in her small study of patients receiving Yescarta that certain point of care cytokine measures could predict the onset of CAR-T-related adverse events and that those events precipitated poorer outcomes (N=20). Biomarkers of note included elevated levels of IL-6, and ANG1/2 ratios at day one that indicate the potential for severe CRS, and potentiate early intervention in these patients. To expand the pool of CAR-T patients who are eligible to be treated, Dahlia Sano, of MD Anderson Cancer Center looked at elderly R/R DLBCL patients (>65) being treated with Yescarta. Sano found the same response rates in the elderly as those seen in younger patients, and this, with roughly the same side effect profile. Sano concluded, “I hope this increases access in a population with a high unmet need.” Add Ons: Ibrutinib; Checkpoints While there are over a thousand trials planned, or already initiated using checkpoint inhibitors in combination, combinations with CARs are just now underway. One of the more promising add-ons seems to be the immune-modulating drug, ibrutinib, currently approved for CLL, as well as several types of lymphoma. Jordan Gauthier, of the Fred Hutchinson Cancer Center, Seattle, reported on the use of ibrutinib in combination with JCAR014, yet another CD19 targeted CAR-T product. JCAR014 had already scored some points in the CLL setting, but there was plenty of room for improvement, according to Gauthier, thus, the addition of ibrutinib. Previous work suggested that ibrutinib may prevent rapid tumor progression (giving CARs time to work); it mobilizes CLL cells from the lymph nodes into the blood (allowing CARs to more easily find them) and it decreases CAR toxicity by perhaps chipping away at some of the tumor burden before CARs fully engage. This retrospective analysis looked at two cohorts of CLL CAR-T patients; one group had no concurrent ibrutinib administration (n=23), the other did (n=18). The response rate in the concurrent cohort was 83% vs 65% for those who received CARs without ibrutinib. Further, no patient developed a severe form of cytokine release in the concurrent ibrutinib group vs 25% for the comparator. Next, these data will seek validation in the prospective, TRANSCEND-CLL trial, currently enrolling. Checkpoint Please This next observation grew out of follow-on work by Shannon Maude, et al, at Children’s Hospital of Philadelphia, as she attempted to rescue Kymriah-treated, pediatric ALL patients who showed early signs of CAR-T loss, or lack of response. “Our hypothesis was that T cells upon activation may become exhausted through activation of checkpoint pathways,” said Maude. Solution: try a checkpoint inhibitor. It was a partial success. For patients who had partial, or no response to CAR-Ts, the treatment was ineffective. In the setting of poor CAR-T persistence, three out of six patients responded. “We saw that some patients who were reinfused with a CAR-T cell product followed by infusion with anti-PD1 had a return of B cell aplasia (a sign of CD19 CAR-T activity), and had sustained CRs— showing continued persistence of their CAR T cells.” Importantly, the added drug did not significantly add to toxicity. To be sure, while these findings are important, “Larger studies are needed to determine if there is a major role for checkpoint inhibitors in this setting.” Next Year’s Models To address the issue of T cell exhaustion, and by extension, CAR-T toxicity, the laboratory of Michel Sadelain, at Memorial Sloan Kettering, NY, NY has developed a CD19 CAR with surface expression of the immune stimulator, 4-1BB. The idea being that by expressing 4-1BB ligand on the surface of the CAR-T it can engage not only the modified CAR-T cells but can also engage the endogenous unmodified T cells of the patients to produce a higher immune response against cancer cells, explained by Jae Park, of MSKCC. This tweak was tested in a first-in-human, dose-ranging trial in a cohort of patients with R/R NHL, and CLL, reported here with a follow-up of 4.8 months (N=29). Of the proposed range of doses, “We hypothesized that the cells would to be more potent (than first-generation CARs), and so perhaps we could use fewer T cells to generate similar, if not superior tumor efficacy, as well as reduced safety profile because we’re using a lesser dose.” Results suggest that this is indeed the case. The optimum dose identified was 3 million cells/kg as opposed to 30 million cells/kg for approved CAR-Ts. Responses in DLBCL at this dose level were 78% (CLL patients responded at a 20% rate, but this was at the lower CAR dose). “In DLBCL patients, most of the CARs were durable,” said Park, “and five out of seven remain in CR, with the longest on-going response of about one year.” Of note, and quite possibly due to the fewer cells used, there was no severe CRS observed, and no grade 4 neurotoxicity. Dual Targeting To address the issue of CD19 antigen escape – the mechanism by which tumor cells can evade the CD 19 CAR, a CD19/CD22 dual targeting CAR is now on the road. “In the ELIANA trial there was a promising 81% overall response rate at month three,” said Nasheed Hossain, of Loyola University, Chicago. “But the 12 month event-free survival is 50%.” Of those who relapsed, 15 of 16 patients no longer express CD19. (Antigen loss occurs in DLBCL as well.) The new CD19/CD22 CAR was taken for a phase I test drive in adults with R/R B cell malignancies (N=9). Results showed no serious drug-related toxicities, and no dose-limiting toxicities. As for observed efficacy, there was a 60% response rate in DLBCL patients at three months, with one ongoing CR. Of two evaluable ALL patients, there was one CR and one PR at day 28. An expansion cohort at dose level 2 (3×106/kg) is planned for Q1 2019. FATE Finally, CARs are super expensive, and that’s a problem. The most high-tech way to bring prices down would be to have off-the-shelf, allogeneic CAR-T cell products. Several companies are chasing this grail, such as Allogene, Cellectis, Servier, but their approach is to engineer mature donor cells, which is problematic. As FATE would have it, the easiest workaround to avoid potential immunogenicity from donor cells is to engineer cells from the get-go, use induced pluripotent stem cells (iPSCs) that can be manipulated at the single cell level, and then expanded. FATE’s initial foray into iPSCs produced NK cells, a cell that bridges the innate and adaptive immune systems and is capable of detecting cancer. The development program for their most advanced NK product is FT500—an allogeneic off-the-shelf NK cell cancer immunotherapy derived from a clonal master iPSC line. For this investigation, FT500 will be combined with anti-PD1s in a basket trial of solid tumors. FATE is currently working with CAR-T pioneer, Michel Sadelain, to develop a line of allogenic, off-the-shelf, CAR-T cells and Wall Street loves it. As of the FDA announcement, FATE, for the first time in company history, achieved a market cap of $1 billion.
more...
No comment yet.