Cancer Immunotherapy Review
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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 | 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.

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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 | Scoop.it
FDA has approved Yervoy (ipilimumab, BMS) under REMS for the treatment of metastatic melanoma. The European expert panel CHMP...
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rosywills's comment, September 22, 2017 4:07 AM
Cancer Immunotherapy Market is expected to reach USD 119.39 Billion by 2021
Download Free Brochure @ http://bit.ly/2cHlrFH
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A bad influence—the interplay between tumor cells and immune cells

A bad influence—the interplay between tumor cells and immune cells | Cancer Immunotherapy Review | Scoop.it
Research at Huntsman Cancer Institute (HCI) at the University of Utah (U of U) yielded new insights into the environment surrounding different types of lung tumors, and described how these complex cell ecosystems may in turn ...
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Therapeutic Immune Modulation against Solid Cancers with Intratumoral Poly-ICLC: A Pilot Trial

Therapeutic Immune Modulation against Solid Cancers with Intratumoral Poly-ICLC: A Pilot Trial | Cancer Immunotherapy Review | Scoop.it
Purpose: Polyinosinic-polycytidylic acid-poly-l-lysine carboxymethylcellulose (poly-ICLC), a synthetic double-stranded RNA complex, is a ligand for toll-like receptor-3 and MDA-5 that can activate immune cells, such as dendritic cells, and trigger natural killer cells to kill tumor cells.
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Nivolumab Misses OS Endpoint in SCLC Study

Nivolumab Misses OS Endpoint in SCLC Study | Cancer Immunotherapy Review | Scoop.it
Single-agent nivolumab (Opdivo) did not improve overall survival compared with standard topotecan or amrubicin, where approved, in patients with small cell lung cancer who relapsed following platinum-based chemotherapy. ...
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Decreased RORC expression and downstream signaling in HTLV‐1‐associated Adult T‐cell Lymphoma/Leukemia uncovers an antiproliferative IL17 link: a potential target for immunotherapy? - Subramanian -...

Decreased RORC expression and downstream signaling in HTLV‐1‐associated Adult T‐cell Lymphoma/Leukemia uncovers an antiproliferative IL17 link: a potential target for immunotherapy? - Subramanian -... | Cancer Immunotherapy Review | Scoop.it
Retinoic acid‐related drugs have shown promising pre‐clinical activity in Adult T‐cell Leukemia/Lymphoma, but RORC signaling has not been explored. Therefore, we investigated transcriptome‐wide interactions of the RORC pathway in HTLV‐1 and ATL, using our own and publicly available gene expression data for ATL and other leukemias. Gene expression data from ATL patients were analyzed using WGCNA to determine gene modules and their correlation to clinical and molecular data. Both PBMCs and CD4+ T‐cells showed decreased RORC expression in four different ATL cohorts. A small subset of RORChi ATL patients was identified with significantly lower pathognomonic CADM1 and HBZ levels but similar levels of other ATL markers (CD4/CD25/CCR4), hinting at a less aggressive ATL subtype. An age‐dependent decrease in RORC expression was found in HTLV‐1‐infected individuals, but not in healthy controls, suggesting an early molecular event predisposing to leukemogenesis. Genes upstream of RORC signaling were members of a proliferative gene module (containing proliferation markers PCNA/Ki67), whereas downstream members clustered in an anti‐proliferative gene module. IL17C transcripts showed the strongest negative correlation to PCNA in both ATL cohorts, which was replicated in two large cohorts of T‐ and B‐cell acute lymphoid leukemia (ALL). Finally, IL17C expression in purified CD4+CCR4+CD26‐CD7‐ ‘ATL‐like' cells from HTLV‐1‐infected individuals and ATL patients was negatively correlated with clonality, underscoring a possible antileukemic/antiproliferative role. In conclusion, decreased RORC expression and downstream signaling might represent an early event in ATL pathogenesis. An antiproliferative IL17C/PCNA link is shared between ATL, T‐ALL and B‐ALL, suggesting (immuno)therapeutic benefit of boosting RORC/IL17 signaling. This article is protected by copyright. All rights reserved
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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 | 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.
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Thermo Fisher Scientific :: Adaptimmune

Thermo Fisher Scientific :: Adaptimmune | Cancer Immunotherapy Review | Scoop.it
Adaptimmune’s affinity enhanced SPEAR T-cell therapeutic candidates are novel cancer immunotherapies that have been engineered to target and destroy cancer cells by strengthening a patient’s natural T-cell response. T-cells are a type of white blood cell that play a central role in a person’s immune response. Adaptimmune’s goal is to harness the power of the T-cell and, through its multiple therapeutic candidates, significantly impact cancer treatment and clinical outcomes of patients with solid and hematologic cancers. The CTS Dynabeads CD3/CD28 play a key role in the activation of Adaptimmune SPEAR T-cells during manufacture. Dynabeads – a key reagent for autologous T-cell manufacture CTS Dynabeads CD3/CD28 are magnetic beads used by Adaptimmune for ex vivo isolation, activation, and expansion of human T-cells. By combining anti-CD3 and anti-CD28 antibodies on the Dynabeads, the beads provide both the primary and secondary co-stimulatory signals that are required for activation and expansion of T-cells. The SPEAR T-cell manufacturing process consists of: isolating T-cells from the blood of cancer patients; transferring affinity enhanced TCRs, which have been modified to recognize cancer cells, into the cells (SPEAR T-cells); activating and expanding the SPEAR T-cells; and, introducing the affinity enhanced cells back into the patient to enable the patient's immune system to respond and attack cancer. Important steps of this manufacturing process include isolation of the T-cells from patient material and subsequent activation and expansion of the T-cells prior to re-infusion. CTS Dynabeads CD3/CD28 are integral to this process and key to the production of active, persistent T-cells. “Dynabeads have unique properties compared to other means of activation and expansion, which we believe make them the optimal approach for manufacturing our affinity enhanced T-cell therapies. These include triggering the T-cells to expand in a natural and controlled manner to generate younger and healthier T-cells and leading to prolonged persistence of therapeutic cells in the blood. These and other attributes are requirements for successful manufacture of T-cell therapeutics.” Gwen Binder, Chief Technology Officer, Adaptimmune Adaptimmune has an exclusive license to this technology for its SPEAR T-cell therapies In 2012 and 2013, Adaptimmune secured exclusive licenses and supply agreements from Life Technologies Corporation (acquired in 2014 by Thermo Fisher Scientific Inc., NYSE: TMO) under certain intellectual property rights covering methods of expanding and activating T cells transduced with engineered T-cell receptors (TCR) in the fields of treating cancer, infectious diseases and autoimmune disease. Commercial Development and Supply Agreement In 2016, Adaptimmune signed a further agreement with Life Technologies Corporation. This new commercial development and supply 10-year agreement augments Adaptimmune’s exclusive license and supply relationship with Thermo Fisher for the Dynabeads CTS for use in the manufacture of Adaptimmune’s SPEAR T-cell therapies. “Thermo Fisher Scientific’s market-leading cell therapy workflow solutions are enabling its customers to address the unique commercialization challenges of this market. Our collaboration with Adaptimmune demonstrates our sustained commitment to significantly advance the development and commercial use of this technology for treating solid tumors as well as other conditions that threaten human health.” Oystein Aamellem, Director of Cellular Medicine, Thermo Fisher CTS DynaMag Electron micrograph shows Dynabeads binding directly to CD3 positive cells (T-cells)
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Tumor-associated Macrophage-derived Interleukin-23 Interlinks Kidney Cancer Glutamine Addiction with Immune Evasion

Tumor-associated Macrophage-derived Interleukin-23 Interlinks Kidney Cancer Glutamine Addiction with Immune Evasion | Cancer Immunotherapy Review | Scoop.it
We found that clear cell renal cell carcinoma (ccRCC) tumor cell-intrinsic glutamine
metabolism enhances the immunosuppressive function of Treg cells through macrophage-derived
interleukin (IL)-23. Patients with a high intratumoral IL-23 level had significantly
worse survival.
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Killer cell immunotherapy offers potential cure for advanced pancreatic cancer | EurekAlert! Science News

Killer cell immunotherapy offers potential cure for advanced pancreatic cancer | EurekAlert! Science News | Cancer Immunotherapy Review | Scoop.it
A new approach to treating pancreatic cancer using 'educated killer cells' has shown promise, according to early research by Queen Mary University of London.
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Omar Castro's curator insight, October 14, 11:11 PM
Reputation-The reputation of the article and where it comes from is a "claimed global source for science", the article itself comes from a university in London Queen Mary. 

Ability to see- This article has the ability to see due to the fact the University has documented its research and explains the capabilities the uses for the research
  
Vested interest- The article doesn't have a particular vested interest in explaining its research.

Expertise - When it comes to expertise the article covered are from scientist looking for a new approach in a University. 

Neutrality- This article leans toward the more optimistic view of the study instead of an analytical approach. So far this article from what is written is very hopeful in making this approach come to fruition.
 
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CAR-T/CAR-NK Cells Generation Service - Creative Biogene

Creative Biogene provides services for generation of CAR-T/CAR-NK cells that can target different tumor antigens that are highly over-expressed in tumors based on Lentiviral vector....
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European Commission approves Imfinzi (durvalumab, Astra Zeneca) for locally-advanced, unresectable NSCLC

European Commission approves Imfinzi (durvalumab, Astra Zeneca) for locally-advanced, unresectable NSCLC | Cancer Immunotherapy Review | Scoop.it

AstraZeneca and MedImmune, its global biologics research and development arm, today announced that the European Commission has granted marketing authorisation for Imfinzi (durvalumab) as monotherapy for the treatment of locally-advanced, unresectable non-small cell lung cancer (NSCLC) in adults whose tumours express PD-L1 on ≥1% of tumour cells and whose disease has not progressed following platinum-based chemotherapy and radiation therapy (CRT). The approval is based on results from the Phase III PACIFIC trial.

 

Phase III PACIFIC trial demonstrated compelling overall survival benefit and progression-free survival of more than 11 months

Imfinzi is the only immunotherapy medicine approved for the treatment of locally-advanced, unresectable NSCLC

 

 

Krishan Maggon 's insight:

About Imfinzi

Imfinzi (durvalumab) is a human monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80, countering the tumour's immune-evading tactics and releasing the inhibition of immune responses.

Imfinzi is approved for unresectable, Stage III NSCLC in the US, Canada, Switzerland, India, Japan, and Brazil based on the Phase III PACIFIC trial. Imfinzi is also approved for the treatment of patients with locally-advanced or metastatic urothelial carcinoma in the US, Canada, Brazil, Israel, Hong Kong, and India.

As part of a broad development programme, Imfinzi is also being tested as a monotherapy and in combination with chemotherapy, radiation therapy, small molecules, and tremelimumab, an anti-CTLA4 monoclonal antibody, as a first or second-line treatment for patients with NSCLC, small-cell lung cancer, locally-advanced or metastatic urothelial carcinoma, head and neck cancer and other solid tumours.

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Nobel Prizes Bring Out the Best and Worst in Pharma

Nobel Prizes Bring Out the Best and Worst in Pharma | Cancer Immunotherapy Review | Scoop.it
Drugmakers help turn scientific breakthroughs into life-saving medicines, but not without costs.

 

There are six marketed drugs in the most successful class of immune-boosting cancer drugs that have emerged from Allison and Honjo’s research. There are many more copycats in development, and firms are working hard to extend the use of these medicines into new populations.

 

Keytruda and its peers already have list prices of more than $150,000 a year, and combos will substantially boost that price tag — particularly in the U.S., where there’s little pricing pressure on cancer drugs. If combos become widespread, health-care budgets will buckle. 

 

As for Humira, it’s part of a much more mature market. The problem is, the drug won’t age gracefully. The medicine was approved to treat rheumatoid arthritis in 2002, but has since seen its use expand to many other conditions. AbbVie has a clear incentive to protect its $20 billion-a-year behemoth, and has surrounded the drug with an impenetrable thicket of patents. As a result, it isn’t likely to face serious generic competition in the U.S. until at least 2022, two decades after its initial approval. In other words, the cost to the health system of AbbVie’s continued exclusive rights to the medicine is in the tens of billions of dollars.

Krishan Maggon 's insight:

The sales of the 6 immunotherapy approved drugs (CTLA4 and PD1/PDL1 inhibitors) are expected to reach $15 billion in 2018 and 25 billion by 2021.

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Pembrolizumab plus Chemotherapy for Squamous Non–Small-Cell Lung Cancer | NEJM

Pembrolizumab plus Chemotherapy for Squamous Non–Small-Cell Lung Cancer | NEJM | Cancer Immunotherapy Review | Scoop.it
In patients with previously untreated metastatic, squamous NSCLC, the addition of pembrolizumab to chemotherapy with carboplatin plus paclitaxel or nab-paclitaxel resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by Merck Sharp & Dohme; KEYNOTE-407 ClinicalTrials.gov number, NCT02775435.)
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Expression of combinatorial immunoglobulins in macrophages in the tumor microenvironment

Expression of combinatorial immunoglobulins in macrophages in the tumor microenvironment | Cancer Immunotherapy Review | Scoop.it
Recent evidence indicates the presence of macrophage subpopulations that express the TCRαβ in chronic inflammatory diseases such as tuberculosis and atherosclerosis and in the tumor microenvironment. Here, we demonstrate that a second subpopulation of macrophages expresses rearranged heavy and...
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Lin − CCR2 + hematopoietic stem and progenitor cells overcome resistance to PD-1 blockade

Lin − CCR2 + hematopoietic stem and progenitor cells overcome resistance to PD-1 blockade | Cancer Immunotherapy Review | Scoop.it
Brain tumors are difficult to treat using existing immunotherapeutic strategies. Here, the authors show that in brain tumors resistant to PD-1 blockade, HSCs expressing CCR2+ can reverse treatment resistance and sensitizes mice to immunotherapy.
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Noxxon Cancer immunotherapy R&D

Noxxon Cancer immunotherapy R&D | Cancer Immunotherapy Review | Scoop.it
Technology


NOXXON's proprietary technology generates compounds we refer to as Spiegelmers*, which are a new class of therapeutics designed to combine the benefits of small chemical molecules and biologicals.

NOXXON's proprietary technology offers a set of significant advantages over existing drug classes:

High affinity and specificity for targets with demonstrated activity on chemokines in clinical trials
Can be manufactured chemically and do not require complex biological production processes
High bio-stability and immunologically passive
Good safety and tolerability profile based on results from more than 10 trials in over 300 human subjects
Spiegelmers use Mirror-image (L-stereoisomer) chemistry to build injectable oligonucleotide (RNA or DNA) therapeutics that directly bind and neutralize protein targets in the extracellular space.
Krishan Maggon 's insight:

NOXXON’s oncology-focused pipeline acts on the cancer immunity cycle by breaking the tumor protection barrier, blocking tumor repair and exposing hidden tumor cells. Through neutralizing chemokines in the tumor micro-environment, NOXXON’s approach works in combination with other forms of treatment to weaken tumor defenses against the immune system and enable greater therapeutic impact. Building on extensive clinical experience and safety data, lead program NOX-A12 will deliver top-line data from a combination trial with the immuno-oncology checkpoint inhibitor, Keytruda®, in metastatic colorectal and pancreatic cancer patients in 2018.

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Pan-tumor genomic biomarkers for PD-1 checkpoint blockade–based immunotherapy

Pan-tumor genomic biomarkers for PD-1 checkpoint blockade–based immunotherapy | Cancer Immunotherapy Review | Scoop.it
Clinical trial data can provide a wealth of information about how drugs work. Yet such information often belongs to pharmaceutical companies and is rarely accessible to the scientific community at large. Cristescu et al. provide exploratory analysis of a cancer genomics dataset, collected from four separate clinical trials of Merck's PD-1 immunotherapy drug, pembrolizumab. This informative public resource examines more than 300 patient samples representing 22 different tumor types. Two widely used signatures that currently predict immunotherapy response are tumor mutational burden and a “hot” T cell–inflamed microenvironment. The study analyzed these two proposed biomarkers in combination to see what predictive clinical utility they may hold.

Science , this issue p. [eaar3593][1]

### INTRODUCTION

Immunotherapy targeting the programmed cell death protein–1 (PD-1) axis elicits durable antitumor responses in multiple cancer types. However, clinical responses vary, and biomarkers predictive of response may help to identify patients who will derive the greatest therapeutic benefit. Clinically validated biomarkers predictive of response to the anti–PD-1 monoclonal antibody pembrolizumab include PD-1 ligand 1 (PD-L1) expression in specific cancers and high microsatellite instability (MSI-H) regardless of tumor type. Tumor mutational burden (TMB) and T cell–inflamed gene expression profile (GEP) are emerging predictive biomarkers for pembrolizumab. Both PD-L1 and GEP are inflammatory biomarkers indicative of a T cell–inflamed tumor microenvironment (TME), whereas TMB and MSI-H are indirect measures of tumor antigenicity generated by somatic tumor mutations. However, the relationship between these two categories of biomarkers is not well characterized.

### RATIONALE

This study assessed the potential for TMB and a T cell–inflamed GEP to jointly predict clinical response to pembrolizumab in >300 patient samples with advanced solid tumors and melanoma across 22 tumor types from four KEYNOTE clinical trials. To assess the individual and joint clinical utility of TMB and GEP, patients were stratified in four biomarker-defined clinical response groups [GEP low and TMB low (GEPlo TMBlo), GEP low and TMB high (GEPlo TMBhi), GEPhi TMBlo, and GEPhi TMBhi] based on predefined cutoffs for TMB and GEP. These patient-defined biomarker groups were further used to guide transcriptome and exome analyses of tumors in a large molecular database \[The Cancer Genome Atlas (TCGA)\] ( n = 6384 tumors) to identify targetable patterns of biology that may modulate response and resistance.

### RESULTS

TMB and GEP exhibited only modest correlation and were independently predictive of response across the KEYNOTE clinical datasets. We found that objective response rates were strongest in patients with GEPhi TMBhi (37 to 57%), moderate in those with GEPhi TMBlo (12 to 35%) and GEPlo TMBhi (11 to 42%), and reduced or absent in those with GEPlo TMBlo (0 to 9%) (see the figure). Additionally, longer progression-free survival times were seen in patients with higher levels of both TMB and GEP. Findings were comparable when TMB and PD-L1 expression were jointly assessed. Within TCGA database, GEP and TMB again had a low correlation, demonstrating the potential to jointly stratify transcriptomic and genomic features across cancer types. Specific gene expression patterns reflective of TME biology showed significant associations with TMB, GEP, or both. In particular, gene set enrichment analysis identified proliferative and stromal, myeloid, and vascular biology corresponding to specific TMB-defined subgroups within GEPhi tumors. In TMBhi tumors, indication-dependent somatic DNA alterations in key cancer driver genes showed a strong negative association with GEP.

### CONCLUSION

This analysis shows that TMB and inflammatory biomarkers (T cell–inflamed GEP and PD-L1 expression) can jointly stratify human cancers into groups with different clinical responses to pembrolizumab monotherapy and identify patterns of underlying, targetable biology related to these groups. TMB and inflammatory biomarkers independently predict response and may capture distinct features of neoantigenicity and T cell activation, respectively. This approach may provide a precision medicine framework for rationally constructing and evaluating anti–PD-1– and/or –PD-L1–based combination therapy regimens.

![Figure][2]

Biomarker-defined responses to pembrolizumab monotherapy identify targetable-resistance biology.
( A ) Tumors have low TMB and low neoantigenicity and lack a T cell–inflamed TME. ( B ) Tumors can evade the immune response despite high TMB and high neoantigenicity. ( C ) Although T cells are present, stromal and/or endothelial factors in the TME, low TMB, and low neoantigenicity impede their activity. ( D ) Tumors have high TMB, high neoantigenicity, and a T cell–inflamed TME, typified by activated T cells and other immune cells with cytolytic roles.



Programmed cell death protein–1 (PD-1) and programmed cell death ligand–1 (PD-L1) checkpoint blockade immunotherapy elicits durable antitumor effects in multiple cancers, yet not all patients respond. We report the evaluation of >300 patient samples across 22 tumor types from four KEYNOTE clinical trials. Tumor mutational burden (TMB) and a T cell–inflamed gene expression profile (GEP) exhibited joint predictive utility in identifying responders and nonresponders to the PD-1 antibody pembrolizumab. TMB and GEP were independently predictive of response and demonstrated low correlation, suggesting that they capture distinct features of neoantigenicity and T cell activation. Analysis of The Cancer Genome Atlas database showed TMB and GEP to have a low correlation, and analysis by joint stratification revealed biomarker-defined patterns of targetable-resistance biology. These biomarkers may have utility in clinical trial design by guiding rational selection of anti–PD-1 monotherapy and combination immunotherapy regimens.

[1]: /lookup/doi/10.1126/science.aar3593
[2]: pending:yes
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Checkpoint inhibitors in patients with metastatic renal cell carcinoma: Results from the international metastatic renal cell carcinoma database consortium - Yip - - Cancer - Wiley Online Library

Checkpoint inhibitors in patients with metastatic renal cell carcinoma: Results from the international metastatic renal cell carcinoma database consortium - Yip - - Cancer - Wiley Online Library | Cancer Immunotherapy Review | Scoop.it
BACKGROUND To the authors' knowledge, outcomes and prognostic tools have yet to be clearly defined in patients with metastatic renal cell carcinoma (mRCC) who are treated with immuno‐oncology (IO) checkpoint inhibitors (programmed death‐ligand 1 [PD‐L1] inhibitors). In the current study, the authors aimed to establish IO efficacy benchmarks in patients with mRCC and update patient outcomes in each International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic class. METHODS A retrospective analysis was performed using the IMDC database with data from 38 centers. It included patients with mRCC who were treated with ≥1 line of IO. Overall response rates (ORRs), duration of treatment (DOT), and overall survival (OS) were calculated. Patients were stratified using IMDC prognostic factors. RESULTS A total of 687 patients (90% with clear cell and 10% with non‐clear cell) were included. The ORR was 27% in evaluable patients (461 patients). In patients treated with first‐line nivolumab and ipilimumab (49 patients), the combination of PD‐L1 inhibitor and vascular endothelial growth factor inhibitor (72 patients), and PD‐L1 inhibitor (51 patients), the ORR was 31%, 39%, and 40%, respectively, and the median DOT was 8.3 months, 14.7 months, and 8.3 months, respectively. The ORR for second‐line, third‐line, and fourth‐line nivolumab was 22%, 24%, and 26%, respectively. The median DOT was 5.7 months, 6.2 months, and 8.3 months, respectively, in the second‐line, third‐line, and fourth‐line settings. When segregated into IMDC favorable‐risk, intermediate‐risk, and poor‐risk groups, the median OS rates for the first‐line, second‐line, third‐line, and fourth‐line treatment settings were not reached (NR), NR, and NR, respectively (P = .163); NR, 26.7 months, and 7.4 months, respectively (P < 0. 0001); 36.1 months, 28.2 months, and 11.1 months, respectively (P = .016); and NR, NR, and 6.7 months, respectively (P = .047). CONCLUSIONS The ORR was not found to deteriorate from the first‐line to the fourth‐line of IO therapy. In the second line through fourth line, the IMDC criteria appropriately stratified patients into favorable‐risk, intermediate‐risk, and poor‐risk groups for OS.
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CAR T-cells for T-cell malignancies: challenges in distinguishing between therapeutic, normal, and neoplastic T-cells

CAR T-cells for T-cell malignancies: challenges in distinguishing between therapeutic, normal, and neoplastic T-cells | Cancer Immunotherapy Review | Scoop.it
Abstract
Chimeric antigen receptor (CAR) T-cells targeting CD19 demonstrated remarkable efficacy for the treatment of B-cell malignancies. The development of CAR T-cells against T-cell malignancies appears more challenging due to the similarities between the therapeutic, normal and malignant T-cells. The obstacles include CAR T-cell fratricide, T-cell aplasia, and contamination of CAR T-cell products with malignant T-cells. Here, we review these challenges and propose solutions to overcome these limitations.
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Allogene Therapeutics allogeneic CAR T cell therapies nets $288 million in IPO

Allogene Therapeutics allogeneic CAR T cell therapies nets $288 million in IPO | Cancer Immunotherapy Review | Scoop.it

 

Allogene Therapeutics has raised $288 million in an IPO, marking one of the biggest stock market debuts for a biotech this year.

 

Allogene is attempting to overcome the limitations of autologous CAR T therapies by creating allogeneic CAR T cell therapies, or AlloCARs™. Unlike autologous cell therapy, allogeneic cell therapy uses T cells from healthy donors. These cells are isolated in a manufacturing facility, engineered to express CARs to recognize and destroy cancer cells, and modified using gene editing to limit an autoimmune response when given to a patient different than the donor. These therapies are then stored for off-the-shelf delivery to patients. We believe that at scale one manufacturing run has the potential to create therapies for approximately 100 patients.

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Affimed halts trial after patient death and SAEs - European Biotechnology

Affimed halts trial after patient death and SAEs - European Biotechnology | Cancer Immunotherapy Review | Scoop.it
Genentech's new partner Affimed NV has halted two blood cancer programmes with its tetravalent bispecific T cell engager AFM11 after a death and two cases of severe neurotoxicity occured in Phase I trails.&nbsp;...
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Targeting the PD-1/PD-L1 axis for the treatment of non-small-cell lung cancer | Meyers | Current Oncology

Targeting the PD-1/PD-L1 axis for the treatment of non-small-cell lung cancer | Meyers | Current Oncology | Cancer Immunotherapy Review | Scoop.it
Targeting the PD-1/PD-L1 axis for the treatment of non-small-cell lung cancer...
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Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma | NEJM

Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma | NEJM | Cancer Immunotherapy Review | Scoop.it
Original Article from The New England Journal of Medicine — Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma...
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Checking into the germinal centers: PD-1 regulates entry

Checking into the germinal centers: PD-1 regulates entry | Cancer Immunotherapy Review | Scoop.it
PD-1 functions on T follicular helper cells to dictate localization within lymph node germinal centers.

 

Program cell death protein 1 (PD-1) is an inhibitory B7 family member; it has been extensively studied for its role in inhibiting CD8+ T cell function within tumors or during chronic infections. This work has led to successful clinical use of checkpoint inhibitors to rejuvenate the antitumor T cell response. PD-1 is also a defining marker of CD4+ T follicular helper (TFH) cells, which are responsible for guiding B cell antibody production. What role it plays on TFH cell function is not well understood. Consistent with its inhibitory function, PD-1 does in fact constrain TFH cell development. However, recent work from Shi et al. demonstrates that PD-1 is also required to fine-tune the TFH-B cell humoral response by regulating TFH cell positioning within lymph nodes (LNs). As CD4+ T cells approach the follicle, they are rebuffed by bystander B cells expressing a ligand for PD-1, which dampens phosphoinositide-3 kinase (PI3K) signaling downstream of the chemokine receptor CXCR5 and thus slows T cell motility. As inducible T-cell costimulator (ICOS) enhances PI3K signals, theoretically only T cells with the highest level of ICOS can overcome this and make it through the inhibitory ring of B cells to the germinal center. PD-1 expression also blocks developing TFH cell distraction from chemokines expressed outside of the follicle by negatively regulating CXCR3 expression. All together then, PD-1 expression by recently activated CD4+ T cells helps to enforce a TFH cell concentration within the antigen-reactive B cell germinal center. An unresolved immunologic mystery is how naïve T cells—after early antigenic stimulation—“choose” a particular differentiation fate. In particular, T helper type 2 (TH2) and TFH cells require similar costimulatory signals from antigen presenting cells, express higher levels of CXCR5 than other T effector fates, and are concentrated in the same region of the LN during activation—the T-B border—where they are activated by type 2 conventional dendritic cells (cDC2s). Based on this recent work, differential expression of ICOS might be the tipping point toward TFH rather than TH2 differentiation. By overcoming PD-1 inhibition, strong ICOS signaling allows passage into the germinal center where the final stage of TFH differentiation occurs.

Highlighted Article

    1. J. Shi
    2. S. Hou
    3. Q. Fang
    4. X. Liu
    5. X. Liu
    6. H. Qi
    PD-1 controls follicular T helper cell positioning and function.Immunity 49264274 (2018).
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  • Copyright © 2018, American Association for the Advancement of Science
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Innate Immunity - ScienceDirect

Innate Immunity - ScienceDirect | Cancer Immunotherapy Review | Scoop.it
Abstract
The innate immune system is the phylogenically oldest component of the human immune system. Although it is ancient, the innate immune system is highly complex and consists of barriers to infection (epithelia of skin, gastrointestinal, respiratory, genitourinary tracts), antimicrobial peptides and proteins, humoral components (i.e. complement and opsonins) and cellular components (i.e. neutrophils, monocytes/macrophages, dendritic cells, and innate lymphoid cells). Innate immunity serves as the front line of host defense and plays an essential role in preventing infection while tolerating normal host flora. Defects in innate immunity are associated with invasive, life-threatening infection. Inappropriate activation of the innate immune system can lead to autoinflammatory states. The innate immune system directs the subsequent development of adaptive immune responses. Its proper function is thus critical for health.
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Checkpoint blockade therapy resistance in Hodgkin's lymphoma

CORRESPONDENCE| VOLUME 392, ISSUE 10154, P1194-1196, OCTOBER 06, 2018 Checkpoint blockade therapy resistance in Hodgkin's lymphoma Published:October 06, 2018DOI:https://doi.org/10.1016/S0140-6736(18)31867-1 About 50 years ago, the enigma of Hodgkin's lymphoma was depicted as the Hodgkin maze in two editorials in The Lancet.1,  2 The uncertainties of the time were expressed through two questions: “Infection or neoplasm?” and “One entity or two (or more)?”.2 Subsequently, advances in cell biology and molecular pathology provided answers to these questions. Substantial evidence now indicates that classical Hodgkin's lymphoma is a distinct neoplastic entity, with heterogeneous pathological features, which might be associated with Epstein-Barr virus infection. Cases with intermediate features between classical Hodgkin's lymphoma and diffuse large B-cell lymphomas have been recognised. Typically, rare Hodgkin and Reed-Sternberg (HRS) cells are surrounded by immune and inflammatory cells, including T helper 2 cells and T regulatory cells.3 HRS cells express programmed cell death ligand (PD-L) 1 and 2, which bind programmed cell death 1 (PD-1), a receptor expressed by T cells (figure). Binding activates the PD-1 signal transduction pathway, which inactivates tumour-specific T cells. The PD-L1–PD-1 pathway, therefore, functions as a checkpoint that regulates T cell-mediated immune responses. Through this mechanism, HRS cells escape immune surveillance and thereby evade immune destruction. Checkpoint-inhibiting antibodies showed promising results in the treatment of relapsed or chemotherapy-refractive classical Hodgkin's lymphoma, with durable clinical responses in heavily pretreated patients, although their tumours developed immune resistance.3 The mechanisms of resistance to checkpoint-inhibiting antibodies have been partially identified in solid tumours,4 but remain largely unknown in classical Hodgkin's lymphoma. These uncertainties mean that we are again in the Hodgkin maze, because of the disease's enigmatic tangle that includes inflammatory responses to HRS cells and Epstein-Barr virus, the aberrant phenotype of HRS cells, deregulated oncogenic pathways, immune escape, and tumor–host interface crosstalk (figure). We can learn about the mechanisms of resistance to checkpoint blockade in classical Hodgkin's lymphoma from progress in solid tumours. For example, a preclinical study showed that resistance correlated with infiltration of the tumour by immunosuppressive myeloid cells.4 Therefore, to understand resistance to checkpoint blockade in classical Hodgkin's lymphoma, we should study the inflammatory and immune cells in the tumour microenvironment and the immunomodulatory proteins these cells express. This research is now possible using multiplexing immunofluorescence and immunohistochemistry, and digital image analysis.5 Such research should reveal how to overcome drug resistance in classical Hodgkin's lymphoma through rational combinations of checkpoint inhibitors and cellular immunotherapy. We thank Valerie Matarese for precious collaboration and editing of the manuscript. We declare no competing interests. References The Lancet The Hodgkin maze. Lancet. 1969; 294: 728-730 The Lancet Further in the Hodgkin maze. Lancet. 1971; 297: 1053-1054 Carbone A Gloghini A Castagna L Santoro A Carlo-Stella C Primary refractory and early-relapsed Hodgkin's lymphoma: strategies for therapeutic targeting based on the tumour microenvironment. J Pathol. 2015; 237: 4-13 View in Article De Henau O Rausch M Winkler D et al. Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells. Nature. 2016; 539: 443-447 View in Article Carey CD Gusenleitner D Lipschitz M et al. Topological analysis reveals a PD-L1-associated microenvironmental niche for Reed-Sternberg cells in Hodgkin lymphoma. Blood. 2017; 130: 2420-2430 View in Article Article Info Publication History Published: 06 October 2018 IDENTIFICATION DOI: 10.1016/S0140-6736(18)31867-1 Copyright © 2018 Elsevier Ltd. All rights reserved. ScienceDirect Access this article on ScienceDirect
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