JITC Letter From the Editor - August 2020

Dear JITC Readers,

Welcome to this latest edition of the JITC digest. The papers highlighted this month offer exciting perspectives on the current state of the immunotherapy field as well as promising future directions for research.

 

Clinical oncologists can find a comprehensive overview of approved and emerging immunotherapies for multiple myeloma, including some of the new CAR T cell therapies currently in development, in the newest clinical practice guideline from SITC, by Nina Shah et al.

 

Promising clinical data on the use of checkpoint blockade for prostate cancer is provided in an original research article by Julie N Graff et al. The paper is the first to demonstrate durable responses with PD-1 inhibition in a subset of prostate cancer patients.

 

The identification of biomarkers to predict response to immunotherapy remains an important and ongoing area of study for our field. Two papers in this month’s digest highlight the key role that tumor metabolism plays in determining outcomes after immunotherapy, offering potential biomarkers for future study.

 

David Chardin and colleagues identify tumor metabolic parameters as measured by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) that are prognostic and predictive for outcomes after anti-PD-1 therapy for non-small cell lung cancer. Another immunometabolic biomarker is identified by Fangming Liu et al, who identify an association between FABP5-positive tumor infiltrating T cells and improved overall and recurrence-free survival in hepatocellular carcinoma.

 

New immunotherapeutic targets is another high-priority topic for research, and Marta Trüb and colleagues demonstrate promising in vitro anti-tumor properties with a novel fibroblast activation protein (FAP)-targeted 4-1BB agonist (FAP-4-1BBL).

 

Finally, do not miss an excellent review by Christopher A Chuckran et al of Neuropilin-1, which acts as a receptor ‘hub’ for sorting signals from diverse ligands to both promote regulatory T cell (Treg) stability in the tumor microenvironment and inhibit anti-tumor CD8+ T cell responses—the latest in the Immune Checkpoints Beyond PD-1 review series.

 

As always, you can also further your reading with highlights from other journals in JITC’s Reading List, selected this month by Claudia M Palena, PhD, of the NCI.

Best regards,

Pedro J. Romero, MD
Editor-in-Chief, Journal for ImmunoTherapy of Cancer

To view the entire August 2020 JITC Digest, please click here. 

JITC Letter from the Editor - October 2019

Dear JITC Readers,

I am pleased to share news of the launching of JITC’s very own Twitter handle (@JITCancer). Managed by JITC’s very own editors, this new platform will provide followers with access to JITC’s latest publications as well as cutting-edge news from throughout the fields of tumor immunology and cancer immunotherapy. Furthermore, it will give authors, readers, and editors a place to connect more directly on a global level.

If you use Twitter, please take a moment to follow @JITCancer and explore its social content. The October edition of the JITC digest also contains several highlighted articles that may be of interest for you to share with your followers. In particular, these highlighted articles show how insight into the interplay between malignant cells and the immune system can unlock new therapeutic strategies and diagnostic tools.

Two papers reveal new insight into which patients may benefit from checkpoint inhibition. The first, “Closed system RT-qPCR as a potential companion diagnostic test for immunotherapy outcome in metastatic melanoma” by Swati Gupta et al., develops a profile based on mRNA expression signatures of four genes (CD274 (PD-L1), PDCDILG2 (PD-L2), CD8A, and IRF1) that correlates with clinical outcomes in melanoma patients treated with anti-PD-1 immunotherapy. With further development, the approach they describe could offer a rapid-turnaround companion diagnostic, without standardization and threshold issues inherent in immunohistochemistry-based diagnostics.
The second article addresses the ongoing question of how T cell responses determine outcomes of checkpoint inhibition. Fehlings et al. shine some light on this issue by identifying a distinctive population of neoantigen-specific CD8+ effector-like T cells in PBMCs from patients with non-small cell lung cancer who responded to anti-PD-L1 treatment. Their findings are described in, “Late-differentiated effector neoantigen-specific CD8+ T cells are enriched in peripheral blood of non-small cell lung carcinoma patients responding to atezolizumab treatment.”

T cell engineering has emerged as an exciting new clinical frontier, with the marked success of chimeric antigen receptor (CAR)-based therapies. In, “A TIGIT-based chimeric co-stimulatory switch receptor improves T cell anti-tumor function,” Hoogi et al. deploy a novel T cell engineering strategy, generating a chimeric costimulatory switch receptor (CSR) that circumvents inhibitory signaling in the cancer milieu by fusing the extracellular ligand-binding domain of the co-inhibitory receptor TIGIT to the intracellular stimulatory domain of CD28. T cells co-transduced with both an antigen receptor and the CSR displayed enhanced cytokine production in vitro and prolonged survival in xenograft models of established melanoma.

The final paper highlighted in this month’s digest describes encouraging results from a phase 1 trial of a humanized anti-IL-8 monoclonal antibody in 15 patients with incurable metastatic or unresectable, locally advanced solid tumors. Bilusic et al. demonstrate that IL-8 blockade is safe and well-tolerated in, “Phase I trial of HuMax-IL8 (BMS-986253), an anti-IL-8 monoclonal antibody, in patients with metastatic or unresectable solid tumors.” What’s more, 11 out of 15 patients achieved stable disease, an encouraging result for ongoing studies investigating IL-8 blockade in combination with checkpoint inhibition.

With best regards,

Pedro J. Romero, MD
Editor-in-Chief, Journal for ImmunoTherapy of Cancer

To view the entire October 2019 JITC Digest, please click here. 

JITC Letter from the Editor - September 2019

Dear JITC Readers,

There are several recent articles I would like to highlight in this September issue of the JITC digest, pointing to the progress we’ve been making toward understanding the immune system and cancer.

First, “PD-1 silencing impairs the anti-tumor function of chimeric antigen receptor modified T cells by inhibiting proliferation activity” by Jianshu Wang et al demonstrates yet another function of PD-1 in T cells. In this case, knock-down of PD-1 does not lead to increased anti-tumor activity; rather, silencing of PD-1 in CAR T cells inhibits their proliferation capability and differentiation, and impairs their anti-tumor effects.

“Development of a new fusion-enhanced oncolytic immunotherapy platform based on herpes simplex virus type 1” by Suzanne Thomas et al outlines the potential of a novel HSV-1-based oncolytic platform, whereby the engineered virus is armed with various modifications to increase its therapeutic effects, essentially allowing effective combination therapy through a single administered agent.

In the article, “Concurrent therapy with immune checkpoint inhibitors and TNF-alpha blockade in patients with gastrointestinal immune-related adverse events”, Yousef R. Badran and co-authors provide insight into management of one of the most common immune-related adverse events, enterocolitis. They describe five patients treated concurrently with checkpoint inhibitors and infliximab, all of whom had symptom resolution and disease control, providing physicians an example for management or severe cases of this common side effect. While the efficacy of this combination to control immune related enterocolitis awaits formal confirmation in controlled clinical trials, the results are indeed in line with recent observations in pre-clinical studies (Perez-Ruiz et al. Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy, Nature 2019).

Daruka Mahadevan et al describe a novel immune checkpoint inhibitor in “Phase I study of samalizumab in chronic lymphocytic leukemia and multiple myeloma: blockade of the immune checkpoint CD200”. In this first-in-human study, the authors observed encouraging efficacy through blockade of CD200 in hematologic malignancies, recommending further dosing optimization for future investigations.

Finally, “Characterization of a whole blood assay for quantifying myeloid-derived suppressor cells” by Minjun C. Apodaca et al addresses a pressing issue with a promising biomarker: quantification of circulating myeloid-derived suppressor cells. They identify a common pathway to their quantification using flow cytometry, and also point out a few pre-analytical variables that have significant impact on MDSC levels as well.

With best regards,

Pedro J. Romero, MD
Editor-in-Chief, Journal for ImmunoTherapy of Cancer

To view the entire September 2019 JITC Digest, please click here. 

JITC Letter from the Editor - August 2019

Dear JITC Readers,

In the August edition of the JITC Digest, I would like to highlight the following articles. First, “The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of squamous cell carcinoma of the head and neck (HNSCC),” by Ezra E.W. Cohen et al. details the first new FDA approvals for patients with squamous cell carcinoma of the head and neck (HNSCC) since 2006, including the most recent 2019 approval of pembrolizumab as first-line treatment for patients with metastatic or unresectable, recurrent HNSCC in combination with chemotherapy for all patients or as monotherapy for patients with HNSCC whose tumors express PD-L1. These consensus guidelines serve as a foundation to assist clinicians’ understanding of the role of immunotherapies in this disease setting, and to standardize utilization across the field for patient benefit.

Furthermore, the article, “T cells expressing NKG2D chimeric antigen receptors efficiently eliminate glioblastoma and cancer stem cells” by Dong Yang et al. confirms the high expression of NKG2DLs in human glioblastoma cell lines, CSCs, and tumor samples and provides evidence that NKG2D CAR T cells effectively target glioblastoma cells and CSCs in an NKG2D-dependent manner, thus reporting on an encouraging therapeutic approach for glioblastoma patients.

Next, the research article entitled “Tumor-released autophagosomes induces CD4+ T cell-mediated immunosuppression via a TLR2–IL-6 cascade,” by Yong-Qiang Chen et al. reveals novel cellular and molecular mechanisms of tumor-derived extracellular vesicles in regulating CD4+ effector T cell function and pinpoints tumor cell-released autophagosomes (TRAPs) as a therapeutic target for cancer immunotherapy, specifically reporting HSP90-alpha on the surface of TRAPs as a novel target.

“Ovarian cancer stem cells and macrophages reciprocally interact through the WNT pathway to promote pro-tumoral and malignant phenotypes in 3D engineered microenvironments,” by Shreya Raghavan et al. details the hanging drop spheroid model developed to investigate pro-tumoral macrophage activation in response to CSCs and the role of WNT pathways in CSC-macrophage interactions. Such insight could provide new targets for reducing CSC-burden in ovarian cancer.

“HERA-GITRL activates T cells and promotes anti-tumor efficacy independent of Fc-gamma-R-binding functionality,” by David M. Richards et al. describes the development of a novel agonistic HERA molecule targeting GITR for which the underlying HERA-GITRL structure overcomes significant limitations of bivalent antibody-based approaches by mimicking the natural trimeric ligand, and thus inducing optimal trimeric assembly of the GITR receptors.

Finally, the clinical study, “First-in-human phase 1 study of IT1208, a defucosylated humanized anti-CD4 depleting antibody, in patients with advanced solid tumors,” by Kohei Shitara et al. reports on single agent IT1208, a humanized anti-CD4 immunoglobulin G1 mAb, which is shown to successfully deplete CD4+ T cells with a manageable safety profile and encouraging preliminary efficacy signals, warranting further investigations, possibly in combination with immune checkpoint inhibitors.

With best regards,

Pedro J. Romero, MD
Editor-in-Chief, Journal for ImmunoTherapy of Cancer

To view the entire August 2019 JITC Digest, please click here. 

JITC Letter from the Editor - June 2019

Dear JITC Readers,

In the June edition of the JITC Digest, I would like to draw special attention to the following articles. First, “Carboplatin/paclitaxel, E7-vaccination and intravaginal CpG as tri-therapy towards efficient regression of genital HPV16 tumors” by Sonia Domingos-Pereira et al. investigates the effects of systemic administration of a chemotherapy doublet in combination with HPV16-E7 synthetic long peptide (E7LP) vaccination, followed by intravaginal immunostimulation in the genital orthotopic TC-1 mouse model. Results from this study suggest that combining novel vaccine formulations with local immunostimulation and standard-of-care chemotherapy have the potential to benefit patients with HPV-associated cancer.

Next, the research article “Selectively hampered activation of lymph node-resident dendritic cells precedes profound T cell suppression and metastatic spread in the breast cancer sentinel lymph node,” by Kim M. van Pul et al. describes the immune status of breast draining lymph nodes (LN) in a quantitative and functional manner using multi-parameter flow cytometry and ex-vivo cultures, and compares it with that of breast-draining axillary LN from healthy donors. This study provides new insights into the mechanisms underlying loco-regional immune suppression in breast cancer and how this relates to clinical parameters and suggests that LN-resident-conventional dendritic cells are potential therapeutic targets.

Furthermore, the article, “Anti-pancreatic tumor efficacy of a Listeria-based, Annexin A2-targeting immunotherapy in combination with anti-PD-1 antibodies,” by Victoria M. Kim et al. shows for the first time, that a Listeria vaccine-based immunotherapy was able to induce a tumor antigen-specific T cell response within the tumor microenvironment of a “cold” tumor such as PDAC and further sensitizes the tumor to checkpoint inhibitor therapy. This combination immunotherapy led to objective tumor responses and survival benefit in mice with spontaneously developed PDAC tumors, supporting Lm-ANXA2 as a therapeutic agent in combination with anti-PD-1 antibody for PDAC treatment.

“Neurologic toxicity associated with immune checkpoint inhibitors: a pharmacovigilance study,” by Douglas B. Johnson et al. leverages Vigibase, the World Health Organization pharmacovigilance database, to further define neurologic toxicities in the largest characterization of neurologic immune-related adverse events (irAEs) associated with ICIs. Results of this analysis pinpointed several categories of neurologic toxicities strongly associated with CNS inflammation or peripheral neuromuscular autoimmune disorders of which clinicians should be aware of in administering checkpoint blockade.

Finally, Hyun Gul Yang et al.’s article, “Discovery of a novel natural killer cell line with distinct immunostimulatory and proliferative potential as an alternative platform for cancer immunotherapy,” presents a novel NK cell line, NK101, from a patient with extra-nodal NK/T cell lymphoma and an assessment of its phenotypic, genomic and functional characteristics, with results suggestive of its therapeutic application as a CAR T-alternative anti-cancer cellular platform with improved efficacy and superior scalability.

With best regards,

Pedro J. Romero, MD
Editor-in-Chief, Journal for ImmunoTherapy of Cancer

To view the entire June 2019 JITC Digest, please click here. 

Cancer Immunotherapy: Simplified…

by Kushal Prajapati

In the field of cancer research, Cancer Immunotherapy, Immuno-Oncology or I-O have been buzzwords for quite a few years now. For those who are not life science professionals but actively follow the developments in the field, these may be some popular terms come across on TV, newspapers or magazines. Yet for many, including some scientists not very familiar with immunology, the understanding of how immunotherapy could treat cancer remains either elusive or a mystery. In this blog, I will try to simplify some key principles of Immuno-Oncology for anyone who has always wanted to learn more about this revolutionary field.

Our body is nature’s highly sophisticated creation equipped with a very efficient defense called the immune system. This immune system is made up of different kinds of cells, each specialized in carrying out certain tasks. One of the cell types, known as killer T cells, can identify the foreign cells/invaders in the body and kill them (yes, literally). You could think of them as the ‘soldiers’ of your body who know how to find intruders and neutralize them. In Immuno-Oncology, scientists use these T cells to recognize and kill cancer cells. But wait…cancer cells are your own cells, not foreigners, right? Why would T cells kill your own cells?! The answer to this lies in the fundamentals of how the T cells identify their targets.

Every healthy cell in our body needs to present a normal pattern of immunological signals, called ‘antigens’, to be accepted as ‘self’ or ‘body’s own’ by the immune system. However, when a cell incurs numerous genetic mutations and/or the biological processes within it go haywire, this pattern of antigen presentation is changed enough to label the cell as ‘foreign’ in the eyes of the immune system. This is often the case for cancer cells. T cells would then identify the abnormal antigens on cancer cells using their receptor- called T cell receptor - and get rid of these cells. But if it was this simple, then no one would ever get cancer as the T cells would keep killing the cancer cells as and when they arise. Hence, there is something that’s certainly not very efficient about this process. While we don’t completely understand the underlying reasons yet, the scientists have been able to turn the tables on cancer by strengthening the T cells’ anti-tumor activity in two major ways in the clinic so far.

The first one is chimeric antigen receptor (CAR) T cell therapy which enables T cells to recognize the cancer cells that are otherwise undetectable. As we talked about antigen presentation in previous paragraph, it is worth knowing that many cancer antigens exist in forms that are not recognizable by the T cell receptors. Consequently, these antigens always go undetected by the T cells. CAR was designed to overcome this limitation. It combines a part of the natural T cell receptor with a part of an antibody that can recognize a desired antigen (the one that’s unrecognizable by T cell receptor). Just like giving a new tool to a solider to spot a hidden enemy! With this technology, scientists can identify new cancer antigens invisible to the immune system, design CARs against them, and put them into our T cells to empower them to accurately kill those cancer cells.

The second approach, called the ‘check-point’ blockade, basically stops the T cells from being stopped by cancer cells. In general, T cells in our body are always on the call of duty, looking out for threats and dealing with them. In this scenario, our body has natural mechanisms in place to control the T cells from over-reacting and potentially hurting the healthy cells. One such mechanism is ‘check-point’ signaling, wherein the T cells that are over-worked show significant presence of check-point receptors like PD-1 and CTLA-4 which serve as ‘brakes’ on them. It’s when these receptors (brakes) are ‘engaged’ by the molecules called check-point ligands, the T cells slow-down their function or stop completely. This very mechanism is exploited by cancer cells to escape the immune system. They increase the engagement of the brakes (PD1, CTLA-4) on T cells by simply increasing the amounts of check-point ligands- resulting in attenuation of T cell function. To tackle this problem, researchers developed antibodies which block the interaction between check-point receptors and their ligands. This allows the T cells to continue killing cancer cells without stopping! So far, the check-point blockades of PD-1 and CTLA-4 signaling have shown resounding success in treating many cancers in the clinic.

So, do we finally have the magic bullet against cancer? Not quite yet. The clinical success of immunotherapy has been exciting; however, studies show that most patients do not respond to it if they have more aggressive, solid tumors. However, the good news is that years of research work has revealed to us biological reasons (e.g. various ways the cancer fights back against immune system) behind failure of immunotherapies in such cases. As the new treatments developed based on this knowledge make their way into the clinical trials, exciting times are waiting ahead for cancer immunotherapy! 

[Disclosure: This blog is intended to educate general public and non-experts about the basic concepts of cancer immunology and clinically available immunotherapies. The author does not intend to undermine the efforts behind other cancer immunotherapy approaches that are currently under clinical investigation]

The METIOR Incubator and Educating the Next Generation of Immuno-Oncology Experts

by Saman Maleki, PhD

In August 2017, SITC brought together a group of 29 young researchers and physicians, from across the world, that were involved in various aspects of immunotherapy research to compete in a bold new program called “Sparkathon.” These people were divided into three teams and tasked to work together to develop a solution tackling the most pressing hurdles facing the fast-growing field of cancer immunotherapy. Each team was assigned a mentor with extensive science and business background and teams formulated their solutions to a business deck and pitched it to a group of SITC leaders, academics, and industry experts.

One of the teams set to address the educational challenge facing early-career researchers ­– from any background/sector – who want to enter the field of Immuno-Oncology. This novel educational program is named Mentoring for Early Translational Immuno-Oncology Researchers (METIOR) incubator. It brings together researchers from various sectors and backgrounds and educates them about Immuno-Oncology while developing a team-based multi-institutional project under the mentorship of immunotherapy experts from academia and industry. The METIOR incubator received $75,000 in seed funding from SITC to assist the establishment of their unique educational program. 

METIOR incubator selected ten participants from a pool of highly qualified applicants with various backgrounds in cancer research and assigned them into two teams: 1) team Checkpoints and 2) team CAR T-cell. Each team is currently working on two different projects that is directly linked to cancer immunotherapy. Participants met each other and their mentors at the first METIOR retreat at The University of Pennsylvania (Philadelphia) in March 2018. After two intense days of mentored brainstorming and project development, each team received $20,000 in seed money to work on their respective projects.

Team checkpoint seeks to identify biomarkers that are associated with the activity of endogenous retroviruses with double-stranded RNAs (dsRNAs) in ovarian cancer that might sensitize these tumors to checkpoint inhibitors.

Team CAR T-cell aims to build a centralized information platform (Virtual Immune-oncology Tissue Consortium, VITC) comprising of reference to clinical and pre-clinical samples with a focus on immunotherapy. This platform will be the first of its kind to efficiently consolidate immunotherapy resources across institutions into a searchable, interactive scientific network accessible to all researchers worldwide.

Teams have monthly teleconference meeting with their mentors and will meet again, in person, with their mentors in early September in London, Ontario for the second METIOR Incubator retreat. They will work on consolidating their ideas and preliminary results to shape a joint grant application with the goal of seeking major peer-reviewed funding. The last METIOR Incubator retreat would be at the SITC 33rd Annual Meeting in Washington, D.C. in November, where each team will present their progresses during the noon hour on Friday (TimIOs) and Saturday (METIOR). For a complete look at the Annual Meet schedule, click here.

Link to METIOR incubator: http://www.sitcancer.org/education/sparkathon/2017-cohort/projects/metior

Link to the Checkpoints team: http://www.sitcancer.org/education/sparkathon/2017-cohort/projects/metior/checkpoints

Link to the CAR T-cell team: http://www.sitcancer.org/education/sparkathon/2017-cohort/projects/metior/car-t

Acknowledgment:

Author wished to thank Ms. Alexandra Cadena and Dr. Sebastiano Battaglia for their proofreading of this article.

The Tumor Glyco-Code and Why Immunologists Should Care About it

by Alexandra Cadena

In science, it’s so easy…tempting even to be sucked down the rabbit hole of a particular mechanism or biological pathway only to find that when you tease out one thread, multiple other avenues of research and discovery spring forth drawing you further and further into scientific specificity. Sometimes we get lost. Let’s say we get so caught up looking at a tree that we fail to see the forest.

I noticed this in a big way when I moved from researching in a lab that was solely dedicated to uncovering the effects of aberrant glycosylation in cancer to another lab solely focused on immunotherapy in combination with radiation. As I write this, I wonder, why do labs “solely” specialize in one arena?

Yes, I know the obvious answer is for funding purposes, but maybe the financial structure of how academic research is awarded in this country is hindering us rather than helping us. Are these “lab niches” in research stagnating us in that they prevent us from seeing the bigger picture? Maybe.

We have to specialize in one thing, and then we stay there, we don’t poke our head out to see what else is out there. One thing’s for sure, immunologists, or at least the ones I collaborate with, don’t give much thought to how glycosylation could be affecting the immune system in the fight against cancer. And I think considering glycosylation in the arena of immuno-oncology is one good step in the direction of looking at the bigger picture---or entire forest as it were.

Glycosylation and its by-product, the glycan, play a crucial role in many cellular processes. Aberrant glycan structures and mutations of the glycosylation pathway have been intricately linked with the development of cancer and more recently with cancer’s ability to escape the innate immune system. Glycosylation’s interaction with the immune system can promote tumor deviation through endogenous lectins, mutated, sialic acid domains and more….so why not move to combine some of our top of the line immune drugs with glycotransferase inhibitors?

This may even be the answer as to why some patients don’t respond to certain lines of immunotherapy treatment. In 2016, Li et al. presented findings in Nature Communications that found immunosuppression activity of PD-L1 was highly regulated by N-linked glycosylation. The Contessa lab group at Yale developed a small molecule inhibitor called NGI-1, which selectively inhibits N-linked glycosylation in only malignant cells. Fruitful collaboration? Possibly.

The tumor glyco-code may hold another secret for immunologists to unlock another avenue of tumor immune escape. There are some groups that are already starting to take note and develop glycan-based CAR T cells. In fact, the Carl June lab recently developed a Tn-MUC-specific CAR T cell, which has been effective in eliminating leukemia and pancreatic cancer in mice.

The advances in recombinant glycotransferase have given researchers the necessary tools to make antigens copy structures of tumor glyco-sites, which consequently enhances immunotherapy’s targeting of cancer. The advent of certain glycan therapeutics, such as glycan-based vaccines and glycotransferase inhibitors, have the potential to serve as powerful tools in combination with current immunotherapy drugs, but the important role they may play in the field of immuno-oncology can only be revealed if we continue to take a step back and see the larger picture and the vast forest that is the immune system, which expands well beyond the tumor microenvironment.

Cancer: A Genetic and Immunological Disorder

by Praveen Bommareddy

Goal: The primary goal of my blog series is to contribute to SITC’s mission in educating patients, clinicians, and researchers about the recent advancements in immunotherapy. I am particularly interested in the use of genetically modified (non-pathogenic) viruses as immune modulators for cancer treatment. 

In this introductory edition of my blog series, I would like to provide an overview of cancer immunotherapy and a brief description on why immunotherapies may not always work well due to heterogeneity in tumor phenotypes and various mechanisms that suppress immune response against cancers.

Target audience: Patients and their families, clinicians, and researchers.