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. 

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.

President's Message - December 2017

Dear Colleagues,

The past year has been one of significant scientific progress for the field of cancer immunotherapy and tumor immunology. Among the highlights:

• Pembrolizumab received U.S. Food and Drug Administration (FDA) approval for treating patients with MSI-H/dMMR-positive solid tumors, marking the first ever “tissue-agnostic” designation for any cancer therapeutic, defining disease based on biomarker status rather than tissue location
• CAR T cell therapies obtained initial FDA approvals for treating both DLBCL and B-ALL following very positive clinical trial results
• Cancer immunotherapies also continued to gain new indications by obtaining initial FDA approvals in hepatocellular carcinoma (nivolumab), Merkel Cell Carcinoma (avelumab), and gastric/GEJ cancers (pembrolizumab)
• Multiple cancer immunotherapeutics including nivolumab, pembrolizumab, durvalumab, avelumab, and atezolizumab became options for treating patients with bladder cancer

As we look ahead to 2018, the Society for Immunotherapy of Cancer (SITC) will continue to create opportunities for collaboration and scientific exchange for our growing membership base and beyond. Today, I’d like to single out two inter-connected workshops SITC has planned for May 2018 on biomarkers and cancer immune responsiveness.

Ten years after its inception, the SITC Immune Biomarkers Task Force will lead a two-day workshop to discuss critical next steps in biomarker science and assay development. Session topics will include best practices and validation; biomarker identification; data and specimen sharing and much more.

SITC’s newly-formed Cancer Immune Responsiveness Task Force will host a two-day workshop on topics that include tumor evolution in the immune competent host and the resulting immune landscape; identification of common pathways that should be targeted to understand and increase immunogenicity among silent or “cold” cancers and more.

The Annual Meeting & Pre-Conference Programs – which will take place at the Walter E. Washington Convention Center, Washington, D.C. in 2018 due to continued growth and excitement – will always be our society’s hallmark event. SITC hosts interim programs throughout the year to provide focused opportunities to move new developments and initiatives forward for improving cancer patient outcomes through the advancement of science and clinical application of cancer immunotherapy.

Both of the workshops mentioned will be open to the public. Stay tuned to SITC in the New Year for additional event information, including dates and location.

Sincerely,

Lisa H. Butterfield, PhD

SITC President

On Tap at SITC 2017 - Nov. 12

On Tap Today

The Society for Immunotherapy of Cancer (SITC) is very happy to welcome our delegates for one more day of scientific exchange at the 32nd Annual Meeting.

Here's a look at what's on tap for today, and continue scrolling to learn about exciting news for the society in 2018.

On Tap at SITC 2017 - Nov. 10

On Tap Today

The wait is over! The 32nd Annual Meeting (SITC 2017) kicks off this morning. On-site registration and badge pickup opens at 7 a.m. for those who are joining us for the first time this week, with a breakfast also available before sessions begin at 8 a.m.

SITC 2017 is the first Annual Meeting for Lisa H. Butterfield, PhD, as President of the society. Dr. Butterfield had served as Vice President of SITC the past two years before becoming the first female President of SITC in its history following last year's Annual Meeting.

President's Message - October 2017

Dear Colleagues,

I invite you to join the Society for Immunotherapy of Cancer (SITC) for our most anticipated event of the year, the 32^nd Annual Meeting & Pre-Conference Programs from Nov. 8-12 in National Harbor, Md. As the largest conference dedicated to the field of cancer immunotherapy, the society has assembled an incredible roster of experts, offering researchers, clinicians, industry professionals and patient advocates the opportunity to hear the latest scientific findings in the most exciting area of cancer research and treatment.

Pre-Conference Programs: Nov. 8-9

The Pre-Conference Programs provide opportunities for attendees of all experience levels to learn the basics of cancer immunotherapy, explore updates on biomarkers and single cell techniques as they relate to our field, develop grant writing skills, and network. SITC will offer the following programs as a precursor to our Annual Meeting:

• Immuno-Oncology Biomarkers: Today’s Imperatives for Tomorrow’s Needs
• 2^nd World Immunotherapy Council Young Investigator Symposium
• Primer on Tumor Immunology and Cancer Immunotherapy™
• Workshop on Single Cell Techniques in Immunology and Cancer Immunotherapy
• Grant Writing Workshop

32^nd Annual Meeting: Nov. 10-12

Featuring three days of cutting-edge presentations attendees have come to expect from the society, the SITC 2017 Annual Meeting provides a multidisciplinary interactive environment focused on basic and translational cancer immunotherapy. Programming will be kicked off with highly anticipated keynote speeches. On Nov. 10, Stephan Grupp, MD, PhD will speak on “The CAR T Revolution in Leukemia.” The following day, Paul Sondel, MD, PhD, and the 2017 Richard V. Smalley, MD Memorial Award and Lectureship recipient, will deliver his speech on "Activation of Innate and Adaptive Immunity as an In Situ Cancer Vaccine.”

Also, do not miss this year’s Hot Topic Symposium, which closes out proceedings on Nov. 12. The Symposium, Advancing the Field: Can Physics and Mathematics Impact the Development of Tumor Immunotherapy?, will bring together leading authorities in tumor immunology, physics and mathematics to offer an overview of the top priorities in tumor immunotherapy and the latest advances in physical science that might impact further biologic understanding and therapeutic approaches for the field.

Social and Networking Activities

Be sure to attend the social and networking activities provided by SITC. These include activities for early career scientists, such as the Meet-the-Expert Lunch on Nov. 9 and evening networking event on Nov. 10. The poster receptions will take place in Prince George’s Exhibition Hall DE from 6:30 – 8 p.m. on Nov. 10-11. Also, plan to attend the State of SITC: Membership Business Meeting on Nov. 10, and the SITC 2017 Award Ceremony with receptions after presentations. And last, but certainly not least, don’t miss The CheckPoints, SITC’s very own house band the evening of Nov. 11.

I look forward to seeing many of you in National Harbor. For those unable to attend the conference, meeting updates, videos and slide decks will be posted on SITC Cancer Immunotherapy connectED, and meeting summaries will be published in the Journal for ImmunoTherapy of Cancer.

Best Wishes,

Lisa H. Butterfield, PhD

SITC President