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. 

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]

Q&A with SITC Vice Presidential Candidate Sandra Demaria, MD

In celebration of Cancer Immunotherapy Month™, we’ve asked SITC leaders to participate in a Q&A series for The Sentinel. We’ve asked them to briefly share why they entered the field, advice they’d share with early career scientists considering a career in cancer immunotherapy and more.

Please see below the Q&A from Sandra Demaria, MD, of Weill Cornell Medical College. Dr. Demaria is a 2018 candidate for SITC Vice President. Learn more about her candidacy here. Voting for the 2018 SITC Election takes place June 14–28, 2018.

1. What initially excited or intrigued you about the cancer immunotherapy field to choose this as your career focus?

I have been fascinated by the immune system since the beginning of medical school when I started volunteering in a research lab working on immunology. Several years later, during my residency in pathology, I matured the decision to devote my research career to study how the immune system interacts with cancer, and how cancer treatment can alter that interaction. Basic immunology had progressed tremendously and after attending a tumor immunology meeting I became really enthusiastic about the possibilities to make progress in cancer treatment. My enthusiasm was further boosted when Jim Allison came to give a lecture and spoke about blocking CTLA-4. It was somewhere in early 2001, before antibodies against CTLA-4 were tested in the clinic, but his vision about the role CTLA-4 blockade in cancer treatment, and how it could be combined with other treatments contributed to shape the direction of my own work.

2. What advice would you share to an early career scientist contemplating a career in cancer immunotherapy?

There is a lot of enthusiasm for the things that work, but you should not be afraid to venture into an area of research that is met with skepticism. Tumor immunology was met with skepticism for a long time. The pioneers who believed in it did not abandon it to work on a more mainstream topic. On the contrary, they worked harder and generated the knowledge that made possible the current revolution in cancer care, with cancer immunotherapy becoming a new treatment strategy that has already saved many lives. There are many critical questions that need to be answered to enhance the effectiveness of cancer immunotherapy. So, think outside the box, do good science, believe in your data, and remember that the value of your work is not really measured by the impact factor of the journals you publish in, but by the impact that it will have on fostering real progress in the field. 

3. What are three of the biggest hurdles facing researchers in the field, and how do you think they can be solved?

Progress can be made only if there is substantial and continuous investment in science at multiple levels (basic, translational and clinical). Scientists and clinicians need to work with patient advocacy groups and other stake holders to leverage public support. Professional societies like SITC are instrumental in leading such efforts. 

Addressing the complexity of tumor-host interactions and understanding how to overcome resistance to immunotherapy requires a multi-disciplinary approach, and a team effort. The current academic structure is still largely based on older paradigms, and is at risk of losing talent that is essential for the research. New types of positions and reward systems that recognize the value of team contributions will help make faster progress and retain the best minds in research.

The bar for success is higher for upcoming and future immunotherapy agents. With increased life expectancy chronic toxicities of immunotherapy may become more important and less acceptable to patients. Improved model systems need to be developed to predict and study the mechanisms of toxicity. 

4. What area of research has you most excited for the future of the field, and why?

I believe that there is a huge potential in leveraging the effects of combination therapies that target different compartments to achieve a synergy with immunotherapy, if done in the context of a system biology approach. I work with radiotherapy, which has the advantage of being a broadly applicable and widely available treatment. But we need to understand how to tailor radiotherapy (and in fact any treatment) the right way for each individual patient. I like to think that there is a combination of specific interventions that will unlock the power of the immune system to reject cancer in every patient, it is just waiting to be discovered!