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! 

Focused Radiation May Help Turn on the Immune System

Focused Radiation May Help Turn on the Immune System

by Christian Hyde, MD

Radiation given in combination with immunotherapy can potentially kick-start an exhausted immune system. This has been most famously observed in a melanoma patient on Ipilimumab, published by Dr. Michael Postow and others in the New England Journal of Medicine. At first, the ipilimumab worked, and her tumors shrank. Then the tumors developed resistance and regrew. By radiating one of her tumors near the spine, with 3 large doses of radiation, her immunity was restored, and all her tumors shrank, not just the irradiated tumor. The combination increased tumor specific T-cells and antibodies.

The result has a scientific nickname: the abscopal effect, derived from a combination (aptly enough) of two words—ab, for “away,” and scopus, for “target.” The effect, first reported about 50 years ago, is currently rare, seen in a small number of patients who undergo radiation therapy for metastatic disease.

Radiation doses of 8 to 10 Gray appear to be ideal to wake up the immune system and cause the tumor to become inflamed such that it is fertile ground for immune activity. Recent work by Dr. Silvia Formenti and others has shown that these high doses of radiation makes cancer cells look and act like virus-infected cells. The radiated cancer cells produce interferon and display more surface antigens, helping to target themselves for immune destruction, using many of the same pathways as a virus-infected cell. 

The abscopal effect is rare because radiation also simultaneously increases the production of inhibitory blomolecules and regulatory T-cells, which stop killer T-cells from overdoing their job. The same processes that activate the immune system thus control how far it can spread, shutting down the immune response before it causes too much collateral damage in the body, keeping radiation responses local.

At least three key pathways have been shown to limit the spread of anti-tumor immunity after radiation:

1. Regulatory T-cells increase in response to radiation. These “Tregs” can be recruited by tumors to help protect tumor cells from immune destruction.
2. Programmed Death-Ligand 1, or PD-L1. Tumor cells increase this protein on their cell membrane in response to radiation, a change that can be detected on circulating tumor cells during a course of radiation therapy. This makes them resistant to CD-8 T-cell killing.
3. IDO-1 is an enzyme that is upregulated in tumor surroundings in response to radiation, which paralyzes killer T-cells crossing into the area, like soldiers getting stuck in a moat.

All three of these mechanisms were shown to be at work by Dr. Elena Muraro and others following 3 daily doses of 10 Gray each in breast cancer patients with up to 6 metastases irradiated. In theory, if a patient takes immunotherapy drugs like ipilimumab, nivolumab, and epacadostat during radiation, it may help deplete the Tregs, overcome PD-L1, and block IDO, respectively, allowing a local immune response to broaden to other metastases. 

Chemotherapy has taught us that multiple drugs, usually 4 or more with independent mechanisms, are needed before cure rates exceed 90%, such as ABVD for Hodgkin’s lymphoma. Blocking one resistance pathway is seldom enough, just like blocking one road into a city won’t stop all traffic; traffic simply increases on all the other roads. There are many available routes of immunity to regulate, including checkpoints, cytokines, antibodies, and cells. It’s probably not until we get multi-drug combinations, added to radiation, that the distant abscopal effect becomes a regular thing. In the meantime, the “adscopal”, or local synergist effects of radiation plus PD-1 inhibitors, are also showing promise.

Why combine immunotherapy with targeted radiation therapy?

by Christian Hyde, MD

In the World War 2 movie, "Saving Private Ryan," a small town held by Allied foot soldiers is being over-run by Nazi tanks. At the crucial moment in the battle, when all hope seems lost, a friendly Allied airplane turns the tide by bombing an armored tank and rallying the exhausted defenders.

Giving Cancer the RadScopal™ Treatment

by Alexandra Cadena

In the past decade, many advances in the field of radio-immunotherapy have taken shape. There is undeniable therapeutic synergy between radiation (XRT) and immunotherapy. 

At the Welsh lab at MD AndersonCancer Center, we strive to find new approaches and effective combinations of radiation with checkpoint inhibitors. In our quest, we found ourselves re-thinking not only what the best combination is, but also what is the safest, least toxic, and most translational treatment regimen.

In to I-O: First Contact

by Dr. Nils Rudqvist

My name is Nils Rudqvist and I have a confession to make: a few years ago, fresh out of grad school, I barely knew what a T cell was. I knew even less about dendritic cells, and don’t get me started on macrophages. I mean, I knew of them, but my understanding was very limited. I understood that the immune system worked hard to keep me safe and healthy, but also that it could malfunction - evident from my friend’s constant joint pain.

Get to Know Sentinel Author: Nils Rudqvist, PhD

Name: Nils Rudqvist

Rudqvist

Title: PhD

Employer: Weill Cornell Medicine

When and why did you become a SITC member?

I became a SITC member in 2016 when I joined the laboratory of Sandra Demaria at Weill Cornell Medicine. My background is in radiation physics/biology, so immunology was quite new to me. One main reason for me to join SITC was to develop the necessary skills and knowledge to become a successful investigator in the field of immuno-oncology.

Get to Know Sentinel Author: Christian Hyde, MD

Name: Christian Hyde, MD

Title: Radiation Oncologist, Diplomate of the American Board of Radiology

Employer: Cancer Treatment Centers of America, in the Southeastern Region

When and why did you become a SITC member?

I joined SITC a few years ago due to a long-standing interest in immunity. One of my earliest experiences with my immune system was at age 12 during a Boy Scout project in Utah clearing trails through the woods. I was exposed to poison oak, causing a mild rash on my legs and arms. When we went back a few weeks later, I volunteered to take care of all the poison oak bushes, thinking my prior exposure had inoculated me against it. I was dead wrong. A few days later I was in the doctor’s office with my face swollen up like a balloon and weepy sores all over my body. I had to take a cortisol injection to turn down my T-cell immune response which was attacking the poison oak antigens on my skin and even attacking areas where I wasn’t directly exposed. Needless to say, I learned a lot that day about the power of the immune system and how little I understood it, and that not all exposures are protective – in fact they can rev up the immune response. We see that with cancer immunotherapy.

Get to Know Sentinel Author: Alexandra Cadena

Name: Alexandra Cadena

Cadena

Title: Research Intern

Employer: MD Anderson Cancer Center

When and why did you become a SITC member?

I became a SITC member about two years ago when I was a college student interning over the summer in the Experimental Rad Onc. Department at MD Anderson. My PI at the time encouraged me to submit an abstract to SITC on a retrospective study I did correlating tumor growth kinetics with response to immunotherapy. My abstract got accepted and I poster presented at National Harbor in 2015. After that experience, I truly fell in love with the SITC community and saw the field of immuno-oncology (IO) as the solution to shifting the scientific paradigm. What I most enjoy about being a SITC member is the diversity of talent the group draws from. I think they have really found an amazing balance of bringing all voices, from all different disciplines to the table to discuss advances in cancer immunotherapy. I find this refreshing in a world that constantly seeks to compartmentalizes and subspecialize what we know.