The Sentinel


Thursday, April 26, 2018

President’s Message – May 2018

Dear Colleagues,

The identification, standardization and validation of biomarkers will assist clinicians to identify the best cancer immunotherapies for patients and inform research scientists about the most critical areas of immunology for further investigation. Data from the last several years has shown the importance of checkpoint molecule expression, tumor mutation burden and CD8+ T cell infiltrate localization in tumors for patient outcomes, yet clinically validated, actionable biomarkers are not yet in hand. As many of you know, biomarker research has long been a research focus of mine and one reason I became a member of the Society for Immunotherapy of Cancer (SITC), as SITC shares this passion to advance immune biomarker science. 
I am proud to have been chairing the SITC Immune Biomarkers Committee, which is working at the forefront of biomarker research. The committee convened in 2014 to review the state of the field and identify challenges and opportunities still facing the community. At the time, the committee was comprised of four working groups (WG) dedicated to the following topic areas:
  • WG 1 – Immunologic Monitoring, Assay Standardization & Validation
  • WG 2 – New Developments in Biomarker Assays & New Technologies
  • WG 3 – Assessment of Immune Regulation & Modulation Systematically (High Throughput Approaches)
  • WG 4 – Prediction of Clinical Outcome Based on Baseline Measures

These hard-working teams published five white papers in the Journal for ImmunoTherapy of Cancer (JITC) – SITC's open-access, peer-reviewed online journal. Building on these efforts, the committee is ready to apply its members' expertise to shaping the future of the field.

The SITC Immune Biomarkers Committee is pleased to invite individuals from across academia, biotech, pharma, government and clinical research communities to our upcoming workshop, Immuno-Oncology Biomarkers: State of the Art, May 16 – 17, 2018, in San Francisco. This small and focused gathering will support cross-disciplinary cooperation across organizations to advance biomarker development, shape innovative new collaborations, and determine future projects of the committee in the coming years.

This Biomarkers Workshop takes place following two days of dynamic collaboration during the Cancer Immune Responsiveness Workshop (May 14 – 15, 2018), which will feature discussions on the role of host genetics and environmental modifiers in cancer biology, adaptive and innate immune mechanisms that initiate a therapeutic response, and the development of improved in vivo models for screening novel therapeutic strategies.

SITC is proud to organize and support meaningful, impactful collaborations involving participants from every expertise. These workshops are an excellent example of SITC's effort to better the field, and I look forward to seeing you in San Francisco!


Lisa H. Butterfield, PhD SITC President

Tuesday, April 24, 2018

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.

Thursday, April 12, 2018

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.

Wednesday, April 4, 2018

President’s Message – April 2018

Dear Colleagues,

I wish everyone a happy spring! The past 16 months as SITC President have been eventful, and I am especially focused on a topic important to me: the role of women in our field.

SITC 2018, scheduled for Nov. 7 – 11 in Washington, D.C., will be my second and final Annual Meeting as President before turning the role over to Mario Sznol's, MD, capable hands. The recent advances we've seen in our field are truly impressive. I look forward to the data presented at this year's Annual Meeting that highlight that progress.

In my tenure as SITC's first female president, I have worked to institute measures within SITC to promote and track the membership, volunteerism and society positions of women in the cancer immunotherapy field. During the SITC 2017 Membership Business Meeting, I shared several of the following statistics of current female involvement within the society:

SITC hasn't previously tracked gender data from members or meeting participants, so these figures are an important baseline by which we can measure our future progress. This information will help us identify gender gaps within our volunteer roles and program numbers, with a societal goal of reducing any gaps and providing equivalent opportunities in the future.

There are many women within SITC contributing in various leadership capacities – serving on the Board of Directors, as Section Editors in the Journal for ImmunoTherapy of Cancer (JITC), as meeting organizers, and through participation on our committees. These women play a critical role in the future of SITC, and I am confident our female contingencies in both membership and participation numbers will grow. I am proud to have helped develop our first "Women in Cancer Immunotherapy" reception at the 2017 Annual Meeting.

More than 30 of my female colleagues joined me to discuss ways we can bring sharper focus to women's contributions in the field, ensuring there is balance between the genders in speaking and leadership roles. Interestingly, I find myself a member of two other similar groups. At my own institution, the UPMC Hillman Cancer Center has convened a Women's Task Force to address any gender issues among the female faculty. I am also pleased to participate in the BMS-led "Women in Oncology and Research" group that includes representation across many societies and institutions. Clearly, there is terrific energy and momentum for addressing the professional experiences of women in many areas.

I look forward to hosting a second reception during the 33rd Annual Meeting & Pre-Conference Programs, this November at the Walter E. Washington Convention Center in Washington, D.C., our new venue. Please stay tuned for the scheduled date and time.

Speaking of the Annual Meeting, this issue of the Immune Monitor is dedicated to our upcoming annual conference. Please read on to learn more about new offerings and recurrent meeting highlights. SITC 2018 registration, available to SITC members at a discounted rate, is now open to the general public.

SITC 2018 promises to be our society's best yet and I look forward to seeing the SITC family in Washington, D.C.!


Lisa H. Butterfield, PhD

SITC President