In 2007, SSO established a Clinical Investigator Award (CIA) program with the goal of promoting patient-oriented research through the training of surgical oncologists in clinical and translational science. Since that time more than twenty SSO members have received research grants for their proposals. This year, Ajay V. Maker, MD, University of Illinois at Chicago and Director of Surgical Oncology at AIMMC/Creticos Cancer Center, received the CIA for his proposal, “Combination Immunotherapy to Treat Colon Cancer Metastases.” SSO briefly spoke with Dr. Maker regarding his proposal.
Q. Please describe your research hypothesis.
A. Evidence suggests that our own immune system recognizes tumors as foreign entities to be cleared from the body, but that through various mechanisms is unable to mount a powerful enough response to successfully attack the cancers fully. Thus, our hypothesis is that we can increase the success of the immunologic attack by first stimulating and trafficking anti-tumor T-cells to the tumor, and second, by removing inhibitory signals within that tumor environment.
Q. Why did you decide to pursue research on this topic?
A. It became increasingly clear that despite our best technical operations and perioperative care, the biology of many tumors, to put it simply, were beyond the reach of the scalpel. Our current ways of treating cancer systemically have a foundation in chemotherapy, a strategy that is difficult to target only to tumor cells and is rarely, if ever, utilized with curative intent for metastatic solid organ malignancies. At the National Cancer Institute/NIH, I was extremely fortunate to be a fellow of Dr. Steven Rosenberg. He charged us with studying the impact of a new antibody that was being tested for the first time in patients with metastatic melanoma that was meant to inhibit suppressive immune signals within the tumors.
On this trial, we enrolled patients that had disease that had grown beyond what could be managed surgically or otherwise – patients that had run out of hope. I got to know these people intimately, as many of them we took to the OR for tissue harvests and we often performed serial bedside biopsies on responding lesions. Most patients succumbed to their disease, but eventually we began to see some amazing responses, even cures. It was one of the most inspiring moments of my professional life. Though this occurred in only a few patients, I will never forget that experience and dedicated my time at the NCI to researching how this antibody, now known as Ipilimumab, worked in vivo. It sent me on a path to apply immune-modulatory therapy for other tumor histologies that were otherwise considered “cold” or “non-immunogenic,” including metastatic tumors to the liver.
Q. What research leading up to the development of this proposal has influenced your study?
A. As I mentioned, the success of checkpoint blockade in melanoma has highlighted the potential for unprecedented responses, but only in a select group of patients with otherwise terminal disease. Unfortunately, many cancers are resistant to current checkpoint blockade therapies, and since then multiple clinical trials have proposed that prediction of response may be tied to something called the neoantigen load. These studies propose that the more different, or mutated a tumor is, and the more it’s differences can be exposed to the circulating immune system – these are the main determinants of response to current immunotherapies. Our research has been influenced by these and other studies that have evaluated novel approaches to deliver immunostimulatory signals into the tumor microenvironment and that elucidate the impact of cell death as a mechanism to expose neoantigens. We are also interested in utilizing combinatorial strategies to tip the balance of our immune system towards cytotoxicity. So all of these things have all influenced the proposal.
Q. When will your research be complete and what do you plan to do with the data?
A. Our proposed goal over the next few years is to evaluate not only whether our interventions can successfully impart tumor regressions in “cold” metastatic tumors, but also to delineate the mechanism of action in vitro and in vivo. The preliminary data is extremely exciting. Our hope is that these discoveries will enable a novel treatment strategy that can be moved quickly from pre-clinical models into clinical trials and the clinic to help our patients directly in the near future.
Q. How did you learn about SSO’s Clinical Investigator Award opportunity?
A. I have always greatly respected the emphasis that the SSO places on inquiry and discovery and have attended the CIA presentations at the Annual Cancer Symposium since I was a resident. The Society’s mission and goals have created a community that I am proud to be part of and greatly enjoy. Having seen the inspirational projects presented in that venue, and then following what those individuals were able to discover or achieve in the years thereafter, made this opportunity an aspirational goal. I want to express my heartfelt thanks to the SSO and the Research Committee for believing us and supporting our work.