Ian Mathews

Predicting patient responses to cancer immunotherapy


FUNDED BY: The generosity of LJI Board Member Gail Naughton

What was the goal of your SPARK project?

Immunotherapies are a novel class of cancer-targeting drugs that reawaken the immune system against a patient’s own tumors. These treatments have shown remarkable clinical success, treating melanoma and some of the most advanced tumors known with efficacy never before shown against these forms of cancer. However, some patients either do not respond to therapy or get worse because of immunotherapy, developing autoimmune-like side effects. Immunotherapy can be miraculous for some and horrendous for others, underscoring the potency of this class of drug. Understanding which patients to give immunotherapy and how we can improve a patient’s response to treatment, therefore are important clinical questions. Under this SPARK award, we set out to measure the tens of thousands of molecules in the blood of cancer patients treated with immunotherapy, in the hope that we could detect molecules that can predict who will respond to therapy, and potentially find signatures that suggest how we might improve patient response.

SPARK project results:

In melanoma patients treated with the immunotherapy ipilimumab (Yervoy), we found molecules that, when high in a patient’s blood, could predict whether that patient would respond to therapy. In addition, we found molecules that either increased or decreased in patients’ blood while on therapy, some of which were only changed in patients who developed autoimmune side effects. These latter molecules may be a window into understanding the still unknown mechanisms by which some patients develop severe side effects while other individuals do not. This study was an important first step in a project we hope to continue all the way to developing a simple blood test for predicting and improving cancer patient response to immunotherapy.

What’s next for this project?

Following the SPARK award, I was able to successfully apply for and receive an F31 Predoctoral Fellowship from the National Cancer Institute (NCI), more than quadrupling the initial funding provided for this project. Additionally, we completed an R01 and an U01 application to the NCI using predominantly data generated over the course of this SPARK-funded study. Both grant applications scored well but didn’t receive funding. However, we were encouraged to resubmit and plan to apply for another NCI R01 in October 2019. We have expanded our immunotherapy blood sampling cohorts to include two additional cohorts, totaling thousands of blood samples from hundreds of cancer patients treated with immunotherapy. Using these cohorts, we were able to identify specific metabolites which associate with Grade III/IV irAEs, the severe side effects of immunotherapy that can take patients off of therapy. We were able to study these metabolites in mice and reduce the severity of these side effects by modulating the levels of these same metabolites. The next steps of this project are twofold: Firstly, we intend to greatly expand our immunotherapy blood sampling cohorts for screening by LC-MS/MS through collaborative efforts and access to preexisting biobanking. Secondly, we intend to further study some of the metabolites discovered in this project via in vivo tumor and irAE modeling, in an attempt to better understand these metabolites’ potential function in tumor and systemic immunity. Cumulatively, these next steps will require funding on the order of hundreds of thousands of dollars, for which we are preparing (and are optimistic in the preparation of) additional applications for funding.

What’s next for Ian?

I hope to graduate with my Ph.D. in Biomedical Sciences from UC San Diego in Summer of 2020, after which I plan to enter medical school to earn an M.D.. My ultimate career goal is one in academic medicine, following research questions in predictive and preventative care for cancer patients not dissimilar to what we pursued with our SPARK award.