San Diego, CA USA (UroToday.com) In this session, Dr. Sharma provided a comprehensive overview of GU Cancer Immunotherapy. Historically, the immune checkpoint era first gained credibility with the anti-CTLA-4 antibody ipilimumab in the setting of melanoma.
In fact, CTLA-4 was the first “off” regulatory step and was identified by Dr. James Allison’s lab at the MD Anderson Cancer Center. He noted that blocking CTLA-4 in mice induces regression of of many different tumor types.
Many years later, this led to approval of ipilimumab. To date over 70,000 patients have been treated with a mostly manageable side effect profile. Specific to GU oncology, 2015 heralded the first FDA-approved immune checkpoint inhibitor for kidney cancer, nivolumab and there are likely more coming in the bladder cancer setting.
Dr. Sharma then introduced the concept of “reverse translation.” That is, instead of a one-way street taking hypothesis-driven work at the bench to the bedside, she proposed using patients to drive the generation of hypothesis that are then tested at the bedside. To date, such trials are small and investigation of concept-type trials which can be scaled up based on results. Typically, these represent pre-surgical tissue based trials that generate a variety of immunogenetic outputs.
One example of such a study has demonstrated the importance of the ICOS pathway, which is now being used as a biomarker of anti-CTLA-4 therapy in melanoma. Tumors with high levels of ICOS correlate with improved survival relative to lower expression levels. Two conclusions can be generated from these data: (1) the ICOS/ICOSL pathway is necessary for optimal anti-tumor responses in the setting of CTLA-4 blockade and (2) the ICOS/ICOSL pathway can be targeted and developed as a combination therapy strategy leading to improved antitumor responses.
Dr. Sharma also highlighted the emerging concepts of mutational load in determining an immunogenic versus non-immunogenic responders. Patients with a high mutational load, for example, already have t-cells in the tumor microenvironment and therefore respond well to checkpoint blockade. She argued that it is possible to covert a “cold” tumor to a “hot” tumor and that the mechanisms for driving t-cells into the tumor microenvironment may hold promise in accomplishing this.
Dr. Sharma’s two main take-home points were the following: (1) the immune response is dynamic and PD-L1 expression at a single time point may not reflect an evolving immune response in the blood or tumor microenvironment; and (2) pre-surgical and tissue-abased clinical trials provide a feasible immune monitoring platform to study biologic effects.
Presented By:Padmanee Sharma, MD, PhD
Reported By: Benjamin T. Ristau, MD, Fox Chase Cancer Center, Philadelphia, PA at the 2016 AUA Annual Meeting - May 6 - 10, 2016 – San Diego, California.
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