My research work has been focused on understanding immunologic mechanisms that can be targeted to improve clinical benefit in cancer patients. My studies have been based on investigations into human immune responses, especially those that occur after treatment with immune checkpoint therapy such as anti-CTLA-4 and anti-PD-1/PD-L1. My work involves novel clinical trials and complementary pre-clinical studies to evaluate response and resistance mechanisms to immune checkpoint therapy.

I proposed the first pre-surgical clinical trial with anti-CTLA-4, which enabled access to pre- and post-treatment samples to investigate immune responses in both the tumor microenvironment and peripheral blood of patients. My work identified the T cell molecule known as inducible costimulator (ICOS) as necessary for optimal anti-tumor immune responses. Furthermore, I demonstrated that targeting the ICOS pathway in combination with anti-CTLA-4 improves tumor rejection in pre-clinical studies, which provided the foundation for a new patent that led to subsequent clinical trials testing novel anti-ICOS antibodies.

My studies also led to the identification of resistance mechanism to anti-CTLA-4 therapy. I identified loss of genes in the interferon signaling pathway in tumor cells as an immune-escape mechanism. In addition, I designed a pre-surgical clinical trial in patients with prostate cancer and identified other immune checkpoint molecules, VISTA and PD-L1, as resistance mechanisms that inhibit anti-tumor immune responses. These data led me to design combination immunotherapy studies to enhance anti-tumor immune responses.

The field of immune checkpoint therapy has led to dramatic clinical responses in patients with cancer, including patients with genitourinary (GU) malignancies such as metastatic renal cell carcinoma and bladder cancer. As a GU medical oncologist and immunologist, it has been my privilege to help lead some of these studies, which enabled FDA-approval, and to elucidate mechanisms that lay the groundwork for improving clinical outcomes with immunotherapy.