JUN 03, 2020 6:00 AM PDT

Keynote Presentation: Development of Rational Immunotherapy Combinations to Overcome the Immunosuppressive Prostate Tumor Microenvironment

C.E. Credits: P.A.C.E. CE Florida CE
Speaker
  • Assistant Professor, Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center
    Biography
      Dr. Sumit Subudhi is a medical oncologist and immunologist whose research focuses on the mechanisms and pathways within the immune system that are responsible for tumor rejection and clinical benefit. Dr. Subudhi's medical training began when he enrolled in the MD/PhD program at The University of Chicago Pritzker School of Medicine in 1998. Dr. Subudhi's predoctoral studies included examining the role of B7-H1 (PD-L1), an immune checkpoint, in regulating T cell-mediated immune responses. He completed his PhD in 2004, his MD in 2007, his internal medicine residency at the New York-Presbyterian Hospital/Weill Cornell Medical Center in 2009, and his medical oncology fellowship at Memorial Sloan Kettering Cancer Center (MSKCC) in 2013. During his medical training, Dr. Subudhi became interested in the field of tumor immunology and subsequently worked in Dr. James P. Allison's laboratory at MSKCC during his fellowship years. In Dr. Allison's laboratory, Dr. Subudhi began to examine the effects of targeting immune checkpoints (e.g., CTLA-4 and PD-1) in prostate cancer and continues to uncover the mechanisms that tumors use to evade the immune system. After completing his fellowship at MSKCC, Dr. Subudhi was appointed as an Advanced Scholar Instructor at MD Anderson Cancer Center in 2013, and as an Assistant Professor in the department of Genitourinary Medical Oncology in 2014. His emphasis is on developing optimal immune checkpoint therapy-based combinations and identifying immunological biomarkers to predict treatment responses, with the hope of ultimately producing durable and even curative responses in patients with prostate cancer. Dr. Subudhi was awarded the Prostate Cancer Foundation (PCF) Young Investigator Award in 2014 and the V Foundation Award (Lloyd Family Clinical Oncology Scholar) in 2017 to pursue these studies. More recently, Dr. Subudhi has been investigating the immunological differences within the primary and metastatic prostate tumor microenvironments. In addition, he has been focused on identifying predictive biomarkers for immune-related adverse events (irAEs) to minimize toxicities and maximize benefit to immune checkpoint therapies.

    Abstract

    Immune checkpoint therapies targeting the CTLA-4 and PD-(L)1 pathways have been largely clinically disappointing for patients with prostate cancer. This can be attributed to the highly immunosuppressive prostate tumor microenvironment, reflected in the paucity of T cells and enrichment of myeloid cells. However, a subset of patients with metastatic prostate cancer respond to ipilimumab (anti-CTLA-4). We recently identified markers associated with Th1 effector T cells responses, such as a high intratumoral CD8 density and/or expression of a high IFN-gamma-response gene signature, which correlated with prolonged clinical responses to ipilimumab.

    To elucidate mechanisms of resistance to ipilimumab, we evaluated pre- and post-treatment prostate tumor tissues. Ipilimumab increased T cell infiltration within the prostate tumor microenvironment, converting it to an immunologically “hot” tumor. However, this was countered by upregulation of the inhibitory immune checkpoints, PD-L1 and VISTA. Simultaneously targeting the PD-(L)1 and CTLA-4 improved survival in murine models of prostate cancer. These data led to the design and accrual of an international study evaluating the combination of nivolumab (anti-PD-1) plus ipilimumab in patients with metastatic prostate cancer. The combination induced durable radiographic responses in a subset of patients, suggesting that adaptive resistance to ipilimumab monotherapy could be overcome by targeting more than one immune checkpoint.

    Despite the striking responses in certain patients, that most did not benefit from the combination of nivolumab plus Ipilimumab implies other mechanisms of resistance to ipilimumab monotherapy. We found high levels of the immunosuppressive cytokine TGF-beta within the metastatic prostate bone tumor microenvironment. In a preclinical model of prostate cancer, concurrently targeting TGF-beta and CTLA-4 promoted Th1 responses associated with improved overall survival. This suggested that high levels of TGF-beta may be a mechanism of primary resistance to ipilimumab, which will need to be confirmed in patients. Taken together, our data supports the rational development of combination therapies to overcome the immunosuppressive prostate tumor microenvironment.

    Learning Objectives:

    1. Explain the mechanisms of action for immune checkpoint therapies

    2. Identify primary and adaptive resistance mechanisms to immune checkpoint therapies

    3. Explain current approaches to combination therapy in the clinic


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