Pilot Project: Blockade Of Immune Checkpoint Receptors For The Treatment Of Pancreatic Cancer
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the United States, with a 5 year mortality rate of 95%. Less than 20% of PDAC patients are eligible to undergo potentially curative surgery due to disease progression at diagnosis. Patients with unresectable PDAC usually succumb to disease within 6 months after diagnosis, and palliative treatment only minimally improves survival. Development of novel immunotherapeutic strategies aimed at counteracting mechanisms of tumor-induced immunosuppression is a promising approach to treat PDAC patients.
PDAC is a poorly differentiated tumor characterized by a profound immunosuppressed tumor microenvironment and desmoplasia.
Failure to recognize and reject transformed cells is correlated with increased expression of inhibitory immune-checkpoints receptors such as programmed death 1 (PD1) on T cells, which induces T cell hyporesponsiveness and tolerance to tumor-associated antigens. Elevated tumor expression of the PD1 ligand, PD-L1, is a poor prognostic factor for patients with PDAC and a valuable marker for predicting treatment benefit with blocking monoclonal antibodies to PD1 or PD-L1 in advanced cancer patient. Even though blockade of PD1 signaling has achieved impressive results in Phase 1 clinical trials for the treatment of various advanced tumors, the mechanisms by which PD1 blockade signaling induces tumor cell death and long-term remissions in patients are not clear.
Our project focuses on the pre-clinical development of a treatment strategy to relieve tumor immunosuppression via PD1 blockade. Our goal is to understand the molecular mechanisms leading to PDAC tumor cell death following treatment using anti-PD1 monoclonal antibody (mAb). studies are conducted using an immunocompetent orthotopic Kras and p53 mutant (KPC) PDAC mouse model. The PDAC tumor line derived from a KPC mouse expresses endogenous PD-L1 and accurately reproduces biochemistry of stromal-cancer cell interactions when administered orthotopically. Single treatment with anti-PD1 mAb induced marked tumor regression in mice with high tumor burden in as short as 3 days after treatment. In addition, treatment with anti-PD1 mAb effectively inhibited PDAC remission for an extended period of time post-tumor implantation. Detailed mechanistic studies to understand how blockade of PD1 signaling networks induces PDAC regression are currently underway. Results of these studies will be submitted to FDA as a modification of the active IND for our MVAp53 vaccine (see Project 4 for more information on the phase 1 MVAp53 clinical trial for the treatment of GI cancers) with a request to enroll less heavily pre-treated patients, as they respond better to immunotherapy than patients who have failed multiple chemotherapy regimens.
1. Salazar, M, Manuel ER, Tsai W, D'Apuzzo M, Goldstein L, Blazar R, Diamond DJ. Evaluation of innate and adaptive immunity contributing to the antitumor effects of PD1 blockade in an orthotopic murine model of pancreatic cancer. OncoImmunology, 10.1080/2162402X.2016.1160184 Available online 03/16
Cancer Center Support Fund - City of Hope (2013-2014) and the Tim Nesvig Lymphoma Research Fund to Don J. Diamond, Ph.D.
Marcela d'Alincourt Salazar, Ph.D., Edwin R. Manuel, Ph.D.
, Nicola Hardwick, Ph.D.
, Bruce Blazar, M.D., collaborator from the University of Minnesota Medical School, and Don J. Diamond, Ph.D