Project 1: Employing CD11b-Agonists to Render PDAC Responsive to Immunotherapy

David DeNardo, PhD and Katrina Pedersen, MD

Pdac Image 3 Website
Depiction of the fibrosis present in the KPC mouse models of PDAC

Project 1 of the Pancreas SPORE seeks to understand if targeting integrins on myeloid cells can impact therapeutic responsiveness to immunotherapy in pancreas cancer. They include studies clinically testing an integrin agonist in PDAC patients and correlative and laboratory studies to understand mechanism of resistance.

Research Overview

Employing CD11b-Agonists to Render PDAC Responsive to Immunotherapy

The potential of checkpoint immunotherapy to combat cancer has been established in several cancer types. However, in pancreatic ductal adenocarcinoma (PDAC), checkpoint immunotherapy has not yet led to clinical benefits. Although multiple factors likely contribute to checkpoint resistance, one significant factor is extensive infiltration of PDACs by multiple lineages of immunosuppressive myeloid cells. These myeloid cells, which include tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), drive T cell exclusion and dysfunction. Thus, one promising therapeutic strategy is to reprogram these myeloid cells to improve T cell-mediated immunity.

Our team has recently developed an allosteric AGONIST of CD11b, A-008. Our published data demonstrate that CD11b-agonism rapidly repolarizes TAMs to support anti-tumor immunity and combining CD11b-agonists with checkpoint immunotherapy leads to tumor regression and long-term survival in pre-clinical PDAC models. These strong data drive our hypothesis that CD11b agonism reprograms the PDAC tumor microenvironment to overcome resistance to checkpoint immunotherapy. To test this hypothesis, we will:

Aim 1: Determine the safety and efficacy of A-008, Gemcitabine and Abraxane and PD-1 blockade in metastatic PDAC patients.

Aim 2: Determine the biomarkers of exposure, response, and resistance to A-008 therapy in PDAC patients.

Aim 3: Determine how tumor-intrinsic and extrinsic factors regulate the impact of CD11b agonist therapy. Impact: These studies will investigate a novel approach to render PDAC responsive to immunotherapy.

Project 1