Project 1: Improving Immunotherapy in pancreatic NETs

University Of Iowa, Iowa City IA

Investigators

Linked publications, trials & patents

Abstract

Project 1 – Summary There is a persistent, unmet clinical need for more effective therapies to treat and potentially cure advanced NETs. Pancreatic NETs (pNETs) are among the most common types of NETs and have risen 4-fold in incidence over the last few decades. Immune checkpoint inhibitor (ICI) therapies can provide sustained anti- tumor responses and improve survival for other tumor types, but trials assessing anti-PD-1 (ICI antibody) monotherapies have failed in pNET patients. Likewise, trials assessing single agent inhibitors of cyclin- dependent kinase 4/6 (CDK4/6), which are hyperactivated in pNETs, have been unsuccessful in these patients. This proposal explores a new approach to sensitize pNETs to ICI therapy – combining immunomodulatory CDK4/6 inhibitors with ICI antibodies to achieve synergistic antitumor immunity. This combination strategy seeks to increase T cell activation in tumors by targeting kinases whose inhibition provokes B and/or plasma cell infiltration. Growing evidence from other tumor types suggests intratumoral B/plasma cells promote T cell activation by increasing formation of tertiary lymphoid structures (TLS). TLS correlate with better response to ICI therapy and improved patient survival. These connections have never been examined in NETs and the anti-tumor role of plasma cells, specifically, has never been tested in any cancer. In pilot studies, pharmacological blockade of the CDK4/6 pathway using MEK and CDK4/6 inhibitors induced B/plasma cell tumor infiltration and robust tumor regression in an immune competent model of functional pNETs (insulinoma). Additional pilot studies showed CDK4/6 blockade sensitized pNETs to ICI therapy targeting programmed death ligand 1 (PD-L1). Three aims will test the central hypothesis that B/plasma cell tumor infiltration due to CDK4/6 blockade enhances anti-tumor immunity and improves the efficacy of ICI therapy in pNETs. • Aim 1. Determine associations between B/plasma cell tumor infiltrates with other immune features, clinical variables and molecular signatures in patient pNETs. • Aim 2. Define the efficacy of CDK4/6 blockade and role of B/plasma cell tumor infiltrates in sensitizing pNETs to ICI therapies in preclinical models. • Aim 3. Conduct a Phase 1b Window of Opportunity Trial in pre-operative pNET patients measuring the effects of CDK4/6 inhibitor plus ICI therapy on immune cell tumor infiltration and activation. The therapeutic combination of CDK4/6 blockade with ICI agents offers the promise of sustained anti-tumor activity, extended patient survival, and potential cure for patients with advanced pNETs. This project will advance our understanding of B/plasma cell infiltrates in pNET biology and may identify new prognostic and predictive NET biomarkers. Studies will also determine, for the first time in any tumor type, the necessity of plasma cells in pNET anti-tumor immunity, which has broad implications for all solid tumors.