Enlightenment of a New Era of Cancer Therapy: Prognostication, Target Selection, and Subsequent Therapy Determined by the Dual Tumor-Immune Phenotype

Objective:

To identify tumor-immune biomarkers that represent prognostic, predictive, and therapeutically actionable targets in patients with neuroendocrine tumors.

A tumor’s capacity to evade and suppress the immune response is a well-established hallmark of cancer. That harnessing the immune response could result in cure of a subset of patients with cancer is a revolution in cancer therapy. However determining the potential of immunotherapy to be efficacious for patients with NETs necessitates an understanding of the tumor-immune phenotype which today remains unknown.

The ultimate goal of this project is to identify tumor-immune biomarkers that represent prognostic, predictive, and therapeutically actionable targets in patients with neuroendocrine tumors.

Research Objectives:

1. To characterize the tumor-immune phenotype including a comprehensive immune profile and tumor genome utilizing the Stanford neuroendocrine tumor tissue microarray that includes 1031 tumors from 690 neuroendocrine tumor patients.
2. To (a) characterize the tumor-immune phenotype including a comprehensive immune profile and tumor genome in serial samples among 20 patients enrolled in a Stanford investigator initiated clinical trial of intratumoral anti-CTLA4 (ipilimumab) immunotherapy with anti-PD-L1 (MPDL3280A) in patients with well-differentiated, progressive neuroendocrine tumors.

Abstract:

Monoclonal antibodies provided a major advance in cancer therapy however, their application is dependent on tumor expression of specific antigens. As cancer treatment enters a new era, that of the immunotherapy revolution, application of immune targeting agents is dependent on understanding the immunogenicity of a tumor based on genetic analysis and immune competency of the patient, based on immunophenotyping of the infiltrating and systemic immune response. The most promising new immunotherapy agent which removes the local immune tolerance blocks the interaction of PD-1 on antitumor immune cells and PD-L1 on tumor cells with likelihood of response predicted by presence and amplitude of expression of PD-L1. Tumor expression of PD-L1 is one of numerous considerations, which remain unexplored and therefore poorly characterized in neuroendocrine tumors. To ensure patients with neuroendocrine tumors benefit from and are not left behind in the new era of immunotherapy, we will perform an in-depth assessment of tumor genome and immune phenotyping applying state of the art genetic and immune analytic tools to over 1000 retrospective neuroendocrine tumor samples, and 20 serially sampled prospective neuroendocrine tumor patients enrolled in an immunotherapy trial at Stanford.