Etay Ziv, MD, PhD

Overview

Aim: Treatment and Therapy

Pancreatic neuroendocrine tumors, also called pNET or PanNETs, are the second most common type of pancreatic tumor, developing from specialized hormone-releasing cells called neuroendocrine cells. Well-differentiated tumors, when cancer cells appear and function similarly to healthy cells, tend to be slow-growing (or indolent) with a good prognosis. However, these types of tumors can and do transform into high-grade aggressive tumors with limited therapeutic options. In the transformation from well-differentiated, indolent tumor to a high-grade and aggressive tumor, cancer cells acquire additional genetic mutations which allows more immune cell activation and infiltration into the tumor microenvironment. Because of this increased immune cell population within high grade PNETs, checkpoint inhibitor immunotherapy, with anti-PD-1 or anti-CTLA4 antibodies, has been evaluated in these patients with disappointing results.

Pilot data from 2026 Hirshberg Foundations PNET Pathway Grant recipient Etay Ziv, MD, PhD, Associate Attending in the Department of Radiology at Memorial Sloan Kettering Cancer Center, demonstrates that while these transformed PNETs do have increased T cells and NK cells (a second type of tumor killing immune cell), tumor cells may be using alternative checkpoint pathways to escape immune cell killing. Instead of using the PD-1 or CTLA-4 pathways to inhibit the immune cells, the PNET cells express a protein called PVR. PVR on PNET cells can interact with two different proteins on immune cells called CD96 and TIGIT, to inhibit their activation and response. While there are CD96 and TIGIT inhibitors in clinical trials, they have not been tested in PNET patients.

In his PNET Pathway Grant project, Overcoming immunotherapy resistance in high grade pancreatic neuroendocrine tumors, Dr. Ziv will use a comprehensive biobank of PNET samples to assess the functional state of T cells in tumor microenvironment across low-grade and well-differentiated tumor to high-grade, aggressive tumors by analysing gene expression. Additionally, Dr. Ziv will map the interactions of CD96 and TIGIT expressing immune cells and tumor cells and correlate that data to tumor grade and survival across a panel of biobank specimens. This project will help establish the proof-of-concept data to support a clinical trial of existing CD96 and TIGIT inhibitors in PNET patients.

The Hirshberg Foundation is happy to support Dr. Etay Ziv’s research to increase the benefits of immunotherapy to PNETs with a 2026 PNET Pathway Grant Award.