Philip Greenberg, MD

ACGT – Edward Netter Memorial Investigator Award in Cell and Gene Therapy for Pancreatic Cancer Research

Patients with pancreatic cancer (PDA) generally present with advanced disease, and standard treatment regimens have provided limited benefit in this setting. Immunotherapy has proven to be a promising new therapy for many malignancies, but yielded only marginal benefit thus far in PDA. We have pursued a strategy for engineering immune cells to be able to recognize tumors, and then administering large numbers of these cells to treat cancers. We demonstrated in a mouse model that CD8 T cells engineered with a tumor-specific T cell receptor (TCR) targeting the tumor antigen Mesothelin can infiltrate pancreatic tumors and mediate therapeutic anti-tumor activity.

This led to a clinical trial in which patients with metastatic PDA were treated with their own CD8 T cells that we engineered ex vivo with a human MesotheIin-specific TCR. Biopsies were obtained after T cell infusions, infiltrating T cells isolated, and the T cells and tumor cells analyzed in depth to elucidate obstacles to efficacy. In both the mouse model and clinical trial, the infused CD8 T cells by day 21 had acquired in the tumor characteristics of exhaustion, becoming dysfunctional and failing to expand at the tumor site. Therefore, we have been developing synthetic strategies for further engineering of T cells to enhance activity for mediating more sustained responses.

For this trial, we have isolated a human TCR specific for mutated KRAS, which in the vast majority of PDA cases is an obligate driver of the cancer, making it difficult for the tumor to evade responses by losing the antigen. To better sustain T cell responses, we are introducing the TCR plus CD8 genes, which improve TCR binding to its target, into both CD4 and CD8 T cells to create a coordinated T cell response in which both CD4 and CD8 T cells can recognize and respond to the same and adjacent tumor cells. These genes can now create functional CD4 T cells, which has been shown in multiple models to not only promote CD8 T cell function, proliferation, and survival, but also delay or prevent exhaustion. Therefore, in this clinical trial for advanced PDA we will treat patients with their own CD4 and CD8 T cells engineered to express both a TCR specific for mutant KRAS and the CD8 genes.

Patients will be biopsied before and after T cell infusions, as our prior experiences highlighted the value of in-depth analysis of the tumor and infiltrating T cells to elucidate reasons for success or failure for building next generation strategies. The high dimensional data will be used to engineer T cells that can overcome encountered obstacles impeding tumor eradication and will be validated in preclinical PDA models. We have already generated synthetic proteins that can convert inhibitory or death signals into costimulatory and survival signals, or suppressive signals into proliferative signals, and will prioritize advancing to next generation trials the synthetic strategy(s) most effective for overcoming observed obstacles.

“What we’ve been trying to focus on is how we can build responses that will eliminate the tumor, not just shrink it. And we’re getting closer and closer in that regard.”