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 has yielded only marginal benefit thus far in PDA. In past trials conducted by Greenberg and colleagues, engineered T cell therapies have shown initial promise, only to quickly become exhausted and dysfunctional at the tumor site.
Now, Greenberg is working to overcome this challenge by developing next-generation T cell therapies targeting mutant KRAS, a non-evadable obligate driver in most PDA cases. To sustain anti-tumor responses and prevent exhaustion, the team will introduce a mutant KRAS-specific TCR plus CD8 genes into both CD4 and CD8 T cells in order to create a coordinated T-cell response in which functional CD4 cells promote CD8 T-cell proliferation, survival, and sustained activity.
In an innovative clinical trial for advanced PDA, patients will be treated with their own engineered CD4 and CD8 T cells. Critical high-dimensional data will be collected via pre- and post-infusion biopsies. This rigorous analysis is essential for elucidating clinical obstacles and informing next-generation strategies. The lab has already developed synthetic proteins that convert inhibitory signals into costimulatory/survival signals, and will prioritize advancing the most effective synthetic strategy(s) for overcoming observed clinical obstacles in subsequent trials.