Therapeutic vaccines could have a transformative impact on cancer therapy, but are currently hindered by inefficient expansion of the correct types of immune cells needed to migrate to tumors and destroy these tissues, while also establishing immune memory that prevents tumor relapse.
The goal of this project is to locally engineer the microenvironment of lymph nodes – the tissues that control immunity – using controlled release vaccine depots. These depots are formulated with activating immune signals, cues to promote immune memory, and DNA encoding molecules commonly upregulated on cancer cells.
Local delivery of these signals to lymph nodes could promote potent tumor immunity and long-lasting anti-tumor T cells. This work will shed new light on how the kinetics and concentrations of tumor vaccine components impact lymph node structure and function and support the development of a new class of cancer vaccines that could clear existing tumors and prevent new tumor growth.
Re-activating and directing a cancer patient’s immune system to reject their tumors and eradicate the cancer with minimal toxicity to the patient is the ultimate goal of the cancer immunotherapy field. The field has made great progress, with multiple immunomodulatory antibody therapies already approved and more in the therapeutic pipeline. Additional progress has been seen in recent successful cancer treatment using genetically modified T cell-based therapy. These advances in cancer immunotherapy represent the clinical translation of research into the signals that activate and inhibit cells of the immune system, particularly T cells.
We believe that through understanding the molecular mechanisms by which recent translational approaches have been successful we can establish a strong foundation for the rational design of new approaches to T cell cancer immunomodulatory therapy.
Specifically, we believe that by investigating connections between two of the signaling molecules targeted in developing antibody and cell based Immunotherapeutics, PD-1 and 4-1BB, and two transcription factors critical to effective and durable T cell immune responses, T-bet and Eomesodermin (Eomes), we will identify T cell molecules and signaling pathways representing promising future targets in cancer immunotherapy.
Our prior work has described the functions of T-bet and Eomes in determining T cell behavior in immune responses. Our preliminary data show that Eomes is essential to cancer immunotherapeutic approaches targeting either PD-1 or 4-1BB on T cells. In the proposed project we will determine how Eomes contributes to T cell anti-tumor activity and determine what, if anything, is needed in T cells beyond Eomes to enact a strong and durable anti-cancer response. The Alliance for Cancer Gene Therapy funded research will provide new insights into the mechanisms of cellular cancer immuno-modulatory therapy that we will use to design and test novel cancer immunotherapeutic approaches.
This Alliance for Cancer Gene Therapy Research Fellow is funded in part by Swim Across America.