UC San Diego Researchers Receive $600,000 Grant to Test PI3Ky Inhibitor

A University of California San Diego School of Medicine and Moores Cancer Center research team studying new drugs that could break resistance to cancer immunotherapy has received a 3-year, $600,000 translational grant from the V Foundation for Cancer Research.

Judith A. Varner, PhD, professor in the departments of pathology and medicine in the School of Medicine, leads the team that, in a study published in 2016, identified the enzyme PI-3 kinase gamma (PI3Ky) as a critical molecular switch between immune stimulation and suppression during inflammation and cancer.

In the study, the researchers demonstrated that PI3Ky induces a transcriptional program that promotes immune suppression during inflammation and tumor growth, and that selective inactivation of microphage PI3Ky promotes an immunostimulatory transcriptional program that restores CD8+ T-cell activation and cytotoxicity.

Synergizing with checkpoint inhibitor therapy, PI3Ky promotes tumor regression and increased survival, and PI3Ky-directed anti-inflammatory gene expression can predict survival probability in patients with cancer. In mouse models, a PI3Ky inhibitor, IPI-549, reversed immune suppression, stimulated response to checkpoint inhibitors, and eliminated cancer in 50% to 100% of test animals.

The research team will use the funds from the V Foundation’s grant to conduct clinical trials testing IPI-549 both alone and in combination with other drugs in head and neck cancers in the hope that this prospective drug will boost the effectiveness of immunotherapy.

In a statement, Ezra Cohen, MD, head of the San Diego Center for Precision Immunotherapy at UC San Diego Health, said, “Immunotherapy holds a lot of promise for patients, but we need to increase its potency to be effective in a larger number of patients. This study could lead to greatly improved outcomes for patients with head and neck cancers and many other malignancies.”

In addition to testing the efficacy of the proposed drug, the team will test a new method of monitoring patients’ immune responses to the therapy, and will investigate cellular and molecular mechanisms behind successful immune responses resulting from these therapeutic approaches.

Varner told The American Journal of Managed Care^® in an e-mail that "The prestigious V Foundation award provides the opportunity to exploit our recent research discoveries to develop an entirely new immunotherapeutic approach toward cancer. While current approaches to immune therapy are promising, there is clearly room to improve their effectiveness and broad applicability to all cancer patients. Our work has identified a new paradigm of immune therapy focused on targeting macrophages that synergizes with recently approved T-cell targeted immune therapies and other anti-cancer drugs. This award will further development of this new type of immune therapy."

Founded in 1993 by ESPN and basketball coach Jim Valvano, the V Foundation for Cancer Research has awarded over $200 million in cancer research grants nationwide.