Enhanced Antitumor Immunity Through Sequential Targeting Of Pi3k Delta And Lag3

Background Despite striking successes, immunotherapies aimed at increasing cancer-specific T cell responses are unsuccessful in most patients with cancer. Inactivating regulatory T cells (Treg) by inhibiting the PI3K delta signaling enzyme has shown promise in preclinical models of tumor immunity and is currently being tested in early phase clinical trials in solid tumors. Methods Mice bearing 4T1 mammary tumors were orally administered a PI3K delta inhibitor (PI-3065) daily and tumor growth, survival and T cell infiltrate were analyzed in the tumor microenvironment. A second treatment schedule comprised PI3K delta inhibitor with anti-LAG3 antibodies administered sequentially 10 days later. Results As observed in human immunotherapy trials with other agents, immunomodulation by PI3K delta-blockade led to 4T1 tumor regressor and non-regressor mice. Tumor infiltrating T cells in regressors were metabolically fitter than those in non-regressors, with significant enrichments of antigen-specific CD8(+) T cells, T cell factor 1 (TCF1)(+) T cells and CD69(-) T cells, compatible with induction of a sustained tumor-specific T cell response. Treg numbers were significantly reduced in both regressor and non-regressor tumors compared with untreated tumors. The remaining Treg in non-regressor tumors were however significantly enriched with cells expressing the coinhibitory receptor LAG3, compared with Treg in regressor and untreated tumors. This striking difference prompted us to sequentially block PI3K delta and LAG3. This combination enabled successful therapy of all mice, demonstrating the functional importance of LAG3 in non-regression of tumors on PI3K delta inhibition therapy. Follow-up studies, performed using additional cancer cell lines, namely MC38 and CT26, indicated that a partial initial response to PI3K delta inhibition is an essential prerequisite to a sequential therapeutic benefit of anti-LAG3 antibodies. Conclusions These data indicate that LAG3 is a key bottleneck to successful PI3K delta-targeted immunotherapy and provide a rationale for combining PI3K delta/LAG3 blockade in future clinical studies.