Despite the remarkable success of biologics-based blockade of immune checkpoint pathways in a wide variety of human cancer types, a significant portion of patients do not experience durable clinical benefit. Furthermore, autoimmune complications affecting various organ systems have been reported in association with such immune checkpoint inhibitors. Our strategy to target a key immuno-metabolic axis with small molecules presents as an alternate and a novel approach to address these clinical barriers. Results from several murine models of different tumor types with “cold” and “hot” TMEs alike using Nirogy’s small-molecule inhibitors, dMCTi suggest that direct manipulation of tumor-derived lactate levels is an effective immunotherapeutic approach. This approach is unique in that the drug can activate both innate and adaptive immune systems, and concurrently kill cancer cells directly by accumulating lactate intracellularly that leads to multiple cell death pathways.
The presence of activated tumor-infiltrating lymphocytes (TILs), particularly CD8+ T lymphocytes, in the TME is generally a prerequisite for a successful endogenous anti-tumor response. In patients who do not respond to CTLA-4 or PD-1 pathway inhibitory therapeutics, however, the cytotoxic immune cells in the TME are rendered non-functional by various extrinsic suppressive mechanisms in the TME. These include, but are not limited to, regulatory T cells (Treg), tumor-associated macrophages (TAM) with M2-like phenotypes, myeloid derived suppressor cells (MDSC), immunosuppressive cytokines such as TGFb and IL-10, and metabolic byproducts. Recently, tumor-derived lactate has emerged as an important immunosuppressive metabolite that contributes to an acidic, hypoxic TME which not only promotes tumor cell survival but also facilitates immune escape of tumor. Nirogy’s dMCTi lowers the lactate levels in the TME, thus blocking multiple immunosuppressive pathways operating in suppressive immune cells leading to overall anti-tumor immunity.
*Jackie E. Bader, et.al., Targeting Metabolism to Improve the Tumor Microenvironment for Cancer Immunotherapy”, Molecular Cell (2020), 78, 1019-1033.