Inhibition of T Cell Lactate Dehydrogenase (LDH) ex vivo Enhances the Anti-tumor Efficacy of Adoptive T Cell Therapy

Adoptive T cell therapy (ACT) with tumor infiltrating lymphocytes (TIL), T cell receptor (TCR) and Chimeric Antigen Receptor (CAR) engineered T cells, or hematopoietic stem cell transplantation, is a promising new approach to cancer treatment. ACT harnesses an individual's adaptive immune system to fight against cancer, with fewer side-effects and more specific anti-tumor activity. Despite their promise of ACT as curative, these therapies are often limited by the persistence and robustness of the responses of the T cells to the cancer cells. Altering metabolic pathways is one way to affect the actions of T cells, and different cellular subtypes vary in how they produce and expend energy. T cell metabolism can be altered by several factors, including cytokine stimulation and by inhibiting lactate dehydrogenase (LDH), which mediates the final step in glycolytic metabolic pathway.

Researchers at the National Cancer Institute (NCI) and the National Heart Lung and Blood Institute (NHLBI) have discovered that preconditioning T cells with LDH inhibitors during in vitro culture with cytokines improves efficacy of these cells once adoptively transferred to a mouse model of melanoma. This was accomplished by investigating the role of metabolic programming in the developmental differences induced by interleukin-21 (IL-21), a cytokine with known antitumor activity. IL-21 alone promoted stem cell memory T cells (TSCM) expansion, and this was enhanced when combined with an LDH inhibitor. This resulted in a more profound antitumor responses and prolonged host survival. Studies revealed that inhibition of LDH activity prior to adoptive transfer of CD8+ T cells promoted maintainence of the cells in a more T stem-cell like state. Combining IL-21 with the LDH inhibitor also prevented the induction of several immune checkpoints/exhaustion molecules known to limit in vivo antitumor responses – including PD-1, TIM-3, LAG3 and 2B4. Results are similar for LDH inhibition of human and murine CD8+ T cells in vitro, underscoring the potential therapeutic benefits of preconditioning with LDH inhibition before ACTimmunotherapy.  

The NCI seeks research co-development partners and/or licensees for clinical evaluation of this invention.