Immunotherapy is uniquely positioned to shift the paradigm of cancer treatment. Cancer cells evade immune destruction in part by generating an immunosuppressive microenvironment. One immunotherapeutic approach to cancer treatment is adoptive tumor-infiltrating lymphocyte (TIL) therapy, in which T cells isolated from tumors are expanded in vitro and then reinfused into the patient to treat other tumors and distant metastases. The most responsive T cells are activated chronically and therefore succumb to a persistent hypo-responsiveness deemed T cell ‘exhaustion.’ As the most reactive to tumor antigens, exhausted T cells are the most desirable for expansion. However, the tumor-infiltrating T cells within the tumor microenvironment that would be crucial to an effective immune response instead display crippling metabolic defects characterized by loss of mitochondrial function and proliferate less vigorously compared to non-tumor-reactive T cells. Thus, most patients derive little benefit from this approach. The metabolic exhaustion of tumor-specific T cells is a significant barrier to adoptive TIL effectiveness, but metabolic reprogramming with pharmacologic agents may represent a solution.
Description
Due to chronic activation, the most tumor-reactive T cells are exhausted and fail to effectively proliferate or kill target cells. Importantly, T cells that infiltrate tumors also fail to generate new mitochondria, and display repressed expression of the transcriptional co-activator PGC1α. Restoration of PGC1α function rescues T cell function and promotes mitochondrial activity within the tumor microenvironment, allowing those cells with the highest tumor specificity to more effectively proliferate alongside their less reactive counterparts and leading to a higher representation in the final cellular product. Rosiglitazone is a PPAR gamma agonist shown to promote mitochondrial biogenesis by upregulating PCG1α expression. Alongside sirtuins and resveratrol that promote PGC1α to target genes and transcriptional activity, these pharmacological compounds may reactivate mitochondrial function to support the expansion of exhausted T cells and promote the efficacy and adoptive TIL therapy.
Applications
· Restore metabolic function to exhausted T cells
· Enable proliferation of exhausted T cells, which are likely more tumor-reactive than their non-exhausted counterparts, for use in adoptive TIL therapy
· Improving on existing immunotherapeutic approaches to treatment of cancer
· Developing new approaches to cancer treatment
Advantages
· No other protocols use pharmacologic intervention of metabolic pathways to promote T cell expansion
Invention Readiness
In vivo data
IP Status
https://patents.google.com/patent/US20240335473A1
