Enhancing Cancer Immunotherapy by Silencing MCT11 to Overcome T-Cell Exhaustion
This invention utilizes modified peripheral blood mononuclear cells (PBMCs) with reduced expression of the Slc16a11 gene or inhibited MCT11 protein activity to treat cancer. By blocking this specific monocarboxylate transporter, the therapy prevents metabolic stress and the subsequent "exhaustion" of T-cells, allowing them to remain active and effective against tumors.
Description
The core technology involves the targeted inhibition of Monocarboxylate Transporter 11 (MCT11), encoded by the Slc16a11 gene, which is found to be highly upregulated in terminally exhausted CD8+ tumor-infiltrating lymphocytes (TILs). These exhausted cells typically suffer from low mitochondrial mass and metabolic stress due to increased lactate uptake from the tumor microenvironment. The invention functions by using siRNAs, gRNAs (via CRISPR/Cas9), or shRNAs to silence Slc16a11, effectively closing the metabolic "gate" that leads to T-cell dysfunction. By preventing the uptake of immunosuppressive metabolites like lactate, the modified T-cells maintain a "progenitor-like" state characterized by high mitochondrial mass, superior polyfunctionality, and increased survival within the tumor.Applications
- Adoptive Cell Therapy (ACT): Enhancement of TIL (Tumor-Infiltrating Lymphocyte) therapies for solid tumors.- CAR-T and TCR-T Engineering: Genetic modification of engineered T-cells to improve their durability and performance in harsh tumor environments.
- Combination Cancer Immunotherapies: Use alongside checkpoint inhibitors (like anti-PD1) to treat resistant or "cold" tumors.
- Precision Medicine: Development of companion diagnostics or RNA-based therapeutics (siRNAs) targeting Slc16a11 expression.
- Solid Tumor Treatment: Specifically targeting metabolic-heavy cancers such as melanoma, colon adenocarcinoma, and HNSCC.
Advantages
- Reverses T-Cell Exhaustion: Prevents the transition of T-cells into a terminally exhausted, non-functional state.- Enhanced Metabolic Resilience: Protects immune cells from the acidic, lactate-rich environment of tumors that usually suppresses their activity.
- Improved Antitumor Efficacy: Demonstrates significant reduction in tumor volume compared to standard wild-type T-cell treatments.
- Increased T-Cell Survival: Maintains higher percentages of live, active CD8+ T-cells within the tumor area.
- Broad Therapeutic Compatibility: Can be applied to various cellular therapies, including CAR-T and TIL-based treatments.
Invention Readiness
The technology is currently in the late discovery/early pre-clinical stage. Researchers have successfully generated in vivo data using mouse models (B16 melanoma and MC38 colon adenocarcinoma), demonstrating that MCT11 knockout (KO) results in significant tumor volume reduction and increased T-cell polyfunctionality. Data also includes RNAseq analysis and pH-sensitive imaging confirming the metabolic shift in modified cells. Further studies are required to validate these effects in human clinical trials and to optimize the delivery methods for the genetic modifiers (siRNAs/gRNAs).IP Status
https://patents.google.com/patent/US20240325537A1Related Publication(s)
Peralta, R.M., Xie, B., Lontos, K. et al. Dysfunction of exhausted T cells is enforced by MCT11-mediated lactate metabolism. Nat Immunol 25, 2297–2307 (2024). https://doi.org/10.1038/s41590-024-01999-3