SUMMARY OF INVENTION
This technology seeks to potentiate the efficacy of T-cell therapy, with an initial focus on mesothelin-expressing solid tumors. Following immune attack, solid tumors upregulate certain molecules (called checkpoints) that can suppress the effect of the cytotoxic T-cells. These molecules can compromise the function of the T-cells, including CAR and TCR T-cells
To inhibit these checkpoints, MSK investigators have genetically engineered a PD-1 dominant negative receptor (DNR) that acts as a decoy receptor with no intracellular inhibitory signaling domain. Antigen-specific CAR T-cells were co-transduced with such PD-1 DNRs. These CAR T-cells showed enhanced T-cell function and led to long-term tumor-free survival in a mouse models of mesothelioma and lung cancer. Preclinical data confirms that these PD-1 DNR T-cells can be combined with other checkpoint blockade therapy such as anti-PD-L1/2 or anti-TIM-3.
Phase 1 trial with CAR T-cells co-transduced with PD-1 DNR is ongoing (NCT04577326).
- Ability to localize T-cell effect at the tumor site
- Consistent PD-1 blockade specific to T-cells produces a higher, more sustained response
- PD-1 DNR acts a co-stimulatory domain to the T-cells
- Platform technology holds the potential for different combinations of checkpoint blockade
The market potential of PD-1 DNR non-cytotoxic immune cell therapy is significant, and this therapy could extend beyond non-small cell lung cancer to other solid and liquid tumors, as well as non-cancerous conditions such as organ transplantation, allergic/infectious/autoimmune disorders, and prevention of fetal loss.
STAGE OF DEVELOPMENT
Pending applications filed Dec. 9, 2015 covering PD-1 DNRs for use in cancer therapy and non-cancer treatments. PCT application PCT/US2016/065578 published; extensive national filings pending.
Adusumilli S. Prasad et al., The Journal of Clinical Investigation, 2016
Prasad S. Adusumilli, MD, Deputy Chief, Thoracic Service, Memorial Sloan Kettering