CAR T-Cell Therapy with PD-1 Intrinsic Checkpoint Blockade

SK2015-111

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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).

ADVANTAGES

  • 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

MARKET OPPORTUNITIES

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

Clinical

PATENT INFORMATION

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.

REFERENCES

Adusumilli S. Prasad et al., The Journal of Clinical Investigation, 2016

LEAD INVESTIGATOR

Prasad S. Adusumilli, MD, Deputy Chief, Thoracic Service, Memorial Sloan Kettering

CONTACT INFORMATION

Eileen Flowers, PhD

Associate Director, Technology Development
Tel: 646-888-1067
E-mail: flowerse@mskcc.org
MSK Internal Code: SK2015-111

Stage of Development

Clinical development