CAR T-cells with Intrinsic Checkpoint Blockade

SK2015-111

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SUMMARY OF INVENTION

  • This technology seeks to expand the efficacy of CAR T-cells to solid tumors, with an initial focus on mesothelin-expressing tumors. Following immune attack, solid tumors upregulate certain molecules (called checkpoints) that can suppress the effect of the CAR T-cells. The molecules can compromise the function of the CAR 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 model of mesothelioma. These CAR T-cells can be combined with other checkpoint blockade therapy such as anti-PD-L1/2 or TIM-3.
  • These CAR T-cells are being tested in animal models with an aim to file an IND application in 12-18 months.

ADVANTAGES

  • Ability to localize T-cell effect at the tumor site
  • Better PD-1 blockade produces a larger, more sustained response
  • Increased penetration of T-cells to the tumor, compared to previous efforts
  • 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 large, and could extend beyond non-small cell lung cancer to other solid tumors as well as non-cancerous conditions such as organ transplantation, allergic/infectious/autoimmune disorders, and prevention of fetal loss.
 
STAGE OF DEVELOPMENT

Preclinical

PATENT INFORMATION

Extensive portfolio of pending U.S. and non-U.S. national applications covering PD-1 DNRs for use in cancer therapy and non-cancer treatments; Published PCTs include:  PCT/US2016/065578 (published Dec. 8, 2016); PCTUS2017/049085 (published Aug. 29, 2017), and PCT/US2018/021249 (published March 7, 2018).
 
REFERENCES

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

LEAD INVESTIGATOR

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

CONTACT INFORMATION

Eileen Flowers, PhD, Senior Manager, Business Development & Licensing

Tel. 646-888-1067; E-mail: flowerse@mskcc.org

MSK Internal Code:  2015-111

Stage of Development

In vitro