Technologies for Treating or Preventing CAR T-cell Toxicities

SK2018-014, SK2017-029

Technologies for Treating or Preventing CAR T-cell Toxicities

SK2018-014, SK2017-029

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SUMMARY OF INVENTION

It is known that CAR T-cell therapy can trigger several toxicities, including neurotoxicity and life-threatening Cytokine Release Syndrome (CRS). These toxicities are a barrier for widespread application of CAR-cell therapy.  In two separate projects, MSK investigators have developed technologies to address these CAR T-cell toxicities. 

Preventing or treating CRS:

A major pro-inflammatory cytokine involved in CRS is Interleukin 1 (IL-1), which binds the IL-1 receptor. Interleukin-1 receptor antagonist (IL-1Rα) is a protein that is naturally expressed in an inflammatory context and binds the IL-1 receptor but does not induce functional signaling. Investigators have developed a CAR T-cell that expresses IL-1Rα, allowing for the CRS to be treated intrinsically by the CAR T-cell itself without the need for external pharmacological intervention.  They have demonstrated that mice treated with the IL1Rα CAR are protected from CRS-related mortality.

Preventing or treating neurotoxicity:

MSK investigators reported that patients who receive CAR T-cell infusion and experience neurotoxic side effects show systemic inflammation, disruption of the blood-CSF barrier, aberrations in the tryptophan-kynurenine pathway and increased activity of the neurotransmitters, NMDA and APMA. Interventions to reduce early inflammation, blood-CSF barrier disruption, myeloid cell accumulation or activation, or NMDA and AMPA receptor activity may reduce neurotoxicity and further improve the safety of CAR T-cells.

 ADVANTAGES

  • MSK investigators have done path-breaking research on CAR T-cells, and are leaders in the clinical development of CAR T-cell therapies
  • The technologies could address some of the serious side effects observed with CAR T-cell treatment, which could allow for these therapies to be used more broadly
     

MARKET OPPORTUNITIES

The ability to prevent or treat CAR T-cell toxicities would deliver significant benefits to patients and address a compelling unmet need. CRS and neurotoxicity are a common and serious side effect observed with CAR T-cell infusion.  In patients with acute lymphoblastic leukemia (ALL), CRS occurs in ~60-90% of patients treated with CAR T-cells.  As many as  50% of patients experience neurotoxicity.

PATENT INFORMATION

National stage and PCT applications pending

REFERENCES

  • Giavridis T. et al. Nat Med 24(6):731-738 (2018)
  • Santomasso, B.D. et al. Cancer Discov 10.1158/2159-8290.CD-17-1319 (2018)

 LEAD INVESTIGATORS

  • Michel Sadelain, MD, PhD, Director, Center for Cell Engineering & Gene Transfer and Gene Expression Laboratory, Memorial Sloan Kettering Cancer Center (MSK)
  • Bianca Santomasso, MD, PhD, Neuro-oncologist and Neurologist, Memorial Hospital, MSK

CONTACT INFORMATION

Eileen Flowers, PhD and Kannan Krishnamurthy, PhD

Associate Directors, Technology Development
E-mails: flowerse@mskcc.org, krishnak@mskcc.org

 

Stage of Development

In vitro