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.
- 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
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.
National stage and PCT applications pending
- 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)
- 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
Eileen Flowers, PhD and Kannan Krishnamurthy, PhD