Interleukin-37 to Enhance Effectiveness of CAR T-cell Therapy

Application

IL-37-expressing CAR T-cells to treat B-cell acute lymphoblastic leukemia.

Key Benefits

Boosts the function of aged T-cells.
Enhances the effectiveness of CAR T-cell therapy.
Therapeutic potential to overcome aging-associated immune-senescence.
Potent suppressor of chronic inflammation or pro-inflammatory cytokines.

Market Summary

Acute lymphoblastic leukemia (ALL) is an aggressive type of leukemia, which requires early treatment; without treatment, most patients with acute leukemia would live only a few months. The most classic treatment for B-cell ALL is chemotherapy to get the leukemia into complete remission. However, cancer related mortality rates are higher in older population due to toxicity complications associated with chemotherapy. If the leukemia is refractory – that is, if it doesn’t go away with the first treatment which happens in about 10% to 20% of patients) – then newer or more intensive doses of chemo drugs may be tried, although they are less likely to work. Immunotherapy (monoclonal antibodies or CAR T-cell therapy) may be an option for patients with B-cell ALL. However, issues with CAR T cell therapy include unsustainable remissions in 60-70% of patients, major toxicity caused by cytokine release syndrome and frequent relapse in less than 2 years resulting from target antigen loss and compromised T-cell function. Thus, more efficient CAR T cell therapies are needed to increase the longevity of CAR T cells and reduce toxicity.

Technical Summary

The invention describes interleukin-37 (IL-37)-expressing chimeric antigen receptor (CAR) T-cells capable of improving the CAR T-cell efficacy in aged backgrounds. Researchers at Emory found that combining rIL-37 and CAR T-cell treatment significantly improves survival and therapeutic efficacy of aged CAR T-cells in a murine model of B-ALL. rIL-37 treatment also increased IL-2 and INF gamma production from aged CD4+ and CD8+ CAR T-cells. IL-37 can improve functionality of CAR T-cell by inducing cytokine homeostasis during T-cell activation and by reducing CRS-related toxicity during treatment. Armored CAR T-cells can be created using bicistronic constructs and a P2A sequence to allow for dual expression of both the CD19-CAR and IL-37. These novel armored CAR T-cells can be used to reduce severe toxicity caused by cytokine release syndrome in patients receiving this form of immunotherapy (>40 of patients).