SUMMARY:
UCLA researchers in the Department of Radiation Oncology at the School of Medicine have identified a cytokine receptor endowing adoptively transferred T cells with new functions that enhance the potency of adoptively transferred T cells for the treatment of solid tumors, namely by restoring their functionality in the absence of conditioning chemotherapy.
BACKGROUND:
T cell-based immunotherapy, wherein a patient’s T cells are re-engineered to specifically target tumors, has shown great promise in revolutionizing the long-term treatment of cancer. Amongst the different types of T cell-based immunotherapy, adoptively transferred genetically engineered T cells, including chimeric antigen receptor T-cell (CAR-T) therapy, have shown substantial anti-tumor activity in patients with hematopoietic malignancies, but have so far demonstrated limited benefit in patients with solid tumors. CAR-T therapy is limited by the ability of adoptively transferred cells to expand and proliferate in vivo and maintain their anti-tumor function. Even those T cells that expand and persist can often become terminally differentiated and dysfunctional in vivo. To mitigate these issues, patients undergo toxic conditioning regimens, including chemotherapy and radiation, to deplete the host immune system prior to adoptive transfer of engineered T cells. Thus, novel approaches of modifying the biology of adoptively transferred T cells to obviate conditioning chemotherapy while maintaining resilient anti-tumor functions in vivo could make CAR-T therapies more clinically feasible and powerful, especially for solid tumors.
INNOVATION:
UCLA researchers led by Dr. Anusha Kalbasi in the Department of Radiation Oncology have engineered T cells with a cytokine receptor not commonly expressed on T cells, which endows the T cells with greater anti-tumor efficacy and new functions removing the need for conditioning chemotherapy. To show that the receptor platform successfully enabled redirection of signaling, the researchers stimulated modified T cells with its cytokine ligand, which resulted in specific and dose-dependent phospho-STAT signaling that was consistent with known signaling through the cytokine, and was not observed in unmodified T cells. They then tested the modified T cells in mouse models and saw that specific stimulation of the cytokine receptor signaling in vivo led to improved anti-tumor activity, without the need for conditioning lymphodepletion in a difficult-to-treat solid tumor model of melanoma. Therefore, by endowing T cells with signaling from a receptor not commonly seen in T cells, the T cells can gain new functions that lead to improved anti-tumor activity for hard-to-treat solid tumors.
POTENTIAL APPLICATIONS:
• TCR-engineered or CAR-engineered T therapy for cancer, especially solid tumors (in vivo use)
• TCR-engineered or CAR-engineered T therapy for cancer, especially solid tumors (ex vivo use during manufacturing)
• Cytokine / receptor-based drug development
ADVANTAGES:
• Improved anti-tumor efficacy of adoptively transferred T cells
• Removes the need for conditioning chemotherapy that can cause severe side effects for patients
• Utilizes native signaling biology and avoids regulatory and safety issues of using synthetic proteins
DEVELOPMENT-TO-DATE:
The researchers have demonstrated the success of this therapeutic method in mouse models.
Related Papers (from the inventors only):
Kalbasi, A., Siurala, M., Su, L. L., Tariveranmoshabad, M., Picton, L. K., Ravikumar, P., ... & Garcia, K. C. (2022). Potentiating adoptive cell therapy using synthetic IL-9 receptors. Nature, 1-6.