Venugopal Gudipati, PhD
MedUni Wien RESEARCHER OF THE MONTH May 2021
Inefficient CAR-proximal signaling blunts antigen detection
Chimeric antigen receptor (CAR)-T cell therapy is a new and revolutionary therapy against cancer: T cells that are isolated from the cancer patients are genetically modified and then infused back into the patient to eliminate cancer cells. Despite the 90% complete remission (CR) rates observed 6 months post CAR-T cell therapy, a significant proportion of patients with CR still relapse with in 18 months. One major factor contributing to the tumor relapse is the down-regulation of tumor antigen by cancer cells. Venugopal Gudipati PhD from the Medical University of Vienna have now discovered why CAR-T cells fail to destroy tumor cells that express tumor antigens in small numbers. Their study, published in Nature Immunology, shows that CAR-T cells fail to initiate adequate intracellular signaling when facing low antigen densities, even though they bind the antigen in a highly efficient manner. The results of this study suggest that future CAR designs based on the architecture of the T cell receptor (TCR) might provide much needed improvements in CAR-T cell antigen sensitivity and long-term CR rates.
- Gudipati, V. et al. Inefficient CAR-proximal signaling blunts antigen sensitivity. Nat Immunol 21, 848-856 (2020).
- Hopfinger, G., Jager, U. & Worel, N. CAR-T Cell Therapy in Diffuse Large B Cell Lymphoma: Hype and Hope. Hemasphere 3, e185 (2019).
- Maude, S.L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371, 1507-1517 (2014).
- June, C.H. & Sadelain, M. Chimeric Antigen Receptor Therapy. N Engl J Med 379, 64-73 (2018).
- Purbhoo, M.A., Irvine, D.J., Huppa, J.B. & Davis, M.M. T cell killing does not require the formation of a stable mature immunological synapse. Nat Immunol 5, 524-530 (2004).