Kombinierter Behandlungsansatz mit GD2-spezifischen chimären Antigenrezeptoren (CAR) und Immun-Checkpoint-Inhibitioren für die Therapie von Hochrisiko-Neuroblastom
Hämatologie, Onkologie
Immunologie
Zusammenfassung der Projektergebnisse
Chimeric antigen receptor (CAR) T cells targeting CD19 have become a potent therapy in some patients with refractory B cell malignancies and were recently approved by the U.S. Food & Drug Administration. Although the approved CAR T cells induce high rates of initial complete remission, long-term sustained responses are obtained only in a fraction of patients, underlining the necessity to further improve CAR therapies. CD28-based CARs induce strong T cell activation and mediate highly performing effector functions, leading to potent antitumor efficacy despite the limited persistence they impart upon T cells. Increasing the longevity of functional CAR T cells should thus enhance their therapeutic potency. T cell persistence may be counteracted by excessive activation arising from redundancy of combined CD3ζ and CD28 signaling in the current 1928ζ CAR design, resulting in early T cell differentiation and exhaustion. We therefore titrated the activation potential of 1928ζ CAR T cells through mutations in the CD3ζ immunoreceptor tyrosine-based activation motifs (ITAM) to impede their downstream signaling. Here, we demonstrate that calibration of ITAM activity in 1928ζ CARs directs T cells to different fates, preserving a less-differentiated T cell state and promoting greater persistence. The number and position of ITAMs impact functional, phenotypic and transcriptional attributes with profound effect on therapeutic potency. 1928ζ CAR T cells with one single functional ITAM – at the right position – are able to maintain potent effector function and also favorably delay T cell differentiation and exhaustion. By directing the CAR to the T cell receptor α constant (TRAC) locus for rigorous comparison in stress test conditions, we identified the novel “1XX” CAR design (1928ζ CARs with functional ITAM1 and mutated ITAMs 2&3) with a favorable balance of effector and memory signatures. “1XX” CAR T cells develop into highly potent long-lived memory T cells capable of effective recall responses, leading to long-term tumor rejection. Preparations for clinical studies utilizing the 1XX CAR design are on the way.
Projektbezogene Publikationen (Auswahl)
- Calibration of CAR activation potential directs alternative T cell fates and therapeutic potency. at Med. 2018 Dec 17
Feucht J, Sun J, Eyquem J, Ho YJ, Zhao Z, Leibold J, Dobrin A, Cabriolu A, Hamieh M, Sadelain M
(Siehe online unter https://doi.org/10.1038/s41591-018-0290-5)
