@article{ec2d37d1177b495aa3195b1e450ebdcc,
title = "Antigen-independent activation enhances the efficacy of 4-1BB-costimulated CD22 CAR T cells",
abstract = "While CD19-directed chimeric antigen receptor (CAR) T cells can induce remission in patients with B cell acute lymphoblastic leukemia (ALL), a large subset relapse with CD19− disease. Like CD19, CD22 is broadly expressed by B-lineage cells and thus serves as an alternative immunotherapy target in ALL. Here we present the composite outcomes of two pilot clinical trials (NCT02588456 and NCT02650414) of T cells bearing a 4-1BB-based, CD22-targeting CAR in patients with relapsed or refractory ALL. The primary end point of these studies was to assess safety, and the secondary end point was antileukemic efficacy. We observed unexpectedly low response rates, prompting us to perform detailed interrogation of the responsible CAR biology. We found that shortening of the amino acid linker connecting the variable heavy and light chains of the CAR antigen-binding domain drove receptor homodimerization and antigen-independent signaling. In contrast to CD28-based CARs, autonomously signaling 4-1BB-based CARs demonstrated enhanced immune synapse formation, activation of pro-inflammatory genes and superior effector function. We validated this association between autonomous signaling and enhanced function in several CAR constructs and, on the basis of these observations, designed a new short-linker CD22 single-chain variable fragment for clinical evaluation. Our findings both suggest that tonic 4-1BB-based signaling is beneficial to CAR function and demonstrate the utility of bedside-to-bench-to-bedside translation in the design and implementation of CAR T cell therapies.",
author = "Nathan Singh and Frey, {Noelle V.} and Boris Engels and Barrett, {David M.} and Olga Shestova and Pranali Ravikumar and Cummins, {Katherine D.} and Lee, {Yong Gu} and Raymone Pajarillo and Inkook Chun and Amy Shyu and Highfill, {Steven L.} and Andrew Price and Linlin Zhao and Liaomin Peng and Brian Granda and Melissa Ramones and Lu, {Xueqing Maggie} and Christian, {David A.} and Jessica Perazzelli and Lacey, {Simon F.} and Roy, {Nathan H.} and Burkhardt, {Janis K.} and Florent Colomb and Mohammad Damra and Mohamed Abdel-Mohsen and Ting Liu and Dongfang Liu and Standley, {Daron M.} and Young, {Regina M.} and Brogdon, {Jennifer L.} and Grupp, {Stephan A.} and June, {Carl H.} and Maude, {Shannon L.} and Saar Gill and Marco Ruella",
note = "Funding Information: M.R. and S.G. hold patents related to CART22. C.H.J. has received grant support from Novartis and has patents related to CAR therapy with royalties paid from Novartis to the University of Pennsylvania. C.H.J. is also a scientific founder and holds equity in Tmunity Therapeutics. S.A.G. has received support from Novartis, Servier and Kite and serves as a consultant, member of the scientific advisory board or study steering committee for Novartis, Cellectis, Adaptimmune, Eureka, TCR2, Juno, GlaxoSmithKline, Vertex, Cure Genetics, Humanigen and Roche. B.E., L.Z., L.P., A.P., B.G., M. Ramones and J.B. are employees of Novartis. S.F.L. has received grant support from Novartis, Tmunity and Cabaletta and has patents related to CAR therapy with royalties paid from Novartis to the University of Pennsylvania; he has acted as a consultant for Kite/Gilead. S.L.M. has served as a member of advisory boards or steering committees for Novartis and Kite. All other authors declare no competing interests. Funding Information: We thank F. Chen and N. Koterba for technical assistance with the cytokine quantification assays and J. Schug for assistance with the RNA sequencing. The pediatric trial was supported by the CHOP Immunotherapy Frontier Program, in addition to support from the Emily Whitehead Foundation, V Foundation and Curing Kids Cancer (S.A.G.). The preclinical research was supported by the Society of Immunotherapy for Cancer Holbrook Kohrt Immunotherapy Translational Fellowship (N.S.); a Breakthrough Bike Challenge Buz Cooper Scholarship (N.S.); Stand Up To Cancer (SU2C) Innovative Research Grant no. SU2C-AACR-IRG 12-17 (D.M.B.; SU2C is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C); National Institutes of Health grant no. R01GM104867 (J.K.B.); a Cancer Research Institute Irvington Fellowship (N.H.R.); National Heart, Lung, and Blood Institute grant no. HL125018 and National Institute of Allergy and Infectious Diseases grant nos. AI124769, AI129594 and AI130197 (D.L.); Japan Agency for Medical Research and Development grant no. P20am0101108 (D.M.S.); NCI grant no. K08CA194256 (S.G.); an American Society of Hematology Scholar Award, NCI grant nos. 1K99CA212302 and R00CA212302 (M.R.); University of Pennsylvania-Novartis Alliance (S.G. and C.H.J.); and NCI grant nos. 1P01CA214278 and R01CA226983 (C.H.J.). Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2021",
month = may,
doi = "10.1038/s41591-021-01326-5",
language = "English",
volume = "27",
pages = "842--850",
journal = "Nature Medicine",
issn = "1078-8956",
number = "5",
}