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Preinfusion polyfunctional anti-CD19 chimeric antigen receptor T cells associate with clinical outcomes in NHL

Rossi, John and Paczkowski, Patrick and Shen, Yueh-Wei and Morse, Kevin and Flynn, Brianna and Kaiser, Alaina and Ng, Colin and Gallatin, Kyle and Cain, Tom and Fan, Rong and Mackay, Sean and Heath, James R. and Rosenberg, Steven A. and Kochenderfer, James N. and Zhou, Jing and Bot, Adrian (2018) Preinfusion polyfunctional anti-CD19 chimeric antigen receptor T cells associate with clinical outcomes in NHL. Blood, 132 (8). pp. 804-814. ISSN 0006-4971. https://resolver.caltech.edu/CaltechAUTHORS:20180618-082158855

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Abstract

After treatment with chimeric antigen receptor (CAR) T cells, interleukin-15 (IL-15) elevation and CAR T-cell expansion are associated with non-Hodgkin lymphoma (NHL) outcomes. However, the association of preinfusion CAR product T-cell functionality with clinical outcomes has not been reported. A single-cell analysis of the preinfusion CD19 CAR product from patients with NHL demonstrated that CAR products contain polyfunctional T-cell subsets capable of deploying multiple immune programs represented by cytokines and chemokines, including interferon-γ, IL-17A, IL-8, and macrophage inflammatory protein 1α. A prespecified T-cell polyfunctionality strength index (PSI) applied to preinfusion CAR product was significantly associated with clinical response, and PSI combined with CAR T-cell expansion or pretreatment serum IL-15 levels conferred additional significance. Within the total product cell population, associations with clinical outcomes were greater with polyfunctional CD4+ T cells compared with CD8+ cells. Grade ≥3 cytokine release syndrome was associated with polyfunctional T cells, and both grade ≥3 neurologic toxicity and antitumor efficacy were associated with polyfunctional IL-17A–producing T cells. The findings in this exploratory study show that a preinfusion CAR product T-cell subset with a definable polyfunctional profile has a major association with clinical outcomes of CAR T-cell therapy. This trial was registered at www.clinicaltrials.gov as #NCT00924326.


Item Type:Article
Related URLs:
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https://doi.org/10.1182/blood-2018-01-828343DOIArticle
ORCID:
AuthorORCID
Heath, James R.0000-0001-5356-4385
Additional Information:© 2018 American Society of Hematology. Submitted January 29, 2018; Accepted May 30, 2018; Prepublished online June 12, 2018. The authors thank Allen Xue of Kite for performing a formal review of the statistical analysis and methods used in this report. This study was funded by Kite, a Gilead Company. Author Contribution: J.R. helped design the study and performed experiments, analysis, and data interpretation; P.P. helped to design the study, performed statistical analysis and visualizations of the presented data, developed the software suite for single-cell data acquisition and analysis, and assisted with writing the manuscript; K.M., B.F., and A.K. performed all single-cell experiments, data acquisition, and validation experiments; Y.-W.S. contributed to product analysis; C.N. and T.C. managed and assisted with execution of single-cell analysis processes, validation processes, and additional related biological procedures; K.G. performed single-cell data acquisition and assisted with statistical analysis; R.F and J.R.H. contributed to the discussion and analysis of the project results and assisted with writing the manuscript; S.M. supervised the project and contributed to the overall analysis and interpretation and the writing of the manuscript; S.A.R. and J.N.K. were the investigators of the clinical study, made intellectual contributions, and shared materials and biospecimens; J.Z. developed the single-cell cytokine profiling experimental protocol, managed the execution of the experiments, and contributed to the data analysis and writing of the manuscript; A.B. oversaw the study and the drafting of the manuscript; and all authors reviewed and provided final approval of the manuscript. Conflict-of-interest disclosure: J.R., Y.-W.S., and A.B. are employed by Kite, a Gilead Company, and have equity ownership in Gilead Sciences, Inc.; P.P. is employed by, has equity ownership in, and is a patent holder with IsoPlexis; K.M., B.F., A.K., T.C., and J.Z. are employed by and have equity ownership in IsoPlexis; C.N. and K.G. are employed by IsoPlexis; R.F. is cofounder and scientific advisor of IsoPlexis; S.M. is employed by, has equity ownership in, and is a patent holder with IsoPlexis and received honoraria from Kite, a Gilead Company; J.R.H. is a founder and board member of IsoPlexis; S.A.R. received research funding from Kite, a Gilead Company, and is a patent holder with National Cancer Institute Cooperative Research and Development Agreement/Kite; and J.N.K. received research funding from Kite, a Gilead Company and BlueBird Bio, is a patent holder with Kite, a Gilead Company BlueBird Bio, and Novartis, and has received travel expenses from Kite, a Gilead Company, and Celgene Corporation. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.
Funders:
Funding AgencyGrant Number
KiteUNSPECIFIED
Issue or Number:8
Record Number:CaltechAUTHORS:20180618-082158855
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20180618-082158855
Official Citation:Preinfusion polyfunctional anti-CD19 chimeric antigen receptor T cells are associated with clinical outcomes in NHL John Rossi, Patrick Paczkowski, Yueh-Wei Shen, Kevin Morse, Brianna Flynn, Alaina Kaiser, Colin Ng, Kyle Gallatin, Tom Cain, Rong Fan, Sean Mackay, James R. Heath, Steven A. Rosenberg, James N. Kochenderfer, Jing Zhou, Adrian Bot Blood Aug 2018, 132 (8) 804-814; DOI: 10.1182/blood-2018-01-828343
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:87182
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:18 Jun 2018 21:12
Last Modified:03 Oct 2019 19:53

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