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, 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
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.
Conflict of interest statement
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.
© 2018 by The American Society of Hematology.
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Source: PubMed