In Vivo Fate and Activity of Second- versus Third-Generation CD19-Specific CAR-T Cells in B Cell Non-Hodgkin's Lymphomas

Carlos A. Ramos, Rayne Rouce, Catherine S. Robertson, Amy Reyna, Neeharika Narala, Gayatri Vyas, Birju Mehta, Huimin Zhang, Olga Dakhova, George Carrum, Rammurti T. Kamble, Adrian P. Gee, Zhuyong Mei, Meng Fen Wu, Hao Liu, Bambi Grilley, Cliona M. Rooney, Helen E. Heslop, Malcolm K. Brenner, Barbara SavoldoGianpietro Dotti

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Second-generation (2G) chimeric antigen receptors (CARs) targeting CD19 are highly active against B cell malignancies, but it is unknown whether any of the costimulatory domains incorporated in the CAR have superior activity to others. Because CD28 and 4-1BB signaling activate different pathways, combining them in a single third-generation (3G) CAR may overcome the limitations of each individual costimulatory domain. We designed a clinical trial in which two autologous CD19-specific CAR-transduced T cell products (CD19.CARTs), 2G (with CD28 only) and 3G (CD28 and 4-1BB), were infused simultaneously in 16 patients with relapsed or refractory non-Hodgkin's lymphoma. 3G CD19.CARTs had superior expansion and longer persistence than 2G CD19.CARTs. This difference was most striking in the five patients with low disease burden and few circulating normal B cells, in whom 2G CD19.CARTs had limited expansion and persistence and correspondingly reduced area under the curve. Of the 11 patients with measurable disease, three achieved complete responses and three had partial responses. Cytokine release syndrome occurred in six patients but was mild, and no patient required anti-IL-6 therapy. Hence, 3G CD19.CARTs combining 4-1BB with CD28 produce superior CART expansion and may be of particular value when treating low disease burden in patients whose normal B cells are depleted by prior therapy. CD19.CAR-T cells are highly active against B cell malignancies, but the optimal CAR structure is controversial. Ramos et al. show that combining 4-1BB and CD28 endodomains produces superior CD19-CAR-T cell expansion and persistence compared to CD28 alone and that these cells are clinically effective and safe in aggressive lymphomas.

Original languageEnglish (US)
Pages (from-to)2727-2737
Number of pages11
JournalMolecular Therapy
Volume26
Issue number12
DOIs
StatePublished - Dec 5 2018
Externally publishedYes

Keywords

  • CAR-T cells
  • CD19
  • chimeric antigen receptor
  • immunotherapy
  • second-generation CAR
  • third-generation CAR

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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  • Cite this

    Ramos, C. A., Rouce, R., Robertson, C. S., Reyna, A., Narala, N., Vyas, G., Mehta, B., Zhang, H., Dakhova, O., Carrum, G., Kamble, R. T., Gee, A. P., Mei, Z., Wu, M. F., Liu, H., Grilley, B., Rooney, C. M., Heslop, H. E., Brenner, M. K., ... Dotti, G. (2018). In Vivo Fate and Activity of Second- versus Third-Generation CD19-Specific CAR-T Cells in B Cell Non-Hodgkin's Lymphomas. Molecular Therapy, 26(12), 2727-2737. https://doi.org/10.1016/j.ymthe.2018.09.009