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Glioblastoma-targeted CD4+ CAR T cells mediate superior antitumor activity
Dongrui Wang, … , Stephen J. Forman, Christine E. Brown
Dongrui Wang, … , Stephen J. Forman, Christine E. Brown
Published May 17, 2018
Citation Information: JCI Insight. 2018;3(10):e99048. https://doi.org/10.1172/jci.insight.99048.
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Research Article Immunology Oncology

Glioblastoma-targeted CD4+ CAR T cells mediate superior antitumor activity

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Abstract

Chimeric antigen receptor–modified (CAR-modified) T cells have shown promising therapeutic effects for hematological malignancies, yet limited and inconsistent efficacy against solid tumors. The refinement of CAR therapy requires an understanding of the optimal characteristics of the cellular products, including the appropriate composition of CD4+ and CD8+ subsets. Here, we investigated the differential antitumor effect of CD4+ and CD8+ CAR T cells targeting glioblastoma-associated (GBM-associated) antigen IL-13 receptor α2 (IL13Rα2). Upon stimulation with IL13Rα2+ GBM cells, the CD8+ CAR T cells exhibited robust short-term effector function but became rapidly exhausted. By comparison, the CD4+ CAR T cells persisted after tumor challenge and sustained their effector potency. Mixing with CD4+ CAR T cells failed to ameliorate the effector dysfunction of CD8+ CAR T cells, while surprisingly, CD4+ CAR T cell effector potency was impaired when coapplied with CD8+ T cells. In orthotopic GBM models, CD4+ outperformed CD8+ CAR T cells, especially for long-term antitumor response. Further, maintenance of the CD4+ subset was positively correlated with the recursive killing ability of CAR T cell products derived from GBM patients. These findings identify CD4+ CAR T cells as a highly potent and clinically important T cell subset for effective CAR therapy.

Authors

Dongrui Wang, Brenda Aguilar, Renate Starr, Darya Alizadeh, Alfonso Brito, Aniee Sarkissian, Julie R. Ostberg, Stephen J. Forman, Christine E. Brown

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Figure 5

CD4+ CAR T cells do not augment the effector function of CD8+ CAR T cells following tumor stimulation.

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CD4+ CAR T cells do not augment the effector function of CD8+ CAR T cell...
(A) Viable tumor cell numbers after in vitro repetitive challenge assay as described in Figure 3A (arrows represent tumor rechallenge), using CD4+, CD8+, or 1:1 CD4/CD8 mixed CAR T cells (total input CD19+ T cell number = 4,000 in each group; n = 3 replicates per point; **P < 0.01, unpaired Student’s t test, compared with the CD4+ group). (B) CD4/CD8 mixed cells were analyzed for CD8+ T cell proportions at D0 (Input), D1, and D7 during the rechallenge assay. (C) Expansion of CD4+ and CD8+ engineered T cells during rechallenge assay, normalized to the input CD19+ T cell number. Comparison of: (top panel) CD4+ vs. CD8+ T cell expansion within the CD4/CD8 mix; (middle panel) CD4+ T cells alone or within the CD4/CD8 mix; and (bottom panel) CD8+ T cells alone or within the CD4/CD8 mix. n = 3 replicates per point, *P < 0.05 and **P < 0.01 using an unpaired Student’s t test. (D and E) CD8+ or 1:1 CD4/CD8 mixed CAR T cells underwent in vivo stimulation, and the CD8+ engineered T cells in both groups were analyzed for inhibitory receptor expression. (F–I) CD8+ or 1:1 CD4/CD8 mixed CAR T cells underwent in vivo stimulation, and CD8+ engineered T cells were isolated from the tumors and restimulated in vitro. Flow cytometric analysis of degranulation (F), intracellular IFN-γ (G), surface expression of activation markers CD69 and 4-1BB (H), or memory markers (CD62L and CD45RO) (I) was performed and compared between CD8+ CAR T cells that were in vivo–stimulated alone (CD8+) or within the CD4/CD8 mix (CD8+ in mix). (F and G) **P < 0.01, using 1-way ANOVA analysis with Bonferroni’s multiple comparison test. All data are representative of 3 different donors; data represents ± SEM.

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