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Enhancing CAR T cell persistence through ICOS and 4-1BB costimulation
Sonia Guedan, … , Regina M. Young, Carl H. June
Sonia Guedan, … , Regina M. Young, Carl H. June
Published January 11, 2018
Citation Information: JCI Insight. 2018;3(1):e96976. https://doi.org/10.1172/jci.insight.96976.
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Research Article Immunology

Enhancing CAR T cell persistence through ICOS and 4-1BB costimulation

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Abstract

Successful tumor eradication by chimeric antigen receptor–expressing (CAR-expressing) T lymphocytes depends on CAR T cell persistence and effector function. We hypothesized that CD4+ and CD8+ T cells may exhibit distinct persistence and effector phenotypes, depending on the identity of specific intracellular signaling domains (ICDs) used to generate the CAR. First, we demonstrate that the ICOS ICD dramatically enhanced the in vivo persistence of CAR-expressing CD4+ T cells that, in turn, increased the persistence of CD8+ T cells expressing either CD28- or 4-1BB–based CARs. These data indicate that persistence of CD8+ T cells was highly dependent on a helper effect provided by the ICD used to redirect CD4+ T cells. Second, we discovered that combining ICOS and 4-1BB ICDs in a third-generation CAR displayed superior antitumor effects and increased persistence in vivo. Interestingly, we found that the membrane-proximal ICD displayed a dominant effect over the distal domain in third-generation CARs. The optimal antitumor and persistence benefits observed in third-generation ICOSBBz CAR T cells required the ICOS ICD to be positioned proximal to the cell membrane and linked to the ICOS transmembrane domain. Thus, CARs with ICOS and 4-1BB ICD demonstrate increased efficacy in solid tumor models over our current 4-1BB–based CAR and are promising therapeutics for clinical testing.

Authors

Sonia Guedan, Avery D. Posey Jr., Carolyn Shaw, Anna Wing, Tong Da, Prachi R. Patel, Shannon E. McGettigan, Victoria Casado-Medrano, Omkar U. Kawalekar, Mireia Uribe-Herranz, Decheng Song, J. Joseph Melenhorst, Simon F. Lacey, John Scholler, Brian Keith, Regina M. Young, Carl H. June

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Figure 3

Third-generation CARs containing ICOS and 4-1BB intracellular domains mediate enhanced antitumor effects and increased T cell persistence.

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Third-generation CARs containing ICOS and 4-1BB intracellular domains me...
(A) NSG mice bearing s.c. pancreatic tumors (Capan-2) were treated 15 days after tumor implantation with 2 doses of T cells redirected with SS1-CARs. A group containing a combination of CD4+ T cells redirected with ICOSz and CD8+ T cells redirected with BBz (ICOSz4-BBz8) was also included. Tumor volume was analyzed at indicated time points. Results are expressed as a mean tumor volume (± SEM) with n = 6–8 mice per group. *P < 0.05 by 2-way ANOVA with Tukey’s multiple comparison test. (B) Waterfall plots of the change in tumor volume on day 34 versus baseline for individual animals. (C) The concentration of CD4+ and CD8+ T cells were determined in the blood of treated animals 21 days after T cell injection. Error bars represent ± SEM. *P < 0.05 by 1-way ANOVA with Tukey post hoc test. ***P < 0.001. For CD8+ T cell counts, data was transformed to reduce variance, and significance was analyzed by 1-way ANOVA with Tukey post hoc test. (D) Correlation of numbers of CD4+ and CD8+ T cells per microliter of blood was plotted versus the tumor volume on day 21 for the animals treated with ICOSz4-BBz8. (E and F) NSG mice were sacrificed on day 34 after treatment, and human T cells were isolated from mouse spleens. (E) CAR expression was analyzed by flow cytometry. Representative of 3–5 animals. (F) CAR T cells recovered from spleen were cocultured with K562 that express mesothelin, and cytokine release was analyzed by ELISA 24 hours after coculture. Box plots show median (line) and 25th to 75th percentile (box). The end of the whiskers represents the minimum and the maximum of all of the data. *P < 0.05 by 1-way ANOVA with Tukey post hoc test.

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