Endogenous T cells prevent tumor immune escape following adoptive T cell therapy
Scott R. Walsh, … , Brian D. Lichty, Yonghong Wan
Scott R. Walsh, … , Brian D. Lichty, Yonghong Wan
Published November 4, 2019
Citation Information: J Clin Invest. 2019;129(12):5400-5410. https://doi.org/10.1172/JCI126199.
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Research Article

Endogenous T cells prevent tumor immune escape following adoptive T cell therapy

Abstract

While the outcome of adoptive T cell therapy (ACT) is typically correlated with the functionality of the inoculated T cells, the role of the endogenous T cells is unknown. The success of checkpoint blockade therapy has demonstrated the potentially curative value of preexisting tumor-primed T cells in cancer treatment. Given the results from checkpoint blockade therapy, we hypothesized that endogenous T cells contribute to long-term survival following ACT. Here, we describe a therapeutic approach combining ACT with an oncolytic vaccine that allows simultaneous analysis of antitumor immunity mediated by transferred and endogenous T cells. We found that, in addition to promoting the expansion and tumor infiltration of the transferred T cells, oncolytic vaccines boosted tumor-primed host T cells. We determined that transferred T cells contributed to rapid destruction of large tumor masses while endogenous T cells concurrently prevented the emergence of antigen-loss variants. Moreover, while transferred T cells disappeared shortly after tumor regression, endogenous T cells secured long-term memory with a broad repertoire of antigen specificity. Our findings suggest that this combination strategy may exploit the full potential of ACT and tumor-primed host T cells to eliminate the primary tumor, prevent immune escape, and provide long-term protective memory.

Authors

Scott R. Walsh, Boris Simovic, Lan Chen, Donald Bastin, Andrew Nguyen, Kyle Stephenson, Talveer S. Mandur, Jonathan L. Bramson, Brian D. Lichty, Yonghong Wan

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Figure 1

Combination of Tcm and VSV-ErkM leads to durable tumor regression.

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Combination of Tcm and VSV-ErkM leads to durable tumor regression. BALB/...
BALB/c mice were inoculated i.d. with CMS5 cells 7 days prior to adoptive transfer of DUC18 Tcm (106 cells/mouse) and, where indicated, were treated with the specified vaccine/virus 24 hours later. Mice receiving VSV-ErkM alone, Tcm alone, or PBS were included as controls. (A, C, and E) Tumor volumes and (B, D, and F) survival of CMS5 TB BALB/c mice were monitored at the specified dpt with 0 dpt representing the day of vaccine inoculation and are expressed as mm3. A tumor volume of 1000 mm3 was used as end point for survival analysis. (G) Mice surviving initial CMS5 tumor challenge after treatment with Tcm plus VSV-ErkM were rechallenged with CMS5 cells 60 days later,and subsequent survival is shown. A group of naive mice challenged with CMS5 cells was included as a control. Data are shown as representative results from 4 (A and B), 3 (C–F), or 2 (F) independent experiments with n = 5 per group. Data were analyzed using a log-rank (Mantel-Cox) test (B, D, F and G). *P < 0.05; **P < 0.01.