Endogenous T cells prevent tumor immune escape following adoptive T cell therapy
Scott R. Walsh, Boris Simovic, Lan Chen, Donald Bastin, Andrew Nguyen, Kyle Stephenson, Talveer S. Mandur, Jonathan L. Bramson, Brian D. Lichty, Yonghong Wan
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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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.