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Oncolytic virus promotes tumor-reactive infiltrating lymphocytes for adoptive cell therapy

Cancer Gene Therapy volume 28, pages 98–111 (2021)Cite this article

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Abstract

Adoptive cell therapy (ACT) using tumor-specific tumor-infiltrating lymphocytes (TILs) has demonstrated success in patients where tumor-antigen specific TILs can be harvested from the tumor, expanded, and re-infused in combination with a preparatory regimen and IL2. One major issue for non-immunogenic tumors has been that the isolated TILs lack tumor specificity and thus possess limited in vivo therapeutic function. An oncolytic virus (OV) mediates an immunogenic cell death for cancer cells, leading to elicitation and dramatic enhancement of tumor-specific TILs. We hypothesized that the tumor-specific TILs elicited and promoted by an OV would be a great source for ACT for solid cancer. In this study, we show that a local injection of oncolytic poxvirus in MC38 tumor with low immunogenicity in C57BL/6 mice, led to elicitation and accumulation of tumor-specific TILs in the tumor tissue. Our analyses indicated that IL2-armed OV-elicited TILs contain lower quantities of exhausted PD-1hiTim-3+ CD8+ T cells and regulatory T cells. The isolated TILs from IL2-expressing OV-treated tumor tissue retained high tumor specificity after expansion ex vivo. These TILs resulted in significant tumor regression and improved survival after adoptive transfer in mice with established MC38 tumor. Our study showcases the feasibility of using an OV to induce tumor-reactive TILs that can be expanded for ACT.

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Fig. 1: Oncolytic VVs elicit tumor-specific antitumor CD8+ T-cell response in the tumor tissue.
Fig. 2: vvDD-IL2 treatments increase the number of TILs.
Fig. 3: Immune status in the TME and spleen post virus treatment.
Fig. 4: OV-induced TILs can be cultured and expanded ex vivo and retain their tumor specificity.
Fig. 5: Analysis of the vvDD-IL2-induced TILs after ex vivo expansion.
Fig. 6: ACT of oncolytic virus-induced TILs led to significant therapeutic efficacy in mice bearing peritoneal carcinomatosis of MC38 colon cancer.

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Acknowledgements

We thank the University Imaging Core Facility for technical assistance in immunostaining and imaging, the Hillman Cancer Center Biostatistics facility for consultation, and Prometheus (San Diego, CA) for human recombinant IL2 used in the study.

Funding

This work was supported in part by David C. Koch Regional Cancer Therapy Center. MF (DFG research fellowship 1655/1-1) and EG were supported by fellowships from German Research Foundation. ED was supported by fellowships from the China Scholarship Council, China. This project has used the University of Pittsburgh shared facilities (Animal Facility, Genomics Research Core, Flow Cytometry) that are supported in part by the NIH grant award P30CA047904.

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  1. David L. Bartlett

    Present address: Allegheny Health Network-Cancer Institute, Pittsburgh, PA, 15212, USA

Authors and Affiliations

  1. Department of Surgery, University of Pittsburgh School of Medicine, and UPMC Hillman Cancer Center, Pittsburgh, PA, USA

    Mathilde Feist, Zhi Zhu, Enyong Dai, Congrong Ma, Zuqiang Liu, Esther Giehl, Roshni Ravindranathan, Stacy J. Kowalsky, Natasa Obermajer, Udai S. Kammula, Andrew J. H. Lee, Michael T. Lotze, Zong Sheng Guo & David L. Bartlett

  2. Department of Surgery, CCM/CVK, Charité - Universitaetsmedizin Berlin, Berlin, Germany

    Mathilde Feist, Zuqiang Liu & Esther Giehl

  3. Department of Oncology and Hematology, The Third Hospital of Jilin University, Changchun, Jilin, China

    Enyong Dai

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Feist, M., Zhu, Z., Dai, E. et al. Oncolytic virus promotes tumor-reactive infiltrating lymphocytes for adoptive cell therapy. Cancer Gene Ther 28, 98–111 (2021). https://doi.org/10.1038/s41417-020-0189-4

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