30th Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2015)
- Poster presentation
- Open Access
Innate and adaptive immunity contribute to the anti-tumor mechanisms of action of OncoVEXmGM-CSF
Journal for ImmunoTherapy of Cancer volume 3, Article number: P338 (2015)
Talimogene laherparepvec, an investigational oncolytic immunotherapy, is a modified herpes simplex virus type-1 (HSV-1) designed to selectively replicate in tumors and to initiate a systemic immune response to target cancer cells. Intralesional administration of talimogene laherparepvec is intended to result in oncolysis within injected tumors, with lytic cell destruction promoting the local release of progeny virus and tumor derived antigens. GM-CSF, a product of the viral transgene, is also produced locally such that it can recruit and stimulate antigen presenting cells to further enhance systemic anti-tumor immune response.
In a retrospective analysis of a Phase III melanoma trial investigators found that about two-thirds of the lesions injected with talimogene laherparepvec shrank 50% or more. Among uninjected tumors similar responses were seen in one third of lesions of the skin and lymph nodes and about a sixth of uninjected visceral lesions providing an indication that the treatment is triggering systemic immune effect.
To further dissect the mechanism of action underlying innate and adaptive immunity following viral administration, a talimogene laherparepvec expressing murine GM-CSF (OncoVEXmGM-CSF) was employed in syngeneic tumor models (A20 and CT26).
When administered intratumorally (3 doses of 5x10^6 PFU) OncoVEXmGM-CSF induces tumor regressions in the injected lesion, but also results in significant anti-tumor effects in a contralateral (uninjected) lesion and marked size increases in injected tumor draining lymph nodes. Flow cytometric profling, gene expression analysis, and IHC revealed infiltration of T cells, innate effector cells and antigen presenting cells in tumors and draining lymph nodes. Innate immune responses in the injected tumor are characterized by the induction of Interferon response gene signatures and result in the systemic release of proinflammatory cytokines. These effects are, at least in part, dependent on STING activity, with in vitro functional assays supporting direct agonism of this pathway by the virus. Systemic anti-tumor responses appear to be T cell driven: T cells expressed higher levels of activation markers as early as 2 days post-treatment in injected tumors, with evidence of T cell activation in contralateral lesion by day 7. To elucidate anti-viral and anti-tumor T cell responses, ex vivo re-challenge assays were performed using splenocyte- and draining lymph node-derived T cells following treatment with OncoVEXmGM-CSF; viral treatment increased systemic anti-tumor immunity and showed induction of anti-viral responses.
In conclusion, in vitro and in vivo observations suggest that intratumoral injection of OncoVEXmGM-CSF activates multiple immune-mediated mechanisms of action, leading to T cell activation and induction of anti-tumor immunity in mice.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.
The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/.
The Creative Commons Public Domain Dedication waiver (https://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
About this article
Cite this article
Cooke, K., Fitzgerald, K., Yang, B. et al. Innate and adaptive immunity contribute to the anti-tumor mechanisms of action of OncoVEXmGM-CSF. j. immunotherapy cancer 3 (Suppl 2), P338 (2015). https://doi.org/10.1186/2051-1426-3-S2-P338
- Drain Lymph Node
- Tumor Drain Lymph Node
- Induce Tumor Regression
- Talimogene Laherparepvec
- Intralesional Administration