Abstract B14: TCR transgenic T cells improve the anticancer potential of oncolytic vesicular stomatitis virus as cell carriers and as synergistic therapeutics
Authors: Melzer Michael Karl , Zeitlinger Lisa , Mall Sabine , Steiger Katja , Krackhardt Angela , Ebert Oliver , Altomonte Jennifer 
Published: February 2019

Abstract
With the clinical approval of Talimogen laherparepvec (T-VEC), an oncolytic Herpes-simplex-Virus 1, in 2015, oncolytic viruses have gained much attention as a versatile and promising platform for cancer therapy. Vesicular stomatitis virus (VSV) represents an attractive oncolytic agent due to its inherent ability to preferentially infect and kill tumor cells, boost an antitumor immune response, and its flexibility to efficiently express transgenes. In order to overcome potential hurdles for the systemic administration of VSV, which include neutralization and nonspecific uptake, we aim to develop a combination therapy which employs T-cell receptor (TCR) transgenic T cells directed against an epitope of Myeloperoxidase (Klar et al. 2014, Leukemia). As genetically engineered T cells are currently undergoing clinical trials, they have the potential to provide an ideal vehicle for a combination therapy with VSV. In our work, we have shown that human CD8+ central memory T cells (CD8+ Tcm) not only transport and deliver infectious virus to their tumor target while eliciting their own potent cytotoxic effector functions, but they also support viral amplification in the absence of significantly decreased cell viability in culture after 24h of viral infection. Moreover, we demonstrate in coculture assays with ML2 leukemia cells, that TCR transgenic CD8+ Tcm profit from the additional virus-mediated tumor cell killing as compared to a monotherapy with TCR transgenic CD8+ Tcm alone. Although viral titers in coculture assays with TCR transgenic cells were slightly decreased compared to those achieved in cocultures with T cells not expressing the TCR, we consider this to be an additional benefit of the combination therapeutic approach to reduce VSV-mediated off-target side effects, as VSV is known for its neurotoxic and hepatotoxic effects in a dose dependent manner. This is supported by our findings that highly immune-deficient NSG mice tolerate similar amounts of virus better if applied together with CD8+ Tcm. Furthermore, we demonstrate that the combination therapy for tumor-bearing NSG mice leads to enhanced transduction efficiency of VSV compared to that achieved by delivery of naked virus, as well as faster tumor cell killing compared to monotherapies with TCR transgenic CD8+ T cm or VSV alone when applied at the maximum tolerated dose. We therefore conclude that the combination of these monotherapies is a crucial step toward a broader and safer option for cancer treatment, as each offers a complimentary approach to tumor cell killing while simultaneously reducing the weaknesses of the other treatment option. We speculate that immune evasion can be efficiently overcome by application of the combination therapy while providing an efficient targeting and delivery vehicle of systemically applied oncolytic VSV with a concomitant reduction of toxicity. As both, rVSV and transgenic T cells are already undergoing clinical testing, our proposed combination therapy has the potential for a seamless translation to clinical application.
Citation Format: Michael Karl Melzer, Lisa Zeitlinger, Sabine Mall, Katja Steiger, Angela Krackhardt, Oliver Ebert, Jennifer Altomonte. TCR transgenic T cells improve the anticancer potential of oncolytic vesicular stomatitis virus as cell carriers and as synergistic therapeutics [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B14.