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Improving the chances of curing patients with cancer who have had surgery to remove metastatic sites of disease is a priority area for cancer research. Pexa-Vec (Pexastimogene Devacirepvec; JX-594, TG6006) is a principally immunotherapeutic oncolytic virus that has reached late-phase clinical trials. We report the results of a single-center, nonrandomized biological end point study (trial registration: EudraCT number 2012-000704-15), which builds on the success of the presurgical intravenous delivery of oncolytic viruses to tumors. Nine patients with either colorectal cancer liver metastases or metastatic melanoma were treated with a single intravenous infusion of Pexa-Vec ahead of planned surgical resection of the metastases. Grade 3 and 4 Pexa-Vec-associated side effects were lymphopaenia and neutropaenia. Pexa-Vec was peripherally carried in plasma and was not associated with peripheral blood mononuclear cells. Upon surgical resection, Pexa-Vec was found in the majority of analyzed tumors. Pexa-Vec therapy associated with IFNα secretion, chemokine induction, and resulted in transient innate and long-lived adaptive anticancer immunity. In the 2 patients with significant and complete tumor necrosis, a reduction in the peripheral T-cell receptor diversity was observed at the time of surgery. These results support the development of presurgical oncolytic vaccinia virus-based therapies to stimulate anticancer immunity and increase the chances to cure patients with cancer., (©2022 The Authors; Published by the American Association for Cancer Research.)

Purpose: Surgical removal of solid primary tumors is an essential component of cancer treatment. Surgery-induced dysfunction in natural killer (NK) cells has been linked to the development of metastases in animal models and patients with cancer. We investigated the activation of NK cells using influenza vaccine in the perioperative period to eradicate micrometastatic disease., Experimental Design: Both the B16lacZ and 4T1 tumor models in immunocompetent mice were used to assess the in vivo efficacy of perioperative influenza vaccine administration. In healthy human donors and cancer surgery patients, we assessed NK cell function pre- and post-influenza vaccination using both in vivo and ex vivo assays., Results: Using the TLR3 agonist poly(I:C), we showed as proof-of-principle that perioperative administration of a nonspecific innate immune stimulant can inhibit surgery-induced dysfunction in NK cells and attenuate metastases. Next, we assessed a panel of prophylactic vaccines for NK cell activation and determined that inactivated influenza vaccine was the best candidate for perioperative administration. Perioperative influenza vaccine significantly reduced tumor metastases and improved NK cytotoxicity in preclinical tumor models. Significantly, IFNα is the main cytokine mediator for the therapeutic effect of influenza vaccination. In human studies, influenza vaccine significantly enhanced NK cell activity in healthy human donors and cancer surgery patients., Conclusion: These results provide the preclinical rationale to pursue future clinical trials of perioperative NK cell activation, using vaccination in cancer surgery patients. Research into perioperative immune therapy is warranted to prevent immune dysfunction following surgery and eradicate metastatic disease., (©2013 AACR.)

Purpose: Early clinical trials are under way exploring the direct oncolytic potential of reovirus. This study addresses whether tumor infection by reovirus is also able to generate bystander, adaptive antitumor immunity., Experimental Design: Reovirus was delivered intravenously to C57BL/6 mice bearing lymph node metastases from the murine melanoma, B16-tk, with assessment of nodal metastatic clearance, priming of antitumor immunity against the tumor-associated antigen tyrosinase-related protein-2, and cytokine responses. In an in vitro human system, the effect of reovirus infection on the ability of Mel888 melanoma cells to activate and load dendritic cells for cytotoxic lymphocyte (CTL) priming was investigated., Results: In the murine model, a single intravenous dose of reovirus reduced metastatic lymph node burden and induced antitumor immunity (splenocyte response to tyrosinase-related protein-2 and interleukin-12 production in disaggregated lymph nodes). In vitro human assays revealed that uninfected Mel888 cells failed to induce dendritic cell maturation or support priming of an anti-Mel888 CTL response. In contrast, reovirus-infected Mel888 cells (reo-Mel) matured dendritic cells in a reovirus dose-dependent manner. When cultured with autologous peripheral blood lymphocytes, dendritic cells loaded with reo-Mel induced lymphocyte expansion, IFN-gamma production, specific anti-Mel888 cell cytotoxicity, and cross-primed CD8+ T cells specific against the human tumor-associated antigen MART-1., Conclusion: Reovirus infection of tumor cells reduces metastatic disease burden and primes antitumor immunity. Future clinical trials should be designed to explore both direct cytotoxic and immunotherapeutic effects of reovirus.