Abstract
Despite improvements in chemotherapy and radical surgical debulking, peritoneal carcinomatosis (PC) remains among the most common causes of death from abdominal cancers. Immunotherapies have been effective for selected solid malignancies, but their potential in PC has been little explored. Here, we report that intraperitoneal injection of an infected cell vaccine (ICV), consisting of autologous tumor cells infected ex vivo with an oncolytic Maraba MG1 virus expressing IL12, promotes the migration of activated natural killer (NK) cells to the peritoneal cavity in response to the secretion of IFNγ-induced protein-10 (IP-10) from dendritic cells. The recruitment of cytotoxic, IFNγ-secreting NK cells was associated with reduced tumor burden and improved survival in a colon cancer model of PC. Even in mice with bulky PC (tumors > 8 mm), a complete radiologic response was demonstrated within 8 to14 weeks, associated with 100% long-term survival. The impact of MG1-IL12-ICV upon NK-cell recruitment and function observed in the murine system was recapitulated in human lymphocytes exposed to human tumor cell lines infected with MG1-IL12. These findings suggest that an MG1-IL12-ICV is a promising therapy that could provide benefit to the thousands of patients diagnosed with PC each year. Cancer Immunol Res; 5(3); 211-21. ©2017 AACR.
Highlights
Peritoneal carcinomatosis is one of the most common and problematic sites of metastases for abdominal malignancies, including gastrointestinal and ovarian cancers [1]
MG1-IL12-infected cell vaccine (ICV) enhanced natural killer (NK) cell–mediated tumor rejection We previously demonstrated that infecting autologous tumor cells ex vivo with oncolytic viruses can elicit a robust immune response against established, nonpermissive, tumors in vivo [18]
To determine whether MG1 and MG1-IL12 could induce an immune response when used as an ICV, we i.v. injected 5 Â 105
Summary
Peritoneal carcinomatosis is one of the most common and problematic sites of metastases for abdominal malignancies, including gastrointestinal and ovarian cancers [1]. Chemotherapy is less effective in patients with peritoneal carcinomatosis, and it cannot be administered once a patient develops a complication, such as a bowel obstruction [2]. Intraperitoneal chemotherapy with surgical debulking is associated with higher. Survival rates than systemic chemotherapy, but results are still disappointing, and treatment is rarely curative [3]. Several independent groups have reported that immune modulating agents can provide a significant therapeutic benefit in preclinical models of peritoneal carcinomatosis
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