Intratumoral expression of IL-7 and IL-12 using an oncolytic virus increases systemic sensitivity to immune checkpoint blockade

Abstract

The immune status of the tumor microenvironment is a key indicator in determining the antitumor effectiveness of immunotherapies. Data support the role of activation and expansion of tumor-infiltrating lymphocytes (TILs) in increasing the benefit of immunotherapies in patients with solid tumors. We found that intratumoral injection of a tumor-selective oncolytic vaccinia virus encoding interleukin-7 (IL-7) and IL-12 into tumor-bearing immunocompetent mice activated the inflammatory immune status of previously poorly immunogenic tumors and resulted in complete tumor regression, even in distant tumor deposits. Mice achieving complete tumor regression resisted rechallenge with the same tumor cells, suggesting establishment of long-term tumor-specific immune memory. Combining this virotherapy with anti–programmed cell death-1 (PD-1) or anti–cytotoxic T lymphocyte antigen 4 (CTLA4) antibody further increased the antitumor activity as compared to virotherapy alone, in tumor models unresponsive to either of the checkpoint inhibitor monotherapies. These findings suggest that administration of an oncolytic vaccinia virus carrying genes encoding for IL-7 and IL-12 has antitumor activity in both directly injected and distant noninjected tumors through immune status changes rendering tumors sensitive to immune checkpoint blockade. The benefit of intratumoral IL-7 and IL-12 expression was also observed in humanized mice bearing human cancer cells. These data support further investigation in patients with non-inflamed solid tumors.

Tumor Infiltrating Effector Memory Antigen-Specific CD8+ T Cells Predict Response to Immune Checkpoint Therapy

“…IL-7/IL-7Ra signalling pathway is crucial for memory CTL formation. The effects of ICT are IL-7 dependent (45), and combination IL-7 and ICT improved therapeutic benefit and long-term memory T cell responses in murine models (46)(47)(48). Increased frequencies of IL-7Ra expressing tumor antigenspecific CTLs found in the present study could indicate increased survival and persistence of memory CTLs in the tumor microenvironment and possibly providing long-term therapeutic benefit to ICT.…”

Localized Interleukin-12 for Cancer Immunotherapy

“…Also, as mentioned in a previous section, i.t. injections of VV-IL-12 and VV-IL7 enhanced the responsiveness of poorly immunogenic tumors to checkpoint inhibition (268). Finally, a recent Phase II study of i.t.…”

“…VV-IL-12 and IL-2 expressing VV (VV-IL-2) exhibited similar inhibition of C6 gliomas ( 265 , 266 ) However, against AE17 mesotheliomas, VV-IL-12 cured 80% of mice compared to only 20% of mice treated with VV-IL2 ( 267 ). Recently, an oncolytic VV-IL-12 was shown to increase lymphocytic infiltration and inhibit LLC and B16F10 tumors with 14–25% complete responses ( 268 ). Antitumor efficacy was enhanced by the addition of an IL-7 expressing VV (VV-IL7) as well as immune checkpoint inhibitors ( 268 ).…”

Administration of fusion cytokines induces tumor regression and systemic antitumor immunity

“…A great deal of clinical practice has indicated that monotherapy of cancer reaches a ceiling, including immunotherapy. Recently, some novel combinational immunotherapies exhibit excellent curative effects (53)(54)(55)(56). These results suggest that multiple immune stimulations have the capability of eliciting immune response to erase malignant tumors.…”