Poxvirus-based active immunotherapy synergizes with CTLA-4 blockade to increase survival in a murine tumor model by improving the magnitude and quality of cytotoxic T cells

Abstract

The dramatic clinical benefit of immune checkpoint blockade for a fraction of cancer patients suggests the potential for further clinical benefit in a broader cancer patient population by combining immune checkpoint inhibitors with active immunotherapies. The anti-tumor efficacy of MVA-BN-HER2 poxvirus-based active immunotherapy alone or in combination with CTLA-4 checkpoint blockade was investigated in a therapeutic CT26-HER-2 lung metastasis mouse model. MVA-BN-HER2 immunotherapy significantly improved the median overall survival compared to untreated controls or CTLA-4 blockade alone (p < 0.001). Robust synergistic efficacy was achieved with the combination therapy (p < 0.01). Improved survival following MVA-BN-HER2 administration was accompanied by increased tumor infiltration by HER-2-specific cytotoxic T lymphocytes (CTL). These tumor-specific CTL had characteristics similar to antiviral CTL, including strong expression of activation markers and co-expression of IFNγ and TNFα. Combination with CTLA-4 blockade significantly increased the magnitude of HER-2-specific T cell responses, with a higher proportion co-expressing TNFα and/or IL-2 with IFNγ. Furthermore, in mice treated with MVA-BN-HER2 (alone or in combination with CTLA-4 blockade), the inducible T cell co-stimulator (ICOS) protein was expressed predominantly on CD4 and CD8 effector T cells but not on regulatory T cells (Treg). In contrast, mice left untreated or treated solely with CTLA-4 blockade harbored elevated ICOS+ Treg, a phenotype associated with highly suppressive activity. In conclusion, poxvirus-based active immunotherapy induced robust tumor infiltration by highly efficient effector T cells. Combination with CTLA-4 immune checkpoint blockade amplified this response resulting in synergistically improved efficacy. These hypothesis-generating data may help elucidate evidence of enhanced clinical benefit from combining CTLA-4 blockade with poxvirus-based active immunotherapy.Electronic supplementary materialThe online version of this article (doi:10.1007/s00262-016-1816-7) contains supplementary material, which is available to authorized users.

Dying to protect: cell death and the control of T‐cell homeostasis

“…The memory cells possess two major subsets, central memory T (T CM ) cells, characterized largely by expression of CD62L and CCR7, and effector memory T (T EM− ) cells, characterized largely by the lack of CD62L expression (13–15). Both subsets are derived largely from the pre-memory cells (MPEC), although recent work suggests that the double positive effector cells (DPEC) may give rise to T EM cells (16, 17). In addition, a recently described subset of tissue resident memory cells has been described.…”

“…[13][14][15] Both subsets are derived largely from the prememory cells (MPEC), although recent work suggests that the DPEC may give rise to T EM cells. 16,17 In addition, a recently described subset of tissue-resident memory cells has been described. These T RM cells reside in tissues, although the origin of these cells (whether they are derived from MPEC, DPEC, or SLEC) remains unclear.…”

Viral based vaccine TG4010 induces broadening of specific immune response and improves outcome in advanced NSCLC

“…Hence, while the repertoire of the immune response induced by TG4010 + CT was slightly broader than that of CT alone, we believe that the difference in overall survival outcome for the patients receiving TG4010 may result from either a change of functional state of generated T cells, a modification of the composition of the tumor micro-environment or a combination of both. Our earlier preclinical work reported the ability of a subcutaneous viral based vaccination to trigger a detectable infiltration of the tumor environment by CD8+ and CD4+ lymphocytes [ 21 ]. Hence, in our case, broadening of the immune response might have synergized with CD8+ T cell enrichment of tumor sites after vaccination, consistently to what has been reported in melanoma [ 22 ].…”

Armed oncolytic viruses: A kick-start for anti-tumor immunity

“…Intratumoral administration of NDV combined with systemic treatment with anti-CTLA-4 (Ipilimumab) showed improved antitumor effect mediated by CTLs and NK cells in a murine melanoma model [70]. Studies using combinations of systemic CTLA-4 blockade with other OVs (VV [71,72] and VSV [20]) showed prolonged survival in renal [71], lung [72] and mammary [20] tumor models, long term protection to re-challenge with tumor cells [71,72], and even cured mice [20]. Moreover, T-VEC combined with systemic CTLA-4 blockade has been evaluated for therapy in melanoma patients, which yielded a tumor growth control that was significantly greater than observed after both monotherapies [73].…”

“…Nevertheless, vectorization of checkpoint inhibitors can also limit the potency of the immune therapies by incorrect localization and timing and no resilience in case of tumor resistance. With regard to localization, a checkpoint receptor, such as CTLA-4, is mainly functional in the lymph node and requires systemic delivery of the blocking antibodies [72]. For instance, the anti-CTLA-4 armed MV proved to be less effective than monotherapy with CTLA-4 inhibitors [75].…”