Herpes Simplex Virus as an in Situ Cancer Vaccine for the Induction of Specific Anti-Tumor Immunity

Abstract

The success of cancer gene therapy is likely to require the targeting of multiple antitumor mechanisms. One strategy involves the use of attenuated, replication-competent virus vectors, such as herpes simplex virus type 1 (HSV-1) mutant G207, which is able to replicate in human tumor cells with resultant cell death and tumor growth inhibition, yet is nonpathogenic in normal tissue. In this study, we demonstrate that infection of established tumors with G207 also induces a highly specific systemic anti-tumor immune response. In a syngeneic, bilateral established subcutaneous tumor model, with mouse CT26 colorectal carcinoma cells in BALB/c mice or M3 melanoma cells in DBA/2 mice, unilateral intratumoral inoculation with G207 caused a significant reduction in the growth of both the inoculated and contralateral noninoculated tumors. This elicited anti-tumor response is dependent on viral infection of the tumor, as intradermal inoculation of G207 in BALB/c mice had no effect on CT26 tumor growth. Treatment of subcutaneous CT26 tumors by intratumoral inoculation of G207 induced a tumor-specific T cell response. CD8+ cytotoxic T lymphocyte (CTL) activity was generated that recognized a dominant "tumor-specific" major histocompatibility complex (MHC) class I-restricted epitope (AH1) from CT26 cells. In immune-competent animals, G207 is acting as an in situ tumor vaccine. Therefore, intratumoral G207 inoculation is able to inhibit tumor growth both by local cytotoxic viral replication in tumor cells and induction of a systemic anti-tumor immune response.

Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial

“…It is evident that the oncolytic effect of the virus accounts for at least a portion of its anti-tumor effects; other studies suggest that an anti-tumor immune response can also be induced by the virus in animal models. 10,11,21 Safety of G207 has been demonstrated by intracerebral inoculation in naive animals including sensitive mouse strains (BALB/c, A/J strain) and highly susceptible primates (Aotus nancymai). No evidence of encephalitis, either clinically or histologically, has been seen in these animals with G207 doses up to 10 9 p.f.u.…”

Immuno-viral therapy of brain tumors by combination of viral therapy with cancer vaccination using a replication-conditional HSV

“…CT26 cells, derived from one of the murine tumors susceptible to G207, are efficiently destroyed by G207 at an MOI of 1 but not 0.1 pfu/cell in vitro. 10 Infection at an MOI of 1 reflects the Figure 6 Involvement of anti -HSV immunity in the significant antitumor effect of the combined treatment. Tumor cells were injected into the brain ( 1Â10 4 CT26 cells ) and skin ( 5Â10 5 P815 cells ) of BALB / c mice ( i.c.…”

“…In contrast, in models with bilaterally established syngeneic tumors in immunocompetent mice, G207 inoculation of one tumor inhibited the growth of both the inoculated and the distant, noninoculated tumors. 10 Unlike the situation in athymic mice, tumor growth inhibition in immunocompetent mice involves the induction of an antitumor T-cell response. 10 -13 These observations suggested that treatment of local tumors with G207 affects distant metastatic tumors through the induction of a specific immune response against tumor antigens.…”

“…10 Peptide AH1, the nonamer SPSYVYHQF, is the immunodominant antigen derived from the envelope protein ( gp70 ) of an endogenous ecotropic murine leukemia virus ( MuLV ) and presented by the major histocompatibility…”

Widespread intratumoral virus distribution with fractionated injection enables local control of large human rhabdomyosarcoma xenografts by oncolytic herpes simplex viruses

“…Most studies of oncolytic viruses have been performed on small tumors. We reviewed 16 studies of oncolytic HSVs in non-CNS tumors published between 1998 and 2003, and found that the average tumor size injected in 14 studies was o150 mm 3 , 17,21,[34][35][36][37][38][39][40][41][42][43][44][45] in two studies was 150-250 mm 3 , 46,47 and in no study was 4250 mm 3 . We used a high-risk alveolar rhabomyosarcoma model to determine the effect of oncolytic HSV injections on large human tumor xenografts.…”