Oncolytic Adenovirus Coding for Granulocyte Macrophage Colony-Stimulating Factor Induces Antitumoral Immunity in Cancer Patients

Abstract

Granulocyte macrophage colony-stimulating factor (GMCSF) can mediate antitumor effects by recruiting natural killer cells and by induction of tumor-specific cytotoxic T-cells through antigen-presenting cells. Oncolytic tumor cell-killing can produce a potent costimulatory danger signal and release of tumor epitopes for antigen-presenting cell sampling. Therefore, an oncolytic adenovirus coding for GMCSF was engineered and shown to induce tumor-specific immunity in an immunocompetent syngeneic hamster model. Subsequently, 20 patients with advanced solid tumors refractory to standard therapies were treated with Ad5-D24-GMCSF. Of the 16 radiologically evaluable patients, 2 had complete responses, 1 had a minor response, and 5 had disease stabilization. Responses were frequently seen in injected and noninjected tumors. Treatment was well tolerated and resulted in the induction of both tumor-specific and virus-specific immunity as measured by ELISPOT and pentamer analysis. This is the first time that oncolytic virus-mediated antitumor immunity has been shown in humans. Ad5-D24-GMCSF is promising for further clinical testing.

Syngeneic Syrian hamster tumors feature tumor-infiltrating lymphocytes allowing adoptive cell therapy enhanced by oncolytic adenovirus in a replication permissive setting

“…It is generally thought that armed oncolytic viruses are more potent than unarmed viruses and therefore the former are typically employed in clinical development. 9,18,21,43 In conclusion, we have shown that oncolytic adenovirus can be used to improve the efficacy of adoptive TIL transfer. Also, this is the first time TIL of the Syrian hamster have been cultured, characterized and used therapeutically.…”

“…8 Several implantable tumor cell lines, with wide histological range, have been identified and utilized in cancer gene therapy studies with oncolytic adenovirus vectors in this fully immunocompetent model. 9,10 Yet, immunological studies of Syrian hamster tumors are scarce, owing to general lack of hamster-specific reagents. With regard to TIL therapy, the features and therapeutic potential of TIL in hamsters are unknown.…”

Impact of novel oncolytic virus HF10 on cellular components of the tumor microenviroment in patients with recurrent breast cancer

“…In addition, a number of studies have shown beneficial effects of antiangiogenic treatment in various cancer models. [66][67][68][69] The angiogenesis caused by oncolytic herpes viruses may have deleterious effects on the late phase of cancer therapy, especially with regard to late recurrences that occur after the end of the treatment regimen. In order to investigate this effect, we initiated a series of preclinical studies combining oncolytic herpes viruses with the monoclonal anti-VEGFA antibody bevacizumab in various cancer models.…”

Targeted cancer immunotherapy with oncolytic adenovirus coding for a fully human monoclonal antibody specific for CTLA-4

“…39 Also, we have demonstrated previously that oncolytic adenoviruses expressing immunomodulatory agents are able to induce tumor-specific immunity by triggering the innate and adaptive pathways of the immune system. 40,41 Of note, the oncolytic platform may be useful for increasing 'danger signals', useful for immunity versus tolerance.…”