Development of an allogeneic whole-cell tumor vaccine expressing xenogeneic gp100 and its implementation in a phase II clinical trial in canine patients with malignant melanoma

Abstract

A xenogeneic melanoma-antigen-enhanced allogeneic tumor cell vaccine (ATCV) is an appealing strategy for anti-cancer immunotherapy due to its relative ease of production, and the theoretical possibility that presentation of a multiplex of antigens along with a xenogeneic antigen would result in cross-reaction between the xenogeneic homologs and self-molecules, breaking tolerance and ultimately resulting in a clinically relevant immune response. In this study, we evaluated the efficacy of such a strategy using a xenogeneic melanoma differentiation antigen, human glycoprotein 100 (hgp100) in the context of a phase II clinical trial utilizing spontaneously arising melanoma in pet dogs. Our results demonstrate that the approach was well tolerated and resulted in an overall response rate (complete and partial response) of 17% and a tumor control rate (complete and partial response and stable disease of >6 weeks duration) of 35%. Dogs that had evidence of tumor control had significantly longer survival times than dogs that did not experience control. Delayed type hypersensitivity (DTH) to 17CM98 canine melanoma cells used in the whole cell vaccine was enhanced by ATCV and correlated with clinical response. In vitro cytotoxicity was enhanced by ATCV, but did not correlate with clinical response. Additionally, anti-hgp100 antibodies were elicited in response to ATCV in the majority of patients tested; however, this also did not correlate with clinical response. This approach, along with further elucidation of the mechanisms of tumor protection after xenogeneic immunization, may allow the development of more rational vaccines. This trial also further demonstrates the utility of spontaneous tumors in companion animals as a valid translational model for the evaluation of novel vaccine therapies.

Cytokine-enhanced vaccine and suicide gene therapy as surgery adjuvant treatments for spontaneous canine melanoma: 9 years of follow-up

“…Even though the PS-CT was less effective than the CS-CT to control the disease, it was significantly better than only surgery (PS-ST: Po0.01 Table 4 and CS-ST: Po0.05, Fisher's Exact test). Thus, this updated study suggests that this CT holds the most promise for cancer patients with minimal residual disease, [6][7][8]16,20 and corroborates the negative prognostic factor for the presence of local disease that substantially shortened patients median overall survival (Tables 4 and 5).…”

“…[1][2][3] We have widely discussed the potential of comparative cancer gene therapy as a preclinical phase for human clinical trials. 5 Different gene therapy approaches have been reported for canine spontaneous melanoma such as: (i) ex vivo human interleukin-2 (hIL-2) producing xenogeneic cells, 6 human granulocytemacrophage colony-stimulating factor (hGM-CSF) producing autologous tumor cells, 7 human gp100 producing allogeneic tumor cells; 8 and (ii) in vivo gene transfer of enterotoxin-B plus GM-CSF, 9 xenogeneic human 10 or murine 11 tyrosinase, human FasL, 12 IL-12 (ref. 13) and CD40 ligand.…”

Cancer immunology and canine malignant melanoma: A comparative review

“…In a clinical trial using allogeneic whole cell vaccination, the canine melanoma cell line, 17CM98, was transfected with xenogeneic human gp100 (a melanocyte specific trans-membrane protein i.e.i.e. a melanoma TAA), killed by irradiation and administered intra-dermally to dogs in an attempt to break tolerance with a combination of self and xenogeneic antigens (Alexander et al, 2006). Hogge and colleagues adopted a Figure. 1 The melanogenesis pathway, enzymes involved in the pathway that act as differentiation antigens are indicated with italics.…”

Cytokine-enhanced vaccine and suicide gene therapy as surgery adjuvant treatments for spontaneous canine melanoma

“…10 Immunotherapy in combination with suicide gene therapy (SG) holds the most promise for malignant melanoma patients with minimal residual disease after surgery. [11][12][13] In a previous controlled study in more than 100 dogs, we demonstrated that repeated concurrent injections of the suicide gene system and engineered xenogeneic IL-2-and GM-CSF-secreting cells into the tumor bed, substantially controlled tumor growth and improved disease-free and overall survival in the treated animals compared to untreated or surgerytreated controls.…”