Enhanced Tumor Protection by Granulocyte-Macrophage Colony-Stimulating Factor Expression at the Site of an Allogeneic Vaccine

Abstract

Murine tumor models have demonstrated that whole tumor cell vaccines engineered to secrete certain cytokines in a paracrine fashion elicit systemic immune responses capable of eliminating small amounts of established tumor. In particular, autologous tumors that express the cytokine GM-CSF induce potent systemic immune responses against poorly immunogenic murine tumors. However, phase I clinical trials have demonstrated the technical difficulty of routinely expanding primary autologous human tumor cells to the numbers required for vaccination, making the generalization of autologous vaccines impractical. Dissection of the mechanism by which antitumor immunity is generated has demonstrated that GM-CSF recruits professional antigen-presenting cells that act as intermediates in presenting tumor antigen to and activating effector T cells. Furthermore, the identification of commonly recognized murine and human tumor antigens indicates that many are shared rather than unique. These findings would suggest that allogeneic as well as autologous tumor cells can be used as the vaccinating cells for activating antitumor immunity. A major concern in the application of allogeneic vaccines relates to the potential interference of allogeneic MHC expression at the vaccine site with priming of tumor-specific T cell responses. Here we describe a series of experiments that directly examines the effects of allogeneic MHC molecules on the immune-priming capabilities of a whole cell tumor vaccine engineered to secrete GM-CSF. The results demonstrate that the expression of an allogeneic MHC molecule by a vaccine cell can actually enhance the induction of systemic antitumor immunity. In addition, allogeneic MHC expression has no inhibitory effect on the ability of GM-CSF-transduced vaccines to induce systemic antitumor immunity. These findings support the design of clinical trials for testing this more feasible and generalizable allogeneic whole tumor cell vaccine approach.

Anti-tumour activity against B16-F10 melanoma with a GM-CSF secreting allogeneic tumour cell vaccine

“…To our knowledge, there is no report of efficacy of GM-CSF secreting allogeneic whole tumour cell vaccine in both prevention and treatment of established tumours. Thomas and colleagues 22 have however demonstrated enhancement of tumour efficacy with GM-CSF genetic modification of autologous tumour cells also genetically engineered to express allogeneic MHC. One report has demonstrated that autologous tumour cells mixed with allogeneic fibroblasts secreting IL-2 could prolong survival of animals with established B16 tumours.…”

“…20,21 As pre-clinical models for autologous vaccines show GM-CSF to be more potent than IL-2, it would seem logical to expect that this may also extend to allogeneic vaccines. A recent report 22 showed that GM-CSF enhanced the protective ability of autologous tumour vaccine cells modified to express an allogeneic MHC. On this basis, Jaffee and colleagues 23 have initiated recruitment for a clinical trial using a GM-CSF-secreting allogeneic vaccine to treat pancreatic adenocarcinoma.…”

Characterization of the MUC1.Tg/MIN transgenic mouse as a model for studying antigen-specific immunotherapy of adenomas

“…The MHC class I peptides confer MUC1 specificity leading to the induction of CTL-mediated anti-tumor responses; the Hepatitis B core antigen-derived MHC class II pan T helper peptide was included to boost CD8 + anti-tumor responses [30,31]; CpG-ODN was included to promote DC activation via its interaction with Toll-like receptor (TLR)-9 [32,33] to enhance CTL responses, expansion and survival [33][34][35][36][37]. GM-CSF promotes antigen presentation and DC recruitment to vaccine sites [38][39][40][41] and is commonly used as a biological adjuvant in preclinical and clinical immunotherapy studies [42,43]. In separate experiments, groups of MUC1.Tg/MIN and MIN mice were immunized with the peptide-based vaccine (peptides + CpG-ODN + GM-CSF) or the non-peptide-based vaccine (CpG-ODN + GM-CSF) on day 66 when the mice harbored large numbers of adenomas.…”

Complete tumor prevention by engineered tumor cell vaccines employing nonviral vectors

“…3 The expression of certain cytokines by these tumor cells can stimulate the immune system, resulting in cell elimination by enhancing tumor immunogenicity with minimal systemic toxicity. 4 Certain immune reactions are involved in tumor rejection, such as ''cross-priming'' processes, 1,5 or direct antigen presentation by vaccine cells, 6,7 resulting in the activation of CD8+ cytotoxic T (CTL) and CD4+ helper T (Th) lymphocyte responses. 8 Cross-priming processes imply cellular antigen transfer from tumor cells to host antigen-presenting cells (APC) for processing and presentation.…”