Limited Antitumor T Cell Response in Melanoma Patients Vaccinated with Interleukin-2 Gene-Transduced Allogeneic Melanoma Cells

Abstract

We have immunized advanced melanoma patients with a HLA-A2-compatible human melanoma line genetically modified to release interleukin-2 (IL-2), to elicit or increase a T cell-mediated anti-melanoma response that may affect distant lesions. Twelve stage-IV patients were injected subcutaneously at days 1, 13, 26, and 55 with IL-2 gene-transduced and irradiated melanoma cells at doses of 5 or 15 x 10(7) cells. Both local and systemic toxicities were mild, consisting of transient erythema at the vaccination site; fever occurred in a minority of patients. Three mixed responses were recorded. Seven patients were evaluable for immunological studies. Mixed tumor-lymphocyte cultures carried out with different allogeneic HLA-A2-matched melanoma lines as stimulators and targets revealed an increase in the MHC-unrestricted, but no changes in the MHC-restricted, cytotoxicity in peripheral blood lymphocytes (PBL) obtained after vaccination as compared with those obtained before vaccination. Increased recognition of the tyrosinase 368-376 peptide occurred in post-vaccination PBL of one patient, whereas a weak increase in recognition of the gp100 280-288 peptide was detectable in another patient; these 2 patients also recognized the gp100 457-466 peptide. After in vitro, stimulation with the only available autologous melanoma line, CD4+ cells with autologous tumor-specific cytotoxicity and ability to release interferon-gamma (IFN-gamma) were found in post- but not in pre-vaccination PBL. In the same patient, as well as in another patient, limiting dilution analysis showed that vaccination resulted in an increased frequency of melanoma-specific cytotoxic T lymphocyte (CTL) precursors. These results indicate that vaccination with cells releasing IL-2 locally can expand a T cell response against antigen(s) of autologous, untransduced tumor, although this response occurred in a minority of the melanoma patients studied.

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

“…However, early reports of allogeneic vaccines modified to secrete IL-2 have reported a limited response. 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.…”

Induction of P815 tumor immunity by recombinant Semliki Forest virus expressing the P1A gene

“…45,46 In addition, a peptide vaccine is limited to the range of the population that carry the corresponding MHC restriction element. Genetically modified whole cell tumor vaccines (such as cytokine-gene transduced autologous cells), [8][9][10] have the disadvantage of introducing a lot of potential irrelevant antigenic material which might cause unspecific and adverse effects, together with the complication of requiring large numbers of individual tumor cells.…”

“…The most widely used vaccines in clinical studies are whole tumor cells either alone or in combination with B7 or cytokine genes. [8][9][10] More recent approaches include vaccination with peptide, recombinant viral and bacterial nucleic acid, heat-shock proteins or dendritic cells (DC). 1,2 However, there is presently no consensus on which of these different vaccine types are optimal for tumor immunotherapy.…”

Cytotoxic T lymphocyte response against non-immunoselected tumor antigens predicts the outcome of gene therapy with IL-12-transduced tumor cell vaccine

“…2,5 The efficacy of vaccination on the generation of immune response is evaluated by comparing immunologic parameters before and after treatment; however, which of such parameters correlates with clinical response remains undetermined. 16 We and others have shown that the induction of antitumor CTL does not correlate with tumor regression in both humans [17][18][19] and mice. 15,20 The present study corroborates this conclusion and shows that activation of CD8 cells is necessary but not sufficient to induce the eradication of lung metastases.…”