Vaccination with IL-7 gene-modified autologous melanoma cells can enhance the anti-melanoma lytic activity in peripheral blood of patients with a good clinical performance status: a clinical phase I study

Abstract

Summary Recently, cytokine gene transfer into tumour cells has been shown to mediate tumour regression in animal models via immunomodulation. Consequently, a number of clinical protocols have been developed to treat cancer patients with cytokine gene-modified tumour cells. Here, we report the results of a clinical phase trial using for the first time autologous, interleukin 7 gene-modified tumour cells for vaccination of ten patients with disseminated malignant melanoma. Melanoma cells were expanded in vitro from surgically removed metastases, transduced by a ballistic gene transfer technique and were then injected after in vitro irradiation s.c. at weekly intervals. Clinically, there was no major toxicity except for mild fever, and no major clinical response towards vaccination was observed. Eight of ten patients completed the initial three s.c. vaccinations and were eligible for immunological evaluation. Post vaccination, peripheral mononuclear cells (PBMCs) were found to contain an increased number of tumour-reactive proliferative as well as cytolytic cells, as determined by a limiting dilution analysis. In three of six patients, the frequencies of anti-melanoma cytolytic precursor cells increased between 2.6-and 28-fold. Two of these patients showed a minor clinical response. Analysis of the autologous tumour cell vaccines regarding IL-7 secretion after gene transfer, HLA class and class 11 cell surface expression, secretion of immunosuppressive mediators (TGF-,1, IL-10) and various melanoma-associated tumour antigens revealed a very diverse expression profile. In conclusion, vaccination using gene-modified autologous melanoma cells induced immunological changes in a group of advanced, terminally ill patients. These changes can be interpreted as an increased anti-tumour immune response. However, immunological modulation was most pronounced in patients in good physical condition. Therefore, patients with minimal tumour load or minimal residual disease might preferentially benefit from tumour cell vaccination in further studies. In order to evaluate the effects of the cytokine gene-modified tumour cell vaccines more precisely, an antigenically better defined vaccine is needed.

Selective responsiveness to common gamma chain cytokines in peripheral blood‐derived cytotoxic T lymphocytes induced by Melan‐A/MART‐127–35targeted active specific immunotherapy

“…Monoclonal antibodies specific for CCR7 and IL-7 receptor a chain were obtained from RnD Systems (Abingdon, UK). Tetramer-PE complexes including MART-1/Melan-A [27][28][29][30][31][32][33][34][35] or influenza matrix 58-66 peptides were obtained from Proimmune (Oxford, UK). Standard surface and intracellular staining procedures were used throughout the study.…”

“…Stage III and IV HLA-A0201þ melanoma patients were immunized according to a previously described protocol with a recombinant vaccinia virus encoding gp100 280-288 , Melan-A/ MART-1 [27][28][29][30][31][32][33][34][35] and tyrosinase [1][2][3][4][5][6][7][8][9] HLA-A0201 restricted TAA derived epitopes together with CD80 and CD86 costimulatory molecules (rVV), followed by boosts with the corresponding native synthetic peptides 4,11 in the context of a systemic GM-CSF treatment. Immunogens were administered intradermally or intranodally.…”

“…Thus, we sampled CD8þ cells from 1 of the patients from which clones were derived at 6 months distance from the end of the immunization protocol, where the typical expansion and contraction phases of CTL response had been observed. Melan-A/MART-1 [27][28][29][30][31][32][33][34][35] tetramer-specific T cells were undetectable in freshly separated PBMC (Fig. 8).…”

“…In this work, we have addressed the responsiveness to cg-c known to be involved in memory CTL survival and proliferation in CD8 T cells specific for MART-1/Melan-A [27][28][29][30][31][32][33][34][35] HLA-A2 restricted epitope in vitro on long-term clones and ex vivo in lymphocytes from immunized patients. We report here that both longterm MART-1/Melan-A [27][28][29][30][31][32][33][34][35] HLA-A2 restricted CTL clones and short-term cultured specific memory CTL respond to IL-2 or IL-15 stimulation but are unresponsive to IL-7.…”

“…We report here that both longterm MART-1/Melan-A [27][28][29][30][31][32][33][34][35] HLA-A2 restricted CTL clones and short-term cultured specific memory CTL respond to IL-2 or IL-15 stimulation but are unresponsive to IL-7.…”