Gene Therapy with Autologous, Interleukin 2-Secreting Tumor Cells in Patients with Malignant Melanoma

Abstract

We vaccinated metastatic melanoma patients with irradiated, autologous melanoma cells genetically engineered to secrete interleukin 2 (IL-2) to investigate whether an anti-tumor immune response would be induced. Melanoma cell cultures were established from surgical specimens and were engineered to secrete IL-2 by infection with recombinant retrovirus. Twelve patients were vaccinated subcutaneously one, two, or three times with approximately 10(7) irradiated, autologous, IL-2-secreting tumor cells. Treatment was well tolerated, with local reactions at 11 of 24 injection sites and minor systemic symptoms of fever and headache after 6 injections. One patient developed anti-tumor DTH after the first vaccination and showed an increased response after the second vaccination. Anti-autologous tumor CTLs could be detected prevaccination in the peripheral blood of seven patients and their activity increased after vaccination in four patients. No UICC-defined clinical responses were seen, but three patients had stable disease for 7-15 months, one of whom has not yet progressed (15+ months). Thus, patient vaccination with autologous, genetically engineered tumor cells is feasible and safe. Anti-tumor DTH and CTLs can be induced in some patients with such a vaccine.

Adenovector engineered interleukin-2 expressing autologous plasma cell vaccination after high-dose chemotherapy for multiple myeloma - a phase 1 study

“…30 Nevertheless, the number of cells injected per vaccine and the IL-2 secreted by gene modified plasma cells was comparable to that employed by other groups in melanoma and neuroblastoma trials. 22,31,32 These studies each reported efficacy as defined by vaccine-induced anti-tumor responses and/or clinical responses.…”

Angiogenesis meets immunology: Cytokine gene therapy of cancer

“…Autologous melanoma cells were established from surgical specimens, engineered for the production of various cytokines, including IFN-c, IL-2 or GM-CSF, and injected intra-tumorally. Although the procedure was well tolerated, however, specific anti-tumor CTLs and local inflammatory infiltration were observed only in some patients (Kusumoto et al, 2001;Nemunaitis et al, 1998;Palmer et al, 1999;Soiffer et al, 1996). Similar studies were extended to patients with prostate and renal cancer, and anti-cancer immune responses were detected; however, efficacy remained unclear (Nelson et al, 2000;Simons et al, 1999;Tani et al, 2004).…”

Overview of Tumor Cell–Based Vaccines

“…The establishment of a CD4 þ =CD8 þ T-cell infiltrate at the site of vaccination with IL-2-secreting autologous fibroblasts seemed to provide some initial hope that CTL responses would be raised [53]. However, limited CD8 þ T-cell responses have been shown against allogeneic [54,55] and autologous [56] vaccines. In one case, humoral responses were generated against a melanoma cell line (Mel 4932) resulting in IgG that could recognize and kill Mel 4932 cells by Antibody-Dependent Cellular Cytotoxicity (ADCC), but not autologous tumor [57].…”