Phase I Study of Autologous Tumor Vaccines Transduced with the GM-CSF Gene in Four Patients with Stage IV Renal Cell Cancer in Japan: Clinical and Immunological Findings

Abstract

We produced lethally irradiated retrovirally GM-CSF-transduced autologous renal tumor cell vaccines (GVAX) from six Japanese patients with stage IV renal cell cancer (RCC). Four patients received GVAX ranging from 1.4 x 10(8) to 3.7 x 10(8) cells on 6-17 occasions. Throughout a total of 48 vaccinations, there were no severe adverse events. After vaccination, DTH skin tests became positive to autologous RCC (auto-RCC) in all patients. The vaccination sites showed significant infiltration by CD4(+) T cells, eosinophils, and HLA-DR-positive cells. The kinetic analyses of cellular immune responses using peripheral blood lymphocytes revealed an enhanced proliferative response against auto-RCC in four patients, and cytotoxicity against auto-RCC was augmented in three patients. T cell receptor beta-chain analysis revealed oligoclonal expansion of T cells in the peripheral blood, skin biopsy specimens from DTH sites, and tumors. Western blot analysis demonstrated the induction of a humoral immune response against auto-RCC. Two of the four patients are currently alive 58 and 40 months after the initial vaccination with low-dose interleukin-2. Our results suggest that GVAX substantially enhanced the antitumor cellular and humoral immune responses, which might have contributed to the relatively long survival times of our patients in the present study.

Enhanced therapeutic efficacy of IL-12, but not GM-CSF, expressing oncolytic herpes simplex virus for transgenic mouse derived prostate cancers

“…27,[52][53][54][55] Interestingly, many cell vaccination studies for cancer therapy have focused on using GM-CSF as the preferred cytokine of choice based on initial data that identified it to be the best cytokine. [56][57][58][59][60] However, in the initial comparison study IL-12 was not tested, 56 and at least one recent study suggests that very high doses of GM-CSF can result in adverse immunosuppressive effects. 61 Taken together, the above-cited studies suggest that IL-12 might be the better cytokine for inducing a more robust antitumoral immunity.…”

TLR7 Ligand Augments GM-CSF–Initiated Antitumor Immunity through Activation of Plasmacytoid Dendritic Cells

“…In recent clinical trials of patients with diverse solid cancers, cancer immunotherapy such as therapeutic vaccination with granulocyte macrophage colony-stimulating factor (GM-CSF) gene-transduced tumor vaccines (GVAX), as well as sipuleucel-T (Provenge; Dendreon), the first FDA-approved GM-CSF-based therapeutic dendritic cell (DC) vaccine for prostate cancer, induced antitumor immune responses with tolerability (1)(2)(3). However, the efficacy of this therapy alone is not satisfactory, raising an urgent need to improve the antitumor effect of GVAX.…”

Absence of LTB4/BLT1 axis facilitates generation of mouse GM-CSF–induced long-lasting antitumor immunologic memory by enhancing innate and adaptive immune systems

“…Among numerous immunostimulatory cytokines used for tumor vaccines, GM-CSF has been the most intensively investigated and widely studied for use in clinical cancer vaccine trials. [1][2][3] Immunization with irradiated tumor cells engineered to secrete GM-CSF stimulates potent tumor-associated antigen (TAA)-specific antitumor immunity in preclinical 4,5 and clinical settings, including solid tumors and acute myeloid leukemia. 6,7 We have recently shown that the GM-CSF gene-transduced murine monocytic leukemia of WEHI3B cells lose their tumorigenicity when subcutaneously administered into wild-type (WT) BALB/c mice.…”