Granulocyte Macrophage Colony-Stimulating Factor–Secreting Allogeneic Cellular Immunotherapy for Hormone-Refractory Prostate Cancer

Abstract

Purpose: This trial evaluated the safety, clinical activity, and immunogenicity of an allogeneic cellular immunotherapy in 55 chemotherapy-naI« ve patients with hormone-refractory prostate cancer (HRPC). The immunotherapy, based on the GVAX platform, is a combination of two prostate carcinoma cell lines modified with the granulocyte macrophage colony-stimulating factor (GM-CSF) gene. Experimental Design: HRPC patients with radiologic metastases (n = 34) or rising prostatespecific antigen (PSA) only (n = 21) received a prime dose of 500 million cells and 12 boost doses of either100 million cells (low dose) or 300 million cells (high dose) biweekly for 6 months. End points were changes in PSA, time to progression, and survival. Results: Median survival was 26.2 months (95% confidence interval, 17, 36) in the radiologic group: 34.9 months (8, 57) after treatment with the high dose (n = 10) of immunotherapy and 24.0 months (11, 35) with the low dose (n = 24).The median time to bone scan progression in the radiologic group was 5.0 months (2.6, 11.6) with the high dose and 2.8 months (2.8, 5.7) with the low dose. In the rising-PSA group (n = 21) receiving the low dose, the median time to bone scan progression was 5.9 months (5.6, not reached), and median survival was 37.5 months (29, 56). No dose-limiting or autoimmune toxicities were seen; the most common adverse events were injection site reaction and fatigue. Conclusions: These results suggest that this GM-CSF^secreting, allogeneic cellular immunotherapy is well tolerated and may have clinical activity in patients with metastatic HRPC. Phase 3 trials to confirm these results are under way.Approximately 27,050 men die annually from metastatic hormone-refractory prostate cancer (HRPC; ref. 1). Although chemotherapy with docetaxel has been shown to prolong survival in HRPC (2, 3), alternatives to chemotherapy remain of considerable interest to many patients and physicians. Recent advances in the understanding of cancer immunology have led to the development of new cancer treatments specifically designed to stimulate the patient's immune system. Although prostate cancer has traditionally been thought of as poorly immunogenic, numerous studies have shown that tumor tolerance can be reversed (4 -6). Prostate cancer is a good target for immunotherapy due to the typically slow growth rate of most prostate tumor cells, which in turn permits an appropriately stimulated immune system time to mount antitumor responses (4, 5).Immunotherapy typically involves presenting one or more tumor antigens to the patient's immune system in vivo or to harvested immune cells in vitro (4, 6). An immune system stimulant may be included in the treatment to enhance the immune response to the antigens. Whole tumor cells have been proposed as an antigen source in immunotherapy because relevant prostate cancer tumor-rejection antigens have not been convincingly identified, and a polyvalent source of antigens can better address ''antigen escape'' resulting from the modulation and down-reg...

A primer on tumour immunology and prostate cancer immunotherapy

“…44 GM-CSF results in recruitment of DCs, which then present antigens to T-cells invoking an anti-tumour cascade of immune responses. The whole tumour cell is used as the antigen, rather than just the PAP, as in sipuleucel-T, facilitating both humoural and cellular immune responses.…”

“…The whole tumour cell is used as the antigen, rather than just the PAP, as in sipuleucel-T, facilitating both humoural and cellular immune responses. Initial phase I/II studies confirmed safety, clinical activity, and immunogenicity; 44,45 however, two phase III studies (VITAL-1, VITAL-2) 46 were closed early due to futility analysis.…”

Allogeneic tumor cell vaccines

“…The regimen consisted of two allogeneic cell lines (PC3, LNCaP) modified to secrete GM-CSF. 73 PC3 is derived from prostate cancer bone marrow metastases and is castration resistant. 74 The LNCaP cell line derived from prostate cancer lymph node metastases is hormone sensitive, and expresses numerous prostate-associated antigens.…”

New developments in cancer vaccines

“…The third is Dendreon's Provenge Ò , which is the only therapeutic cancer vaccine approved by the USA. regulatory Agency FDA for the treatment of metastatic hormone-refractory prostate cancer [5,6]. Although this vaccine represents an important proof of concept, it is able to induce a limited improvement in overall survival, with associated elevated costs of production, which indicates that significant improvements are needed.…”