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...

BACKGROUNDThis open‐label, multicenter, dose‐escalation study evaluated multiple dose levels of immunotherapy in patients with metastatic hormone‐refractory prostate cancer (HRPC). The immunotherapy, based on the GVAX platform, consisted of 2 allogeneic prostate‐carcinoma cell lines modified to secrete granulocyte‐macrophage‐colony‐stimulating factor (GM‐CSF).METHODSDose levels ranged from 100 × 106 cells q28d × 6 to 500 × 106 cells prime/300 × 106 cells boost q14d × 11. Endpoints included safety, immunogenicity, overall survival, radiologic response, prostate‐specific antigen (PSA) kinetics, and serum GM‐CSF pharmacokinetics.RESULTSEighty men, median age 69 years (range, 49‐90 years), were treated. The most common adverse effect was injection‐site erythema. Overall, the immunotherapy was well tolerated. A maximal tolerated dose was not established. The median survival time was 35.0 months in the high‐dose group, 20.0 months in the mid‐dose, group, and 23.1 months in the low‐dose group. PSA stabilization occurred in 15 (19%) patients, and a >50% decline in PSA was seen in 1 patient. The proportion of patients who generated an antibody response to 1 or both cell lines increased with dose and included 10 of 23 (43%) in the low‐dose group, 13 of 18 (72%) in the mid‐dose group, and 16 of 18 (89%) in the high‐dose group (P = .002; Cochran‐Armitage trend test).CONCLUSIONSThis immunotherapy was well tolerated. Immunogenicity and overall survival varied by dose. Two phase 3 trials in patients with metastatic HRPC are underway. Cancer 2008. © 2008 American Cancer Society.

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