Phase 1/2 dose‐escalation study of a GM‐CSF‐secreting, allogeneic, cellular immunotherapy for metastatic hormone‐refractory prostate cancer

Abstract

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.

Immunobiology and immunotherapy in genitourinary malignancies

“…In phase I/II trials, chemotherapy-naïve patients with "hormone-refractory" prostate cancer, received GVAX as a priming intradermal injection followed by boost injections every 2 weeks (five different dose levels). The results of these trials showed that GVAX was well tolerated with a safe toxicity profile, as well as effectiveness, demonstrating a median OS of 35 months in the high-dose group of patients (19). Following these results, two phase III trials were designed to evaluate GVAX in mCRPC patients.…”

Immunotherapy against cancer: A comprehensive review

“…In the other hand, the use of allogeneic tumour cell lines for the whole-tumourcell vaccination was favored because of its ability to introduce multiple antigens and therefore to stimulate a better immune response. An example to this class of cancer vaccines is called GVAX which uses Allogeneic Prostate Cancer Cell Lines VITAL-1 and VITAL-2 that are manipulated to secrete GM-CSF (Higano et al, 2008). Despite its success in phase I and II clinical trials, the application of GVAX was terminated in phase III clinical trials against prostate cancer due to the increased rate of deaths and the low chance of reaching to its end point (Drake, 2009).…”

Allogeneic tumor cell vaccines

“…The trial demonstrated that patients receiving the vaccine had a median OS of 26.2 mo, comparable to patients that receive chemotherapy. 77 Based on the findings of these small phase I/II trials, two large Phase III randomized studies (VITAL-1 and VITAL-2) were developed to test the clinical efficacy of GVAX in treating metastatic prostate cancer. 78 Production of GVAX was halted after both VITAL-1 and VITAL-2 were terminated due to the inefficacy of GVAX and excessive deaths, respectively.…”