Phase I/II Trial of an Allogeneic Cellular Immunotherapy in Hormone-Naïve Prostate Cancer

Abstract

Purpose: To determine the toxicity, immunologic, and clinical activity of immunotherapy with irradiated, allogeneic, prostate cancer cells expressing granulocyte macrophage colony-stimulating factor (GM-CSF) in patients with recurrent prostate cancer. Patients and Methods: A single-institution phase I/II trial was done in hormone therapy^naI« ve patients with prostate-specific antigen (PSA) relapse following radical prostatectomy and absence of radiologic metastases.Treatments were administered weekly via intradermal injections of1.2 Â 10 8 GM-CSF gene^transduced, irradiated, cancer cells (6 Â 10 7 LNCaP cells and 6 Â 10 7 PC-3 cells) for 8 weeks.Results: Twenty-one patients were enrolled and treated. Toxicities included local injection-site reactions, pruritus, and flu-like symptoms. One patient had a partial PSA response of 7-month duration. At 20 weeks post first treatment, 16 of 21 (76%) patients showed a statistically significant decrease in PSA velocity (slope) compared with prevaccination (P < 0.001). Injection site biopsies showed intradermal infiltrates consisting of CD1a + dendritic cells and CD68 + macrophages, similar to previous clinical trials using autologous GM-CSF-transduced cancer cells. Posttreatment, patients developed new oligoclonal antibodies reactive against at least five identified antigens present in LNCaP or PC-3 cells. A high-titer antibody response against a 250-kDa antigen expressed on normal prostate epithelial cells was induced in a patient with partial PSA remission; titers of this antibody decreased when treatment ended, and subsequent PSA relapse occurred. Conclusions: This non-patient-specific prostate cancer immunotherapy has a favorable safety profile and is immunologically active. Continued clinical investigation at higher doses and with longer boosting schedules is warranted.

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

“…These cell lines were modified with a human GM-CSF gene to secrete high levels of bioactive GM-CSF. An initial phase 1/2 trial in hormone-naBve patients with prostate cancer showed a favorable safety profile, statistically significant changes in the slope of prostate-specific antigen (PSA) velocity, and a PSA decline of >50% in one patient, suggesting an antitumor effect (13).An open-label, phase 1/2, multicenter trial was therefore conducted to evaluate the safety, clinical activity, and immunogenicity of the GM-CSF -secreting, allogeneic cellular immunotherapy in chemotherapy-naBve patients with metastatic HRPC. The protocol was amended to allow administration of a higher dose level after an interim analysis showed that the initial dosage tested was well tolerated.…”

Sipuleucel-T for the treatment of metastatic prostate cancer

“…In the GVAX product, further cell division is prevented through irradiation. [34][35][36][37] This whole-cell approach enables multiple tumor antigens to be targeted simultaneously and large quantities of vaccine to be manufactured.…”

Entering a New Era – Prostate Cancer Immuno-Therapy After the FDA Approval for Sipuleucel-T

“…The injection sites were found to have invasion of inflammatory cells and APCs on histopathology. At 20 weeks after the first treatment, 16 of 21 treated patients showed a statistically significant decrease in PSA velocity (slope) compared with prevaccination PSA course (Simons et al, 2006) (Urba et al, 2008). Two further uncontrolled single-arm phase II studies included asymptomatic CRPC patients with (n = 34) or without (n = 21) metastases (G9803 trial) and only men with metastases (n = 80) (G0010 trial).…”

“…sipuleucel-T) xenogeneic PAP as target (Higano et al, 2009a;Kantoff et al, 2010a) (Fong et al, 2001) 1.1.3 Allogeneic whole-tumor cells (modified ex vivo) PSMA as target (Tjoa et al, 1999;Fishman, 2009) e.g. GVAX (Simons et al, 2006;Higano et al, 2008;Higano et al, 2009b) PSA as target (Barrou et al, 2004) (Hildenbrand et al, 2007) e.g. OnyP (Michael et al, 2005) PSCA as target (Thomas-Kaskel et al, 2006) e.g.…”