A phase I dose escalation trial of vaccine replicon particles (VRP) expressing prostate-specific membrane antigen (PSMA) in subjects with prostate cancer

• Published in: Vaccine Vol. 31; no. 6; pp. 943 - 949
• Main Authors: Slovin, Susan F., Kehoe, Marissa, Durso, Robert, Fernandez, Celina, Olson, William, Gao, Jian P., Israel, Robert, Scher, Howard I., Morris, Stephen
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 30.01.2013; Elsevier; Elsevier Limited
• Subjects: Aged; Aged, 80 and over; Allergy and Immunology; Alphavirus; Antibodies; Antibodies, Neutralizing - blood; Antigens; Antigens, Surface - genetics; Antigens, Surface - immunology; Applied microbiology; Atoms & subatomic particles; Biological and medical sciences; Blood; Cancer therapies; Cancer vaccines; Cancer Vaccines - administration & dosage; Cancer Vaccines - adverse effects; Cancer Vaccines - genetics; Cancer Vaccines - immunology; Castration; cell-mediated immunity; Clinical trials; encephalitis; Encephalomyelitis, Venezuelan Equine - genetics; Enzyme-linked immunosorbent assay; Fundamental and applied biological sciences. Psychology; Genetic Vectors; Glutamate Carboxypeptidase II - genetics; Glutamate Carboxypeptidase II - immunology; horses; Humans; Immune response; Immunotherapy; Influenza; Leukocytes, Mononuclear - immunology; Male; Medical prognosis; Medical sciences; Metastases; Metastasis; Microbiology; Middle Aged; neutralization; neutralizing antibodies; patients; Prostate cancer; prostatic neoplasms; Prostatic Neoplasms - therapy; Proteins; PSMA; Replicon; Skin cancer; Toxicity; Treatment Outcome; Tumors; Vaccine; Vaccines; Vaccines, antisera, therapeutical immunoglobulins and monoclonal antibodies (general aspects); Vaccines, Synthetic - administration & dosage; Vaccines, Synthetic - adverse effects; Vaccines, Synthetic - genetics; Vaccines, Synthetic - immunology; VEE; Venezuelan equine encephalitis; viruses; VRP; PSMA; Vaccine; VRP; Prostate cancer; Immunotherapy; VEE; Urinary system disease; Prostate disease; Malignant tumor; Antigen; Phase I trial; Urogenital system; Male genital diseases; Prostate; Cancer
• ISSN: 0264-410X; 1873-2518; 1873-2518
• DOI: 10.1016/j.vaccine.2012.11.096

► The alphavirus-based replicon vaccine strategy has advantages over other vaccines. ► PSMA-VRP is a propagation defective, viral replicon vector system encoding PSMA. ► A phase I first in human study of PSMA VRP in prostate cancer was safe. ► All subjects had immunologic competence noted by responses to standard mitogens. ► No cellular responses to PSMA was seen; few patients had a humoral response to PSMA. PSMA-VRP is a propagation defective, viral replicon vector system encoding PSMA under phase I evaluation for patients with castration resistant metastatic prostate cancer (CRPC). The product is derived from an attenuated strain of the alphavirus, Venezuelan Equine Encephalitis (VEE) virus, and incorporates multiple redundant safety features. In this first in human trial, two cohorts of 3 patients with CRPC metastatic to bone were treated with up to five doses of either 0.9×107IU or 0.36×108IU of PSMA-VRP at weeks 1, 4, 7, 10 and 18, followed by an expansion cohort of 6 patients treated with 0.36×108IU of PSMA-VRP at weeks 1, 4, 7, 10 and 18. No toxicities were observed. In the first dose cohort, no PSMA specific cellular immune responses were seen but weak PSMA-specific signals were observed by ELISA. The remaining 9 patients, which included the higher cohort and the extension cohort, had no PSMA specific cellular responses. PSMA-VRP was well-tolerated at both doses. While there did not appear to be clinical benefit nor robust immune signals at the two doses studied, neutralizing antibodies were produced by both cohorts suggesting that dosing was suboptimal.