Vaccination of advanced prostate cancer patients with PSCA and PSA peptide‐loaded dendritic cells induces DTH responses that correlate with superior overall survival

Abstract

Prostate stem cell antigen (PSCA) and prostate‐specific antigen (PSA) are overexpressed in most prostate cancers. PSCA‐ and PSA‐derived, HLA‐A2 binding peptides are specific targets for T‐cell responses in vitro. A phase I/II trial was performed to demonstrate feasibility, safety and induction of antigen‐specific immunity by vaccination with dendritic cells (DC) presenting PSCA and PSA peptides in patients with hormone‐ and chemotherapy‐refractory prostate cancer. Patients received 4 vaccinations with a median of 2.7 × 107 peptide‐loaded mature DC s.c. in biweekly intervals. Clinical responses were assessed 2 weeks after the 4th vaccination. Immune monitoring was performed by DTH and HLA multimer analysis. Twelve patients completed vaccination without relevant toxicities. Six patients had stable disease after 4 vaccinations. One patient had a complete disappearance of lymphadenopathy despite rising PSA. Four patients with SD and 1 progressor developed a positive DTH after the 4th vaccination. With a median survival of all patients of 13.4 months, DTH‐positivity was associated with significantly superior survival (p = 0.003). HLA tetramer analysis detected high frequencies of peptide‐specific T cells after 2 vaccinations in 1 patient who was also the sole responder to concomitant hepatitis B vaccination as an indicator of immune competence and survived 27 months after start of vaccination. Vaccination with PSA/PSCA peptide‐loaded, autologous DCs may induce cellular responses primarily in immunocompetent patients, which appear to be associated with clinical benefit. Testing of DC‐based vaccination is warranted for patients at earlier stages of prostate cancer. © 2006 Wiley‐Liss, Inc.

DAP12-Based Activating Chimeric Antigen Receptor for NK Cell Tumor Immunotherapy

“…Recently, PSCA was also found to be expressed in prostate cancer metastases (40) and prostate-unrelated carcinomas such as renal clear cell carcinoma (41), pancreatic adenocarcinoma (42), and glioblastoma (43). PSCA has been successfully used as target molecule for various immunotherapeutic approaches (37,38,(44)(45)(46). In this article we show that the DAP12-based CAR led to ZAP-70 phosphorylation upon cross-linking with its Ag and therefore efficiently reprogrammed the cytotoxicity of YTS-NK cells toward otherwise resistant PSCA-positive tumor cells in vitro and in vivo.…”

Skin reactions to human papillomavirus (HPV) 16 specific antigens intradermally injected in healthy subjects and patients with cervical neoplasia

“…[14][15][16] Delayed-type hypersensitivity reactions have been used to demonstrate an encounter with pathogens (e.g., Mantoux Test), vaccineinduced immune responses, [17][18][19][20] and in particular to show HPVspecific immune responses in various animal models.…”

Immunology and immunotherapy approaches for prostate cancer

“…169 In a phase I/II clinical trial, 12 patients with advanced PC were treated with four vaccinations of DC pulsed with PSA-and PSCAderived peptides. 170 This vaccination approach induced DHT responses that was correlated with superior overall survival, and six patients had a stable disease and one patient showed a complete disappearance of lymphadenopathy. Multi-epitope immunotherapy strategy using DC loaded with antigenic peptides derived from PSCA, PAP, PSMA and PSA was used for treating six HLA-A2 þ patients with hormone-refractory PC.…”