Prostate cancer (PCa) ranks as the second leading cause of cancer-related deaths among men in the United States. Prostate-specific membrane antigen (PSMA) represents a well-established biomarker of PCa, and its levels correlate positively with the disease progression, culminating at the stage of metastatic castration-resistant prostate cancer. Due to its tissue-specific expression and cell surface localization, PSMA shows superior potential for precise imaging and therapy of PCa. Antibody-based immunotherapy targeting PSMA offers the promise of selectively engaging the host immune system with minimal off-target effects. Here we report on the design, expression, purification, and characterization of a bispecific engager, termed 5D3-CP33, that efficiently recruits macrophages to the vicinity of PSMA-positive cancer cells mediating PCa death. The engager was engineered by fusing the anti-PSMA 5D3 antibody fragment to a cyclic peptide 33 (CP33), selectively binding the Fc gamma receptor I (FcγRI/CD64) on the surface of phagocytes. Functional parts of the 5D3-CP33 engager revealed a nanomolar affinity for PSMA and FcγRI/CD64 with dissociation constants of KD = 3 nM and KD = 140 nM, respectively. At a concentration as low as 0.3 nM, the engager was found to trigger the production of reactive oxygen species by U937 monocytic cells in the presence of PSMA-positive cells. Moreover, flow cytometry analysis demonstrated antibody-dependent cell-mediated phagocytosis of PSMA-positive cancer cells by U937 monocytes when exposed to 0.15 nM 5D3-CP33. Our findings illustrate that 5D3-CP33 effectively and specifically activates monocytes upon PSMA-positive target engagement, resulting in the elimination of tumor cells. The 5D3-CP33 engager can thus serve as a promising lead for developing new immunotherapy tools for the efficient treatment of PCa.

• MeSH
• antigeny povrchové * imunologie   metabolismus   MeSH
• glutamátkarboxypeptidasa II * imunologie   metabolismus   MeSH
• lidé MeSH
• monocyty * imunologie   metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádory prostaty * imunologie   patologie   metabolismus   terapie   MeSH
• protilátky bispecifické imunologie   farmakologie   MeSH
• receptory IgG metabolismus   imunologie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny povrchové * MeSH
• FOLH1 protein, human MeSH Prohlížeč
• glutamátkarboxypeptidasa II * MeSH
• protilátky bispecifické MeSH
• receptory IgG MeSH

IMPORTANCE: DCVAC/PCa is an active cellular immunotherapy designed to initiate an immune response against prostate cancer. OBJECTIVE: To evaluate the efficacy and safety of DCVAC/PCa plus chemotherapy followed by DCVAC/PCa maintenance treatment in patients with metastatic castration-resistant prostate cancer (mCRPC). DESIGN, SETTING, AND PARTICIPANTS: The VIABLE double-blind, parallel-group, placebo-controlled, phase 3 randomized clinical trial enrolled patients with mCRPC among 177 hospital clinics in the US and Europe between June 2014 and November 2017. Data analyses were performed from December 2019 to July 2020. INTERVENTIONS: Eligible patients were randomized (2:1) to receive DCVAC/PCa (add-on and maintenance) or placebo, both in combination with chemotherapy (docetaxel plus prednisone). The stratification was applied according to geographical region (US or non-US), prior therapy (abiraterone, enzalutamide, or neither), and Eastern Cooperative Oncology Group performance status (0-1 or 2). DCVAC/PCa or placebo was administered subcutaneously every 3 to 4 weeks (up to 15 doses). MAIN OUTCOMES AND MEASURES: The primary outcome was overall survival (OS), defined as the time from randomization until death due to any cause, in all randomized patients. Survival was compared using 2-sided log-rank test stratified by geographical region, prior therapy with abiraterone and/or enzalutamide, and Eastern Cooperative Oncology Group performance status. RESULTS: A total of 1182 men with mCRPC (median [range] age, 68 [46-89] years) were randomized to receive DCVAC/PCa (n = 787) or placebo (n = 395). Of these, 610 (81.8%) started DCVAC/PCa, and 376 (98.4%) started placebo. There was no difference in OS between the DCVAC/PCa and placebo groups in all randomized patients (median OS, 23.9 months [95% CI, 21.6-25.3] vs 24.3 months [95% CI, 22.6-26.0]; hazard ratio, 1.04; 95% CI, 0.90-1.21; P = .60). No differences in the secondary efficacy end points (radiological progression-free survival, time to prostate-specific antigen progression, or skeletal-related events) were observed. Treatment-emergent adverse events related to DCVAC/PCa or placebo occurred in 69 of 749 (9.2%) and 48 of 379 (12.7%) patients, respectively. The most common treatment-emergent adverse events (DCVAC/PCa [n = 749] vs placebo [n = 379]) were fatigue (271 [36.2%] vs 152 [40.1%]), alopecia (222 [29.6%] vs 130 [34.3%]), and diarrhea (206 [27.5%] vs 117 [30.9%]). CONCLUSIONS AND RELEVANCE: In this phase 3 randomized clinical trial, DCVAC/PCa combined with docetaxel plus prednisone and continued as maintenance treatment did not extend OS in patients with mCRPC and was well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02111577.

• MeSH
• dendritické buňky patologie   MeSH
• docetaxel škodlivé účinky   MeSH
• dvojitá slepá metoda MeSH
• imunoterapie škodlivé účinky   MeSH
• lidé MeSH
• nádory prostaty rezistentní na kastraci * farmakoterapie   MeSH
• prednison MeSH
• protokoly protinádorové kombinované chemoterapie škodlivé účinky   MeSH
• senioři MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• docetaxel MeSH
• prednison MeSH

One type of anticancer vaccine relies on the administration of DNA constructs encoding one or multiple tumor-associated antigens (TAAs). The ultimate objective of these preparations, which can be naked or vectored by non-pathogenic viruses, bacteria or yeast cells, is to drive the synthesis of TAAs in the context of an immunostimulatory milieu, resulting in the (re-)elicitation of a tumor-targeting immune response. In spite of encouraging preclinical results, the clinical efficacy of DNA-based vaccines employed as standalone immunotherapeutic interventions in cancer patients appears to be limited. Thus, efforts are currently being devoted to the development of combinatorial regimens that allow DNA-based anticancer vaccines to elicit clinically relevant immune responses. Here, we discuss recent advances in the preclinical and clinical development of this therapeutic paradigm.

• Klíčová slova
• AFP, α-fetoprotein, APC, antigen-presenting cell, CDR, complementarity-determining region, CEA, carcinoembryonic antigen, CIN, cervical intraepithelial neoplasia, CTLA4, cytotoxic T lymphocyte protein 4, DAMP, damage-associated molecular pattern, DC, dendritic cell, FDA, Food and Drug Administration, GM-CSF, granulocyte macrophage colony-stimulating factor, GX-188E, HCC, hepatocellular carcinoma, HNSCC, head and neck squamous cell carcinoma, HPV, human papillomavirus, IL, interleukin, OS, overall survival, OVA, ovalbumin, PAP, prostate acid phosphatase, SCGB2A2, secretoglobin, family 2A, member 2, SOX2, SRY (sex determining region Y)-box 2, T, brachyury homolog, TAA, tumor-associated antigen, TLR, Toll-like receptor, TRA, tumor rejection antigen, Treg, regulatory T cell, VGX-3100, WT1, Wilms tumor 1, adjuvants, dendritic cell, electroporation, mucosal immunity,
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH