Phase I trial of antigen-targeted autologous dendritic cell-based vaccine with in vivo activation of inducible CD40 for advanced prostate cancer

Abstract

This phase I trial reports the safety and activity of BPX101, a second-generation antigen-targeted autologous antigen presenting cell (APC) vaccine in men with metastatic castration-resistant prostate cancer (mCRPC). To manufacture BPX101, APCs collected in a single leukapheresis were transduced with adenoviral vector Ad5f35 encoding inducible human (ih)-CD40, followed by incubation with protein PA001, which contains the extracellular domain of human prostate-specific membrane antigen. The ih-CD40 represents a modified chimeric version of the dendritic cell (DC) co-stimulatory molecule, CD40, which responds to a bioinert membrane-permeable activating dimerizer drug, rimiducid (AP1903), permitting temporally controlled, lymphoid-localized, DC-specific activation. Eighteen men with progressive mCRPC following ≤1 prior chemotherapy regimen were enrolled to evaluate three doses of BPX101 (4 × 10⁶, 12.5 × 10⁶ and 25 × 10⁶ cells) administered intradermally every 2-4 weeks followed by rimiducid (0.4 mg/kg) intravenous (IV) infusion 24 h after each BPX101 dose. There were no dose-limiting toxicities. Immune upregulation as well as anti-tumor activity was observed with PSA declines, objective tumor regressions and robust efficacy of post-trial therapy. This novel antigen-targeted and in vivo activated immunotherapy platform may warrant further development as monotherapy and as a component of rational combinations.

Keywords: Castration-resistant prostate cancer; Dendritic cell vaccine; Immune response; Metastatic; PSMA; Rimiducid.

Fig. 1

Objective measurable disease responses with BPX101. a Complete regression of measurable lung metastases in one patient receiving BPX101. b Partial response of a retroperitoneal lymph node in another patient receiving BPX101 and c complete regression of bulky liver metastases with combination docetaxel-based chemotherapy following completion of BPX101 therapy

Fig. 2

Maximum PSA change within 12 weeks in evaluable patients (n = 17). Six of 17 (35.3%) evaluable patients exhibited a PSA decline of any level and one patient had a >30% decline

Fig. 3

Immune response to BPX101. The figure shows a injection site erythema and induration in a patient, b tumor immunohistochemistry showing CD4+ T cells (left extreme panel), CD8+ T cells (left-middle) and CD20+ B cell infiltration (right middle) surrounding PSMA-expressing tumor cells (right extreme) in a sample from transurethral resection of the prostate and c showing cytokine spikes in a patient in the low-dose cohort