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 × 10, 12.5 × 10 and 25 × 10 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.

Trial watch: dendritic cell vaccination for cancer immunotherapy

“…Additional TAA sources explored in recent clinical studies include (Figure 1): lysates of autologous (tumor) stem cells, lysates of allogeneic cancer cell lines, and TAA-encoding viral vectors. [353][354][355] Of note, one of these clinical studies involved DC vaccines based on personalized antigenic peptides. 335 Moreover, a Phase I clinical study investigated an acute myeloid leukemia (AML)-derived cell line as allogeneic DC vaccine (DCP-001), owing to its DC-like behavior and expression of AML-relevant antigens.…”

What’s in a Name? Drug Nomenclature and Medicinal Chemistry Trends using INN Publications

“… 67 Similar are those twin drugs intended to bind two identical target proteins (albitiazolium bromide, 68 miridesap 69 ). In this regard, it is interesting to see that the Chemically-Inducible Dimerization (CID) technology 70 has led to the development of rimiducid, 71 a tacrolimus analogue that behaves as a protein dimerizer, triggering the homodimerization of Fv-containing drug-binding domains of genetically engineered proteins such as the Caspase 9, Fas intracellular domain, and iCD40 receptor. Molecules where symmetry can be found as a means to complex metals are plerixafor 72 (zinc) and elesclomol 73 (copper).…”

Cancer immunotherapy beyond immune checkpoint inhibitors

“…BPX101 is another DC-derived vaccine which was recently evaluated in a phase I clinical trial in 18 men with progressive metastatic castrate-resistant prostate cancer [ 103 ]. Results revealed no dose-limiting toxicities, one case of CR, and two PR.…”