HB-300, a novel arenavirus-based cancer immunotherapy in patients with metastatic castration-resistant prostate cancer.
Authors: Chism David D. , Saraiya Biren , Dorff Tanya B. , Curti Brendan D. , Posadas Edwin Melencio , St. Paul Carlyle , Mukhopadhyay Subhendu , Desai Leena , Lauterbach Henning , Nassirpour Rounak , Grill Alexander , Manouchehri Ali , Katchar Kia , Hibbert Kevin , Schlienger Katia , Slovin Susan F. 
Published: June 2023

TPS5108 Background: Prostate cancer is the most frequent type of malignant neoplasia in men. Immunotherapy targeting self-antigens in prostate cancer is evolving and requires overcoming multiple mechanisms that mediate immune tolerance. Sipuleucel-T, a cell-based therapy recognizing prostatic acid phosphatase (PAP) protein, is approved for treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) and induced PAP-specific T cell responses correlating with overall survival (OS). Poxvirus vectors encoding prostate-specific antigen (PSA) increased PSA-specific T cell levels and were associated with OS benefit, although not confirmed in a Phase 3 study. Arenaviral vectors used in preclinical tumor models could overcome self-tolerance by inducing strong self-antigen specific CD8 T cell responses. In humans, arenaviral vectors encoding HPV16 E7E6 fusion protein (HB-200) induced unprecedented E6E7-specific CD8 T cell levels in patients with recurrent/metastatic HPV16+ cancers. Preliminary clinical activity and favorable safety and tolerability were observed in these heavily pre-treated, checkpoint inhibitor-resistant patients (ref: Fu et al. ASCO 2022; NCT04180215). It is therefore hypothesized that HB-300, a live-attenuated arenaviral vector therapy encoding the self-antigens PAP and PSA, will induce substantially stronger T cell responses in prostate cancer patients than previously tested active immunization approaches. Methods: This is a Phase 1/2 open-label clinical study of HB-300 in ~ 70 patients with advanced mCRPC. A 3+3 Dose Escalation will be followed by a dose-expansion to confirm the recommended Phase 2 dose (RP2D). HB-300 consists of HB-302 (Pichinde virus based) alternating with HB-301 (LCMV based) vectors, administered IV every 3 weeks (Q3W) for 5 doses then Q6W. The program’s entry into the clinic with a mini dose-escalation was supported by the submission of a data master file along with the HB-300 Investigational New Drug application, based on arenavirus vector platform data collected in the HB-200 program. Trial inclusion criteria include male participants age ≥ 18; documented mCRPC (adenocarcinoma without neuroendocrine or small cell features); receipt of at least 1 androgen deprivation therapy and no prior chemotherapy regimens (docetaxel in the castration-sensitive setting is allowed); ≥1 measurable lesion; ECOG PS 0-1. Exclusions are uncontrolled pain or symptoms; active auto-immune disease; immunosuppression; active central nervous system or liver metastasis; and active infection. Phase 1 primary objectives include safety/tolerability and determination of RP2D, secondary objectives include preliminary efficacy, and exploratory assessments include antigen-specific T cell response and circulating tumor cell analysis. Clinical trial# NCT05553639. Clinical trial information: NCT05553639 .