Updated results on the bispecific PSMAxCD3 antibody CC-1 for treatment of prostate cancer.
Authors: Heitmann Jonas S. , Hackenbruch Christopher , Walz Juliane S. , Jung Susanne , Pflügler Martin , Schlenk Richard F. , Ochsenreither Sebastian , Hadaschik Boris A. , Darr Christopher , Jung Gundram , Salih Helmut R. 
Published: June 2024

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Background: While being efficient in hematological malignancies, bispecific antibodies (bsAbs), like CAR T cells, are not yet established in solid tumors. Moreover, all T cell-mobilizing strategies cause side effects that endanger patients and may limit applicable doses and thus efficacy. We report on the clinical development of CC-1, a PSMAxCD3 bsAb in an IgG-based format that induces fully target cell-restricted T cell activity against prostate cancer (1). Targeting PSMA, which is expressed on both the malignant cells and the neovasculature, improves accessibility of the tumor site for immune effector cells as critical prerequisite for therapeutic success in solid tumors. Methods: A FIH trial evaluating CC-1 included patients with metastatic castration resistant prostate carcinoma (mCRPC) (NCT04104607) and consisted of two parts: Dose escalation (n=10-66) using a novel intra-individual dose escalation design to rapidly reach the target dose of 826µg to determine safety, tolerability and maximum tolerated dose (MTD) (2), and Dose expansion, which exposed patients to CC-1 at MTD and explored efficacy to define RP2D (n=14). Currently, subcutaneous (SC) application as different application mode is being evaluated. Based on very favorable safety and preliminary efficacy data, another phase I trial was initiated where CC-1 is evaluated as first line treatment in patients with hormone sensitive biochemical recurrence (BCR) of PC (NCT05646550), where tumor burden is low and accordingly lower side effects and long-lasting efficacy are expected. Results: Recruitment in the FIH trial in mCRPC has been completed. 28 patients completed treatment with the most frequently observed (86%) toxicity being cytokine release syndrome (CRS, max. 2°). Other adverse events (all ≤2°) included hematologic events (93%) as well as elevated liver enzymes (61%), hypertension (18%) and xerostomia (7%). A rapid and profound decline of PSA levels with up to 62% reduction compared to baseline was documented in all but one of the heavily pretreated patients that received the target dose. Twelve patients received multiple treatment cycles. Recruitment of patients to receive SC application of CC-1 is currently ongoing. In the phase I trial in BCR of PC, the first four dose cohorts have so far been completed. CC-1 application was well tolerated in all patients. In all but one of so far treated patients, mild CRS (transiently elevated temperature) that ceased within 24h upon dosing with antipyretics was observed. No other CC-1 related toxicities were observed and recruitment is ongoing. Conclusions: CC-1 is a promising compound with a favourable toxicity profile and promising clinical activity. Details on study designs and updated data from the clinical trials will be presented at the meeting. 1. Zekri et al, EMBO Mol Med, 2020. 2. Labrenz et al, Pharm Stat, 2022. Clinical trial information: NCT04104607 .