In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. CT141-CT141
Abstract:
While highly efficient in hematological malignancies, bispecific antibodies (bsAbs), alike the closely related CAR T cells, are as of yet not successful in solid tumors. Moreover, all presently available T cell-mobilizing strategies cause substantial side effects that endanger patients and limit applicable doses and thus efficacy. Here we report on the development of CC-1, a PSMAxCD3 bsAb that is constructed in a novel IgG-based format (IgGsc) and contains a proprietary PSMA binder with extended reactivity. CC-1 displays a prolonged serum half-life, especially when compared to the BiTE bsAb format. Extensive in vitro and in vivo characterization demonstrated the potency of CC-1 to induce T cell activity in a highly target cell-restricted manner, resulting in profound antitumor activity, which among others allowed for elimination of large established tumors in humanized mice (Zekri et al, EMBO 2020). Exclusively funded by public resources, we conducted GMP production of CC-1 and in November 2019 initiated a first in human trial enrolling castration resistant prostate carcinoma patients (NCT04104607). The trial consists of two parts: a dose escalation phase with intra-individual dose escalation until the target dose of 826µg to determine overall safety, tolerability as well as the maximum tolerated dose (MTD), and a dose expansion phase, where patients are treated on the MTD level to detect possible efficacy. In August 2021, recruitment in the dose escalation phase was completed and the target dose was reached without DLT upon treatment of the 9th patient. A total of 14 patients were treated, with the most frequently observed toxicity being cytokine release syndrome (CRS) in 79% of patients. CRS did not exceed grade 2 according to the Lee et al. grading system (Lee et al., 2014) and resolved in most cases without additional application of tocilizumab. Besides hypertension (observed in 50% of patients), no further CC-1 related toxicities (i.e., Xerostomia, or anaphylactic reaction) were observed. As expected, after prophylactic tocilizumab application decreased neutrophile counts and elevated liver enzymes were observed in 86% and 43% of patients, respectively. In terms of efficacy, a rapid and profound decline of elevated PSA levels was observed in all the heavily pre-treated patients, with up to 60% reduction compared to baseline. Three patients of the dose escalation phase received multiple treatment cycles at the highest dose level, based on clinical tolerability, documented induction of potent T cell activation as well as rapid and profound decline of elevated PSA levels. Taken together, CC-1 is a promising compound with a favorable toxicity profile and promising clinical activity. Recruitment in the dose expansion phase is ongoing with the respective data to be presented at the meeting. Citation Format: Jonas S. Heitmann, Juliane S. Walz, Martin Pflügler, Maddalena Marconato, Christian M. Tegeler, Julia Reusch, Jannik Labrenz, Richard Schlenk, Gundram Jung, Helmut Salih. CC-1, a bispecific PSMAxCD3 antibody for treatment of prostate carcinoma: Results of the ongoing phase I dose escalation trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT141.
Type of Medium:
Online Resource
ISSN:
1538-7445
DOI:
10.1158/1538-7445.AM2022-CT141
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2022
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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