Abstract CT141: CC-1, a bispecific PSMAxCD3 antibody for treatment of prostate carcinoma: Results of the ongoing phase I dose escalation trial

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.

Bi-specific T-cell engagers (BiTEs) in prostate cancer and strategies to enhance development: hope for a BiTE-r future

“…Severe CRS can be treated with tocilizumab, an anti-IL-6 receptor mAb, without affecting therapeutic activity ( Kauer et al, 2020 ). The occurrence of any-grade CRS in the studies on BiTE therapies in mCRPC to date ranges from 5% with JNJ-902% to 88% with CC-1, although it should be noted that there were no reports of associated mortality even with higher rates of CRS ( Calvo et al, 2022 ; Heitmann et al, 2022 ).…”

T-Cell redirecting bispecific antibodies: a review of a novel class of immuno-oncology for advanced prostate cancer

“…Three patients in the dose escalation phase received multiple treatment cycles at the highest dose level and benefited from the rapid and profound decline of elevated PSA. 75 Altogether, CC-1 has a favorable toxicity profile and promising clinical activity.…”

Tumor-associated antigen targets for novel immune-based strategies in prostate cancer

“…Prostate stem cell antigen (PSCA) is a surface glycoprotein that was first identified as a TAA overexpressed in prostate cancer. PSCA has been hypothesized to be involved in intracellular signaling; however, its true physiologic function and regulatory mechanisms remain largely unknown [95] . PSCA has been noted to have minimal expression in non-neoplastic tissue, with its highest degree of expression in prostate glandular tissue; however, it is also present with limited expression in the bladder, pancreas, stomach, kidney, skin, and esophagus [95][96][97] .…”

“…PSCA has been hypothesized to be involved in intracellular signaling; however, its true physiologic function and regulatory mechanisms remain largely unknown [95] . PSCA has been noted to have minimal expression in non-neoplastic tissue, with its highest degree of expression in prostate glandular tissue; however, it is also present with limited expression in the bladder, pancreas, stomach, kidney, skin, and esophagus [95][96][97] . PSCA is expressed in 94% of primary prostate cancers and 100% of metastatic prostate cancers with bone involvement express PSCA [98] , and increased PSCA expression correlates with increased Gleason grades and has been associated with advanced disease and poor prognosis [95][96][97][98][99][100] .…”