Abstract 3186: An Erythrocyte-αPD-1 conjugate suppresses cancers resistant to checkpoint blockade immunotherapy: A first-in-human study

Abstract

Abstract Background: Immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment, yet resistance to this therapy can lead to immune escape and disease progression. Here, we introduce WTX-212, an erythrocyte-antibody conjugate covalently linking anti-PD-1 antibody to erythrocyte membranes. Unlike conventional antibodies, WTX-212 naturally accumulates in the spleen and remodels the splenic immune landscape in tumor-bearing mice. Pre-clinical studies have demonstrated that T cells activated by WTX-212 reduce the splenic reservoir of immunosuppressive myeloid cells, including those within tumors. This results in a systemic anti-tumor immune response and suppression of tumor growth in xenograft tumor models resistant to anti-PD-1 immunotherapies. A first-in-human (FIH) clinical trial is now investigating its potential in human cancer patients. Methods: The FIH trial (NCT05707325) is aimed to investigate the safety, pharmacokinetics, mechanisms and preliminary efficacy of WTX-212 in cancer patients with advanced malignancies. All of patients had previously received anti-PDs therapies and developed resistance to these treatments. By November 15th, 2023, 7 patients across two cohorts had received WTX-212 monotherapy (1 × 1011-2 × 1011 cells, Q3W IV). The tumor lesions were assessed using RECIST v1.1 criteria. Blood and tumor samples were collected for correlative analysis. Results: 7 patients with various solid tumors, having undergone a median of 3.1 prior lines of therapy (ranging from 1-6), received WTX-212 monotherapy. No dose-limiting toxicities or treatment-related adverse events greater than Grade 3 were reported. WTX-212 was detectable in peripheral blood at the end of cycle in a dose dependent manner. Disease control, including partial remission (PR) and stable disease (SD), was observed in 5/7 patients (DCR, 71%). One patient with esophageal cancer achieved a PR with a significant 44% reduction in target lesion size after two cycles of treatment. Two patients, one with esophageal cancer (3 lines prior therapies) and another with HPV-negative cervical cancer (4 lines prior therapies), maintained disease control for over 30 weeks after WTX-212 treatment. Consistent with preclinical findings, WTX-212 systemically induced anti-tumor responses, leading to a reduction of myeloid-derived suppressor cells (MDSCs) particularly the PMN-MDSC subset in 6/7 patients (reductions ranging from 24%-82% compared to baseline), and a median 1.5-fold increase of T cells in 7/7 patients in the peripheral blood after the 1st cycle of treatment. Conclusion: The initial promising data support further investigation and exploration of the combination therapy strategies to expand the therapeutic potential of WTX-212 in cancer patients. Erythrocyte-drug conjugation may serve as a unique strategy for targeting the peripheral immune system to treat cancers. Citation Format: Liu Yang, Xiaoqian Nie, Zheling Chen, Yuehua Liu, Jiawei Zheng, Xiaofei Gao. An Erythrocyte-αPD-1 conjugate suppresses cancers resistant to checkpoint blockade immunotherapy: A first-in-human study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3186.