Erythrocyte-αPD-1 conjugates overcome resistance to checkpoint blockade immunotherapy: A first-in-human study.

Abstract

2557 Background: While the immune checkpoint blockade (ICB) therapy has revolutionized the field of tumor therapy. the resistance remains a major challenge. We have previously developed WTX-212, an erythrocyte-antibody conjugate covalently linking anti-PD-1 antibody to erythrocyte membranes. Unlike conventional antibodies, WTX-212 exhibits natural accumulation in the spleen and remodels the splenic immune landscape in tumor-bearing mice. WTX-212 treatment efficiently activates CD8+ T cells in the spleen, which subsequently infiltrate into tumors and exhibit anti-tumor cytotoxicity. Additionally, activated T cells reduce the splenic reservoir of Myeloid-derived suppressor cells (MDSC) and those within tumors, further enhancing overall anti-tumor responses. Pre-clinical studies have demonstrated that WTX-212 can significantly suppress 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 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 Feb 5th, 2024, the tumor lesions were assessed using RECIST v1.1 criteria. Blood and tumor samples were collected for correlative analysis. Results: 7 metastasized patients with various solid tumors, having undergone a median of 3.1 prior lines of therapy (ranging from 1-6), received WTX-212 monotherapy. None of patients treated with WTX-212 experienced treatment-related adverse events greater than Grade 3, indicating a high safety profile. WTX-212 was detectable in peripheral blood at the end of cycle in a dose dependent manner. Disease control was achieved in 5/7 patients (DCR=71%). Specifically, a patient with esophageal cancer, achieved a confirmed complete remission after 6-cycle treatment. Additionally, two patients, one with esophageal cancer (3L) and another with HPV-negative cervical cancer (4L), maintained stable disease for over 40 and 30 weeks, respectively. Consistent with our pre-clinical findings, a substantial reduction in MDSCs were observed in 6/7 patients (ranging from 24%-82%). Furthermore, a median 1.5-fold increase in T cells was noted in all patients in the peripheral blood after the 1st cycle of the treatment. Conclusions: WTX-212 treatment is safe and tolerable and shows promising clinical signs in cancer patients resistant to anti-PD-1 immunotherapy, supporting further investigation and exploration of WTX-212 monotherapy and combination therapy. Clinical trial information: NCT05707325 .