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

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 5 th , 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 1 st 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 .