Effect of erythrocyte-antibody conjugates on cancers resistant to checkpoint blockade immunotherapy: A phase I trial.

Abstract

2506 Background: Despite the clinical success of immune checkpoint blockade therapy, the majority of patients do not benefit due to inadequate efficacy as well as immune-related adverse toxicities. We have previously developed WTX-212, an erythrocyte-antibody conjugate that covalently links anti-PD-1 antibodies to erythrocyte membranes. Unlike conventional antibodies, WTX-212 accumulates in the spleen, where it effectively remodels splenic immune landscape by expanding effector T cells and reducing the reservoir of immunosuppressive myeloid cells. These changes further reprogram the tumor microenvironment and suppress tumor growth in syngeneic mouse models. Based on promising preclinical results, we have investigated WTX-212 in cancer patients resistant to checkpoint blockade therapy (NCT06026605). Methods: This is an investigator-initiated trial designed to assess the safety, tolerability, and preliminary efficacy of autologous WTX-212 monotherapy in patients with advanced malignancies. The primary outcome measures include safety and tolerability according to NCI-CTCAE v.5.0. Secondary outcome measures preliminary efficacy based on RECIST 1.1 criteria. As of January 15, 2025, 14 heavily treated patients with 11 types of solid tumors, who had received PD-1/PD-L1 antibody-containing regimens as their last line of treatment but developed resistance, were enrolled. These patients received WTX-212 monotherapy in two dose cohorts (2 × 10¹¹ or 3 × 10¹¹ cells, with 6-10 mg of conjugated antibody). Results: Repeated WTX-212 treatment showed no DLTs or TRAEs ≥3. No patient discontinued treatment due to AEs. WTX-212 monotherapy demonstrated promising anti-tumor activity, with a DCR of 78.6% (11/14) and an ORR of 42.9% (6/14), including 1 CR and 5 PR. In the higher-dose cohort (3 × 10¹¹ cells), DCR and ORR increased to 85.7% (6/7) and 57.1% (4/7), respectively, suggesting dose-dependent efficacy. Additionally, responders (CR+PR) exhibited higher baseline levels of circulating polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) compared to non-responders (PD+SD), indicating that patients with elevated PMN-MDSCs may benefit more from treatment. Importantly, WTX-212 treatment rapidly reduced PMN-MDSCs in the peripheral blood of responders compared with non-responders, consistent with preclinical data. These preliminary results suggest that WTX-212 is safe, well-tolerated, and effective at low doses, supporting further investigation into WTX-212 monotherapy and combination therapies. Conclusions: Our study suggests that PD-1 blockade in the spleen using erythrocyte-antibody conjugates triggers systemic anti-tumor responses while maintaining a favorable safety profile. Erythrocyte-drug conjugates represent a novel approach for targeting immune cells in the spleen, with broad implications for cancer treatment and drug development. Clinical trial information: NCT06026605 .