MHC II类接合器免疫疗法治疗急性髓系白血病

Introduction: The treatment of acute myeloid leukemia (AML) remains a challenge due to disease heterogeneity and therapeutic resistance to traditional cytotoxic drugs and immunotherapy. To address this, we developed LTI-214, a novel recombinant Major Histocompatibility Complex class II (MHCII) engager linked with AML antigen sialic acid binding Ig-like lectin 3 (CD33). MHCII is a critical player in antigen presentation, and studies have shown that MHCII function is essential for effective cancer immunotherapy. MHCII directly educates CD4+ helper T cells against specific antigens. CD4+ T cells then orchestrate a coordinated immune response by communicating cytokine signals to virtually all immune effector cells including CD8+ cytotoxic T cells, B cells, NK cells, and others. CD33 is a myeloid cell surface glycoprotein highly expressed on AML blasts. However, while ~90% of AML cases express CD33, 50% of these patients harbor a single nucleotide polymorphism (SNP) that eliminates the antibody binding epitope for existing CD33-targeted antibody therapeutics such as gemtuzumab ozogamicin (Mylotarg®). Mylotarg® induces objective responses in AML patients, but its efficacy is limited by this splice variant. Therefore, while CD33 was validated as an actionable target in AML, more effective CD33-directed therapies are needed. Methods: To demonstrate the therapeutic potential of LTI-214, we used the murine C1498 AML xenotransplant model in syngeneic and immunocompetent C57BL/6 mice. Animal survival was a primary endpoint along with pharmacodynamic markers of immune response including measurement of anti-CD33 specific IgGs and antigen-specific T cell recall. Results: We found that LTI-214 (M2T-CD33) induced a robust polyclonal anti-CD33 humoral response characterized by induction of the full immunoglobulin repertoire. LTI-214 significantly improved animal survival in a CD4+ and CD8+ T cell dependent manner. The immune response was elicited against both the full length and spliced version of CD33, unlike existing anti-CD33 MAbs (gemtuzumab and lintuzumab), which bound exclusively to the IgV domain fragment. LTI-214 showed a favorable safety profile with no evidence of cytokine release syndrome or organ toxicity, and minimal impact on normal hematopoiesis at concentrations 40-fold higher than the efficacious dose. LTI-214 was enhanced by combinations with anti-PD-1 therapy potentially due to the inducible nature of PD-L1 expression of C1498 AML cells. Conclusions: These experiments demonstrate the potential of LTI-214 in AML and emphasize the importance and targetability of MHCII in cancer immunotherapy.