Category: Formulation and Quality
Purpose: Acute myeloid leukemia (AML), which is characterized by over 20% bone marrow blasts, is associated with significant mortality and morbidity. Despite an initially high complete response rate of chemotherapy, many patients relapse and die of leukemia recurrence. Allogeneic hematopoietic stem cell (HSC) transplantation provides an alternative option for AML therapy, while infection and graft-versus-host disease impose major challenges in clinic. Recent developments in chimeric antigen receptor (CAR)-modified T cell engineering have demonstrated great potential for leukemia prevention and intervention. However, genetic engineering of T cells often involves complex and expensive ex vivo manipulation. In addition, alleviation of the side effects, such as cytokine storm and B cell aplasia, remains clinically challenging. In light of this, to fully exploit therapeutic potential by boosting patient’s own immunity, whilst avoiding severe toxicities, we have developed a HSC-platelet assembly conjugated with anti-programmed death-1 (aPD-1) antibody (designated as S-P-aPD-1) for enhanced AML immunotherapy.
Methods: The construction of HSC-platelet assembly is mediated by conjugation of platelet toward the HSC plasma membrane through a click reaction. Immune checkpoint inhibitor aPD1 is covalently decorated on the surface of platelets. Furthermore, the release of aPD1 can be promoted through the generation of platelet-derived microparticles (PMPs) after activation of platelets. To investigate the treatment efficacy of S-P-aPD1 toward AML, the C1498 cells were intravenously injected into the C57B6 mice, and then treated with three doses of saline, HSCs, platelets, free aPD1, S-aPD1, P-aPD1, S+P-aPD1 and S-P-aPD1 every other day after one week at the aPD1 dose of 0.5 mg/kg. The growth of leukemia was monitored via the bioluminescence signal of C1498 cells.
Results: By taking advantage of bone marrow homing capability of HSC, HSC-platelet could efficiently deliver aPD-1 to the bone marrow, where aPD-1 could be released after in situ activation of platelet in the leukemia microenvironment (Figure. 1). We demonstrated that the platelet could be readily decorated on the surface of HSC through a click reaction and the amount of platelets could be precisely tuned. Furthermore, after in vivo administration, S-P-aPD1 accumulated in bone marrow where residue leukemia cells locate after chemotherapy and locally and sustainedly release aPD1 to prime T cells. Utilizing mice bearing C1498 leukemia cells, we found that this HSC-platelet conjugates induced 5-fold increase in the number of active T cells with enhanced production of cytokines and chemokines when compared to saline treated group (Figure 2). Additionally, this delivery strategy remarkably increased the survival time of leukemia-bearing mice and further induced resistance to re-challenging leukemia cells (Figure 3).
Conclusion: In summary, our study presents a new “cell combination” drug delivery approach—one cell for targeting and the other for active release, to achieve effective immune responses for the complete elimination of leukemia cells. Moreover, the S-P-aPD1 delivery system could potentially minimize the immunogenicity and side effects since the constituents are derived from patients themselves.
Quanyin Hu, Wujin Sun, Jinqiang Wang, et al. "Conjugation of haematopoietic stem cells and platelets decorated with anti-PD-1 antibodies augments anti-leukaemia efficacy." Nature Biomedical Engineering, 2, 831–840, 2018.