Acute myeloid leukaemia (AML), which is characterized by over 20% bone marrow blasts, is associated with significant mortality and morbidity. Despite a high initial complete response rate of chemotherapy, many patients relapse and die of leukaemia recurrence1. Allogeneic hematopoietic stem cell (HSC) transplantation provides an alternative option for AML therapy, while infection and graft-versus-host disease impose major challenges in clinic2. Recent developments in chimeric antigen receptor (CAR)-modified T cell engineering have demonstrated great potential for leukaemia prevention and intervention. However, alleviation of the side effects, such as cytokine storm and B cell aplasia, remains clinically challenging 3. Thus, we proposed to find a strategy to inhibit leukaemia development and prevent recurrence effectively after treatment.
Our research group is interested in engineering bioinspired and biomimetic drug delivery systems, which are inspired by effective approaches found in natural particulates. Recently, we are focusing on engineering platelets as drug delivery carriers to transport therapeutics. Previously, we have engineered platelet membrane-coated nanoparticles to treat primary tumours and eliminate circulating tumour cells via merits of specific interactions between platelet and tumour cells mediated by P-selectin and CD44 receptor4. Furthermore, by taking advantage of the intrinsic properties of platelet that migrate to surgical wound, we applied the whole platelet as the delivery vehicle to deliver immune checkpoint inhibitor to treat the tumour recurrence after surgery5. We also genetically engineered platelets expressing PD1 receptor for targeting tumour site as well as delivering therapeutics6. Continuously attracted by the unique physiological properties of platelets, in this work, we first engineered the platelets with conjugation of immune checkpoint blockade therapeutics—anti-programmed death-1 (aPD-1) antibody to treat AML, aiming at exploiting therapeutic potential by boosting patient’s own immunity, whilst avoiding severe toxicities. However, we found that the platelet-aPD-1 showed insignificant accumulation in the bone marrow where the residual leukaemia cells reside after treatment. To address this, we tried various targeted delivery strategies, among which one specific type of cells—haematopoietic stem cell (HSC) drew our attention. HSCs that give rise to majority of blood cells could home to bone marrow. During clinical bone marrow transplant, HSCs can travel to the bone marrow after intravenous injection and generate new blood composition7. Thus, we decided to exploit a cell combination-mediated drug delivery approach for bone marrow targeted drug delivery based on the inherent properties of both HSC and platelet. We simply assembled HSC and platelet (decorated with aPD-1 antibody) together via a click reaction (Figure 1). By taking advantage of bone marrow homing capability of HSC, HSC-platelet could deliver aPD-1 to the bone marrow, where aPD-1 could be released through in situ activation of platelet in the leukaemia microenvironment. We demonstrated that the platelet could be readily anchored on the surface of HSC through a click reaction and the amount of platelets could be well tuned. After in vivo administration, the cellular conjugates could accumulate in the bone marrow and release aPD-1 to prime T cells. After treated with this method, the leukaemia-bearing mice achieved enhanced immune response and survival rates with inhibition of leukaemia development.
Figure 1. False colour scanning electron microscope (SEM) imaging of HSC-platelet conjugates. Purple: HSCs; green: platelets.
In summary, our study demonstrated an HSC-platelet cell combination strategy for targeted delivery and in situ release of immune checkpoint inhibitors, which could produce long-lasting immunity for both established and re-challenged leukaemia. This cellular combination method could be further extended for different biomedical applications upon varying cell types and assembling approaches.
Our paper: Hu, Q. et al. Conjugation of haematopoietic stem cells and platelets decorated with anti-PD-1 antibodies augments anti-leukaemia efficacy. Nature Biomedical Engineering (2018).
1 Advani, R. et al. Treatment of refractory and relapsed acute myelogenous leukemia with combination chemotherapy plus the multidrug resistance modulator PSC 833 (Valspodar). Blood 93, 787-795 (1999).
2 Blazar, B. R., Murphy, W. J. & Abedi, M. Advances in graft-versus-host disease biology and therapy. Nat. Rev. Immunol. 12, 443 (2012).
3 Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507-1517 (2014).
4 Hu, Q. et al. Anticancer Platelet-Mimicking Nanovehicles. Adv. Mater. 27, 7043-7050, doi:10.1002/adma.201503323 (2015).
5 Wang, C. et al. In situ activation of platelets with checkpoint inhibitors for post-surgical cancer immunotherapy. Nature Biomedical Engineering 1, 0011 (2017).
6 Zhang, X. et al. Engineering PD-1-Presenting Platelets for Cancer Immunotherapy. Nano Lett. 18, 5716-5725 (2018). 7 Laughlin, M. J. et al. Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia. N. Engl. J. Med. 351, 2265-2275 (2004).