What is the background to the development of micrograft technology?

Traditional bone marrow transplantation (also known as clear marrow transplantation) for leukemia began in the 1950s and 1960s with “lethal” pretreatment of the patient and complete removal of lymphocytes and bone marrow cells, with the advantage of better implantation of normal donor hematopoietic stem cells and graft-versus-leukemia effect (GVL). In 1997, non-cleared marrow HSCT was introduced, in which lymphocytes are removed during pretreatment and bone marrow cells are partially removed, thus reducing pretreatment toxicity and GVHD incidence, which is considered to be “highly efficient and highly toxic”. Microtransplantation (MSTTM) can be a revolution in leukemia treatment after clear marrow transplantation and non-clear marrow transplantation. It was originally developed by Professor Ai Huisheng, Director of the Department of Hematology at the 307 Hospital of the PLA Academy of Military Medical Sciences. In a microtransplant, patients receive only chemotherapy that is highly effective in killing leukemia and tumor cells. Subsequently, the cells provided by the donor are processed in vitro and imported into the patient to activate the recipient’s immune system, which works together to fight leukemia. The treatment-related toxicity is low and the complications are few, so it can be called “highly effective and micro-toxic”. Microtransplantation research has also received funding from the National Natural Science Foundation of China, the National 12th Five-Year Plan, and the 12th Five-Year Plan of the Army. In 2011 and 2012, papers on microtransplantation for the treatment of acute myeloid leukemia in elderly and young adults were published in the top hematology journal BLOOD and the clinical oncology journal JCO, respectively, and were praised by Professor Mackinnon of the Royal Hospital in the UK and Professor Mattiuzzi of the Anderson Cancer Center in the US as “important progress in the most difficult field. The Beijing team’s research will hopefully lead to a new frontier pathway for curing leukemia”. Professor Spitzer of Harvard Medical School, USA, further described the micrograft as a new template for separating graft-versus-tumor effect (GVT) and graft-versus-host disease (GVHD). The results of the study showed that over 70 elderly patients with acute myeloid leukemia treated with microtransplantation achieved an 80% complete remission rate and an early mortality rate of only 6.7%, a significant advantage compared to conventional chemotherapy. This clinical outcome has been clinically validated in multiple centers in China, the United States, Australia and Spain. Based on the results of the previous study and to further validate the efficacy of microtransplantation and explore the related immune mechanisms internationally, the “International Open, Randomized, Controlled Clinical Study of Microtransplantation for the Treatment of Acute Myeloid Leukemia in the Elderly (IMCG-EAML2014)” was initiated by Prof. Hui-Sheng Ai in 2014, including Duke University Medical Center and three other hospitals in the United States are participating in this study. In August 2014, the Academy of Military Medical Sciences approved the establishment of the “Academy of Military Medical Sciences Microtransplantation Treatment Center” in its affiliated 307 Hospital. In November 2014, CMIK made a strategic investment in Beijing Newseal Biotechnology Co. Principle of action of microtransplantation 1. Allogeneic permutation immunotherapy GVT/RVT effect through CTL Microtransplantation is not only applied to leukemia treatment, but also to tumor treatment. Foreign cases have reported that patients with malignant tumors (such as melanoma) can obtain tumor remission after receiving hematopoietic stem cell transplantation. In patients with hematopoietic stem cell transplantation, not only the hematopoietic system is reconstructed, but also the immune system of healthy donors is transplanted, and the organism reconstructs tumor immune surveillance to exert the graft-versus-tumor (GVT) effect to achieve containment of the original tumor. However, due to multiple factors such as HLA matching, treatment cost, and patient’s physical ability, very few patients with solid tumors are able to receive HSCT. Moreover, post-transplantation-related complications are an added detriment to such treatment. Our experience with microtransplantation in malignant hematologic diseases suggests that intermittent multiple HSC transfusions in conjunction with strong chemotherapy can assist in counteracting the myelosuppression of chemotherapy, obtaining microchimeric implantation, generating CTL and other immune responses against cancer cells, and exerting a graft-versus-leukemia/lymphoma (GVL) effect or a recipient-versus-leukemia/lymphoma (RVL) effect. The composition of peripheral blood hematopoietic stem cell collection after donor mobilization contains immunologically active cells such as T lymphocytes, B lymphocytes, and NK cells in addition to about 1% CD34+ hematopoietic stem cells. After multi-step cellular treatment in vitro, the killing power against cancer cells is greatly enhanced and their anti-tumor potency is further strengthened, and they are used for tumor immunotherapy after return transfusion. Compared with immunotherapy with autologous cells, the allogeneic cells have stronger recognition and killing of tumor cells. 2.Designed strong chemotherapy to kill tumor cells Promote hematopoietic recovery through hematopoietic stem cells Unlike the current common clinical over-the-top immunotherapy, the transplantation procedure for malignant hematological diseases and solid tumors incorporates the concept of strong chemotherapy, and stronger chemotherapy helps to minimize tumor load and remove micro residual disease (MRD) under the guarantee that micro-implanted cells promote hematopoietic recovery. 3. intermittent microchimeric implantation to achieve a more durable immunotherapeutic effect Results have confirmed that intermittent hematopoietic stem cell infusion can obtain microchimeric implantation of donor components without taking immunosuppressive drugs to prevent GVHD. and, CTL and microchimerism were detected to play a more durable therapeutic effect compared with traditional overt immunotherapy, although microchimerism gradually disappeared with time. Clinical superiority of microtransplantation 1, good efficacy, low treatment risk In elderly AML, microtransplantation induced remission rate reaches 80%, internationally recognized elderly remission rate is less than 40%; microtransplantation 2-year disease-free survival (DFS) rate reaches 40%, internationally recognized DFS is less than 20%. In young and middle-aged, low-risk AML, the 6-year DSF of 84.4% and overall survival (OS) of 89.5% were the same as the internationally recognized allogeneic blood-related allozygous HSCT efficacy, but without the risk of GVHD and with lower treatment-related mortality. The 2-year DFS in the older age group (60-88 years) was 18.9% higher than the currently accepted efficacy. Moreover, there was rapid recovery of leukocytes and platelets 9-12 days after transplantation, and no transplantation-related complications such as GVHD were observed in all cases. 2. Easy and safe operation, fast hematopoietic recovery, low rate of serious infection. Clinicians with strong chemotherapy and internal medicine experience and ability can operate. 3. Easy to accept by patients and families No HLA mapping restrictions, wide range of donor selection. The cost of treatment is about one-third of that of conventional treatment. High quality of life for patients and short hospital stay.