â…  Cord Blood Megakaryocyte Progenitor Cell Injection Effectiveness â…¡ Clinical Trial Of Human Hematopoietic Function Of GATA-1 Transcription Factor

BackgroundsShortage of blood supply has been more and more severe in China. At present, theproportion of free blood dontation in clinical blood collection in China is0.84%, which ismuch lower than4.54%in high-income countries and1.01%in middle-income countries.Clinical bood demand in China is increasing at a rate of10-15%each year, while bloodcollection increases at a low rate, taking2.9%in Beijing and6.5%in Tianjing forexamples. The huge gap between blood supply and demand has forming an extremeintense situation in many cities, thus greatly impacts clinical treatment. On the other hand,blood supply plays an important role in military medicine. Modern warfare, althoughpresent in every historical period of military history, has assumed more complex forms ofhighly advanced technology which include the potential threats of nuclear weapons. Sincenuclear weapons, chemical weapons and biological weapons can cause bone marrowdamage, complicated thrombocytopenia, anaemia, and then massive destruction in the end,suitable and efficient artificial blood is in urgent demand. This type of artificial blood willnot only substitute partial clinical blood usage, but also provide technical support andblood reserve during wartime, which has great social value and stragetic significance.It is well known that hematopoietic stem cells (HSCs) have been successfully appliedinto both support and immune treatment of malignant tumors and varies hematologicdiseases, attributing to the advantage of both self-renewal and multiple lineagesdifferentiation. Previous studies in our lab have proved that plenty of hematopoieticstem/progenitor cells (HSCs/HPCs) with strong reproductive activity are present inumbilical blood. Most of these cells are in mitotic phase and can both proliferate anddifferentiate at the same time under practical culture condition and with proper culturetime. Massive produced cells include megakaryoblasts, erythroid progenitor cells,granulocytes, terminal differentiated platelets, erythrocytes, dendritic cells, NK cells, etc.Our lab has developed two types of new umbilical hematopoietic cell products, umbilicalerythroblast injection and umbilical megakayoblast injection, and both injections havebeen authorized by SFDA for clinical trials. It will be great breakthrough and milestone in transfusion and supportive hematopoiesis treatment when these cell products pass clinicaltrials by proving their security and efficiency and being gived license of clinical use.Then we use malignant tumor as clinical indications to verify the security and efficiencyof our products. A malignant tumor is not self-limited in its growth, is capable of invadinginto adjacent tissues, and may be capable of spreading to distant tissues. Malignant tumoris one of the most lethal diseases that threaten peoples’ health, and currently chemotherapyis the most common treatment. However chemotherapy can cause severe hematopoiesisdamage, leads to decrease and destruction of erythrocytes, leucocytes and platelets, whichclinical manifestation is accordingly anaemia, hemorrhage, infection and even death.Particularly, hematologic malignancies patients will suffer more hematopoiesis damagefrom not only chemotherapy but also HSCT pretreatment and GVHD. Although EPO andG-CSF/GM-CSF have been used in clinical treatment to ameliorate anaemia andgranulopenia induced by chemotherapy, there aren’t any drugs that can efficientlyameliorate hematocytopenia. Another common treatment is platelets and erythrocytestransfusion which can prevent autogenous hemorrhage, ameliorate anaemia, and supportanti-cancer drugs and chemotherapeutics being applied throughout treatment. Statisticsshows that2million units of blood are used to ameliorate hypocytomsis caused bychemotherapy each year in USA, while the number is over15million in China. However,treatments of these diseases have been great infected by blood supply shortage.Meanwhile, repeat platelets transfusion may be useless, repeat erythrocytes transfusionmay cause hemosiderosis, secondary hemochromatosis, cirrhosis, heart failure, diabetes,gonadal dysfunction and other complications. Meanwhile transfusion inevitably increasesthe probability of infection and transfusion reaction.We first characterized preparation period and preservation time of umbilical bloodderived blood cell products, then we communicated with multiple hospitals for clinicaltrial program, finally we choosed hematopoietic damage caused by chemo-radiation ofmalignant tumor especially hematologic malignancies as clinical indication to carry outclinical trials. It will be of great social value and bring tremendous economical benefit ifthe problems of the blood resource and therapeutic effects can be resolved. PURPOSESTo verify the security and efficiency of cell products and then being authorized forclinical usage by relative authorities, to provide a new source for clinical transfusion andbeing blood reserve during wartime. In this research we choosed hematopoiesis damagecaused by chemo-radiation of malignant tumor especially hematologic malignancies asclinical indication to carry out clinical trials and revised standard operation protocols ofcell product preparation and quality control according to clinical indications. Umbilicalblood derived megakayoblasts injection which has been authorized clinical trial license bySFDA was put into clinical trials at first, and transfusion time is regular or scheduledaccording to chemotherapy treatment. Meanwhile, because this cell product is a newtherapeutic stem cell product which strictly sticks to the Drug Administration Law of ThePeople’s Republic of China and relative international standards, we will strictly stick toauthorization paper, Methods clinical management of medical technology (NationalMinistry of Health), Guidelines for the Clinical Translation of Stem Cells (ISSCR) andother standards in our clinical trials.CONTENTS&METHODS：1. Based on Phase Ⅰclinical trial data of umbilical blood derived megakayoblastsinjection, we revised and optimized standard operation protocols of cell productpreparation, quality control, transportation and preservation, and clinical transfusion.2. We set up PhaseⅡ clinical trial program of umbilical blood derived megakayoblastsinjection and accordingly established standard operation protocols of serial tests.3. We collected “Clinical trial of umbilical blood derived megakayoblasts injection intreatment of thrombocytopenia caused by chemo-radiation” related materials, applied forclinical new techniques of the Ministry of health of the General Logistics Department, andcarried out clinical trials.4. We set up standard PhaseⅡ clinical trial program of umbilical blood derivedmegakayoblasts injection to make sure that collected data are standard, real, controllableand scientific.5. We produced cell products that can be used in clinical trials in GMP facility in our labwith quality control and index examinations. Then we collected, sorted and analysedPhase Ⅱ clinical trial data. RESULTS1. We collected and analyzed data of cell products preparation, quality control andPhaseⅠ clinical trials. Then we changed formats of original trial sheets and revisedstandard operation protocols of cell products preparation, quality control, transportationand preservation, and clinical transfusion.2. We collected “Clinical trial of umbilical blood derived megakayoblasts injection intreatment of thrombocytopenia caused by chemo-radiation” related materials, whichinclude cell products preparation in lab and quality control. We then applied for clinicalnew techniques of the Ministry of health of the General Logistics Department and, and gotauthorization in May2011.3. We produced45qualified umbilical blood derived megakayoblasts injections underquality control from Oct.2011to Apr.2013. Cells are in good health with5-10folds ofproliferation, survive rate over90%, and negative results for bacteria, fungi, mycoplasmaand endotoxin detection.40-60%cells are CD41+cells (cell surface marker ofmegakayoblasts).4.45injections produced above have been used in clinical transfusion. Elementaryanalysis shows that platelets inside patients can be increased by injections according tovalid cases.