The Clinical Application of Chimeric Antigen Receptor T Cells in the Treatment of CD19 Positive Recurrent Refractory B Cell-derived Hematological Malignancies
The Clinical Application of Chimeric Antigen Receptor T Cells in the Treatment of CD19 Positive Recurrent Refractory B Cell-derived Hematological Malignancies
CD19 is expressed in most B malignant tumors, especially in the former B cells ALL. This
 makes CD19 a natural target of immunotherapy. In terms of safety, the lack of B cells caused
 by CD19 targeted therapy will not cause life-threatening side effects (of course, Ig
 supplementation is necessary in the long-term B cell inhibition therapy). Moreover, the
 number of B cells can be restored after removing anti-CD19 treatment measures (such as
 anti-CD19 CART cells). In addition, CD19 has been chosen as the target of B-ALL therapy for
 the following reasons: ① as the BCR signal "amplifier", CD19 plays a role in PAX-5-mediated
 tumor formation; ② by activating MYC (as the oncogene controlled by PAX-5, C-MYC plays a key
 role in promoting the malignant proliferation of B cells), CD19 can cause B-ALL formation.
 Based on the above reasons, CD19 has become an ideal target in the treatment of B-cell
 cancer.
Inclusion Criteria:

 -  1. At the time of initial diagnosis, the age is 18-70 years old, regardless of gender
 or race

 -  2. Morphological analysis showed that the load of lymphoma was ≥ 5%

 -  3. Estimated survival time > 12 weeks

 -  4. The main investigator and the attending physician of the patient think that there
 is no other feasible and effective alternative treatment, such as hematopoietic stem
 cell transplantation

 -  5. Relapsed / refractory B-cell acute lymphocytic leukemia (all): A. objective
 remission rate (or) of grade 2 or higher bone marrow recurrence B. bone marrow relapse
 after allogeneic stem cell transplantation (SCT), SCT treatment is more than 6 months
 and in or state before cart-19 reinfusion C. refractory patients (CR status is not
 reached after 2 rounds of standard chemotherapy (CR refers to the load of myeloma
 detected by morphology < 5%)) D. Philadelphia chromosome positive (Ph +) and tyrosine
 kinase inhibitor (TKI) treatment failed twice or TKI failed to maintain or E.
 treatment with allogeneic SCT

 -  6. For patients with relapse, CD19 was detected in bone marrow or peripheral blood by
 flow cytometry within 3 months before admission

 -  7. CD19 expression on lymphoma cells: immunohistochemistry > 15% or flow cytometry >
 30%

 -  8. The main organ functions are sound, including: A. renal function: radioisotope
 glomerular filtration rate > 60 ml / min / 1.73 m2, or serum creatinine clearance rate
 in line with relevant age / gender standards B. alanine transferase (ALT) < 5 times
 the normal maximum value of the same age C. bilirubin < 2.0 mg / dl D. to achieve the
 minimum pulmonary function: ≤ grade I dyspnea and indoor blood oxygen concentration >
 91% E. echocardiography or multi gated angiography (MUGA) showed that the left
 ventricular short axis shortening rate (LVSF) was ≥ 28%, or left ventricular ejection
 fraction (LVEF) was ≥ 45%

 -  9. Karnofsky score (age ≥ 16 years old) ≥ 50 or zubrod-ecog-who score ≤ 2

 -  10. Sign written informed consent and obtain consent before any research is carried
 out

 -  11. When the above other conditions are met, the cell culture factory must receive
 fresh blood samples from patients. In the case of monocultured cells, they can only be
 accepted by the cell culture factory if the relevant tests are qualified

 Exclusion Criteria:

 -  1. Recurrence of isolated extramedullary diseases

 -  2. The patient is accompanied by the following genetic syndrome: Fanconi syndrome,
 Kostmann syndrome, Shwachman syndrome or any known myelofailure syndrome. Patients
 with Down syndrome are not included in the exclusion criteria

 -  3. Patients with Burkitt's lymphoma / leukemia (i.e. patients with mature B cell all,
 B cell surface immunoglobulin positive (SIG +) and light chain kappa or lambda type,
 morphology Fab L3 or myc ectopic expression)

 -  4. Patients with previous history of malignant tumor but cured skin or cervical
 carcinoma in situ and patients with inactive tumor are not included in the exclusion
 criteria

 -  5. Previous use of gene therapy

 -  6. Previous use of anti-CD19 / CD3 combination therapy or any other anti-CD19
 treatment

 -  7. Hepatitis B or C or HBV / HCV or other uncontrolled infection at the time of
 screening

 -  8. Screening with HIV infection

 -  9. Acute or chronic graft-versus-host reaction (GVHD) of level 2-4

 -  10. Use the following drugs: A. steroid: it is forbidden to use within 72 hours before
 cart-19 reinfusion, but physiological steroid treatment dose (< 6 - 12 mg / m2 / day)
 or equivalent hydrocortisone can be used B. allogeneic cell therapy: no donor
 lymphocyte infusion (DLI) is allowed within 6 weeks before cart-19 reinfusion C. GVHD
 treatment: any GVHD treatment (such as calmodulinase inhibitor, methotrexate,
 mycophenolate ester, steroid (see above), rapamycin, thalidomide or immunosuppressive
 antibody (such as anti-CD20 / TNF / IL6 / IL6R)) must be stopped within 4 weeks before
 cart-19 infusion D. chemotherapy: I. The following drugs should be stopped for at
 least one week before cart-19 infusion, and it is better not to accompany or follow
 the lymphocyte elimination chemotherapy plan: hydroxyurea, vincristine,
 6-mercaptopurine, 6-thioguanine, methotrexate < 25 mg / m2, cytarabine < 10 mg / m2 /
 day, asparaginase; II. The following drugs should be stopped for at least four weeks
 before cart-19 infusion: remedial chemotherapy (such as chlorine method) Lapin,
 cytarabine > 100 mg / m2, anthracycline drugs, cyclophosphamide), lymphocyte clearance
 chemotherapy drugs are not included in the exclusion criteria E. central nervous
 system (CNS) disease prevention: CNS prevention and treatment should be stopped at
 least one week before cart-19 reinfusion (such as MTX injection into spinal cord)

 -  11. For CNS infiltration of malignant tumors, refer to the guidelines of national
 comprehensive cancer network (NCCN) cns-3. Note: the patients with CNS diseases who
 have been effectively treated are not included in the exclusion criteria. The patients
 cannot participate in the drug trial within 30 days before screening

 -  12. Pregnant or lactating women: 48 hours before reinfusion, the female test
 participants must carry out serum or urine pregnancy test, and the test result is
 positive

 -  13. Women of childbearing age and all men did not take effective contraceptive methods
 within one year after cart-19 transfusion