Senl_1904A and Senl_1904B Chimeric Antigen Receptor （CAR） T-Cell in the Treatment of r/ r Acute B Lymphocytic Leukemia
Senl_1904A and Senl_1904B Chimeric Antigen Receptor （CAR） T-Cell in the Treatment of r/ r Acute B Lymphocytic Leukemia
This is an open, two arms, mask phase I clinical study to evaluate efficacy and safety of two
 different chimeric antigen receptor T cell immunotherapies (Senl_1904A and Senl_1904B)
 targeting cluster of differentiation antigen 19 （CD19） in the treatment of Acute lymphocytic
 Leukemia. A total of 20 patients are planned to be enrolled following up half a year.
The CARs consist of an anti-CD19 single-chain variable fragment（scFv） that was derived from
 the FMC63 mouse hybridoma, a portion of the human CD137（4-1BB） molecule, and the
 intracellular component of the human CD3ζ molecule. Autologous T cells will be gene
 engineered with the CAR gene using a lentivirus vector. Compared to Senl_1904A, Senl_1904B
 has a higher and more stable transfection efficiency and secretes lower levels of cytokines
 in functional assays, thus having the potential to significantly reduce the incidence of
 serious adverse events while ensuring the same complete response rate. Prior to T cell
 infusion, the patients will be subjected to preconditioning treatment. After T cell infusion,
 the patients will be evaluated for one month after infusion for adverse reactions and
 efficacy.
Inclusion Criteria:

 -  Subjects with acute lymphocytic leukemia who voluntarily signed informed consent and
 met the following criteria:

 1. Patients with relapsed and refractory acute B lymphocytic leukemia with any of
 the following:

 1. Recurrence after remission by chemotherapy or autologous stem cell
 transplantation (including B-ALL patients with bone marrow recurrence of
 morphology and recurrence of micro-residual );

 2. Primary B-ALL patients who cannot be completely relieved by repeated
 chemotherapy twice or more;

 3. High-risk initial onset B-ALL patients not completely relieved after 1 or 2
 times of chemotherapy but not suitable for re-chemotherapy ;

 2. Tumor cells confirmed CD19 positive by Flow cytometry (FCM)

 3. For B-ALL patients with simple extramedullary recurrence , there must be at least
 one evaluable lesion;

 4. Eastern Cooperative Oncology Group (ECOG) ≤ 2 points;

 5. Age 3 - 65 years old;

 6. The bone marrow tumor load value (morphology) > 5% at the time of enrollment;

 7. The main organ function needs to meet the above conditions: cardiac ultrasound or
 multiple gated image acquisition analysis （MUGA） scan indicate the cardiac
 ejection fraction is ≥50% , and there is no obvious abnormality in the
 electrocardiogram; blood oxygen saturation≥90%; creatinine ≤1.6mg/dl; alanine
 amino transferase (ALT) and Aspartate transaminase (AST)≤3 times normal range,
 total bilirubin（TBil） ≤2.0mg/dl;

 8. The expected survival time is longer than 3 months;

 9. The pregnancy test for women of childbearing age must be negative; Subjects with
 a pregnancy plan must agree to take contraception before the enrollment study and
 after the study lasts for one year; if the subject is pregnant or suspects of
 pregnancy, the investigator should be notified immediately

 10. An informed consent form is required.

 Exclusion Criteria:

 -  1) Severe cardiac insufficiency; 2) A history of severe pulmonary dysfunction; 3)
 Combined with other malignant tumors; 4) Combined with serious infections or
 persistent infection and cannot be effectively controlled; 5) Combined with metabolic
 diseases (except DM); 6) Combined with severe autoimmune diseases or congenital immune
 defects; 7) Active hepatitis (HBV DNA or HCVRNA detection positive); 8) HIV infection
 or syphilis infection; 9) A history of severe allergies to biological products
 (including antibiotics); 10) Subjects with recurrence after allogeneic hematopoietic
 stem cell transplantation 11) chronic lymphocytic leukemia（CLL） /myeloproliferative
 neoplasms with acute lymphoid transformation or CLL transform to ALL ; 12) Any drug
 that has been used against graft-versus-host disease（GVHD） for nearly 4 weeks, such as
 methotrexate or other chemotherapeutic drugs, mycophenolate mofetil, immunosuppressive
 antibodies, etc.; 13) Subjects who have received any anti-CD19 medication; 14)
 Subjects who have used anti-cluster of differentiation antigen 20（CD20） drugs (such as
 rituximab) for nearly 4 weeks; 15) Subjects who have participated in any other
 clinical drug trials in the past six months; 16) Female patients who are pregnant and
 lactating, or have a pregnancy plan within 12 months; 17) The investigator believes
 that it may increase the risk of the subject or interfere with the outcome of the test
 (with a history of severe mental illness, drug abuse and history of addiction).

 Exit criteria：

 1. The subjects request to withdraw from the study before CAR-T infusion

 2. The subjects seriously violate the protocol

 3. Before CAR-T infusion, the following indicators are still abnormal after treatment:

 Platelets <20x10^9/L, hemoglobin ≤80g/L, peripheral finger oxygen <90%, AST / ALT /
 alkaline phosphatase（ALP） ≥ 2.5 upper limits of normal（ULN）, total bilirubin ≥ 1.5ULN
 , creatinine clearance rate <70ml / min, left ventricular ejection fraction <50%, the
 researcher judged that the test needs to be terminated early;

 4. The therapeutic dose of steroids was not stopped within 72 hours prior to CAR-T
 infusion and the investigator determined that the trial needs to be terminated .
 However, the following physiologically acceptable doses of steroids are permissible:
 hydrocortisone or equivalent <6-12 mg/m2/day ;

 5. Not enough T cells for manufacture standard CAR-T cells

 6. Other serious adverse events occurred

 7. MRD become negative after preconditioning regiment