cd19 car-t consolidation therapy for acute lymphoblastic leukemia

Conditions: Acute Lymphoblastic Leukemia, Adult B-Cell

Summary: this is a single-arm, open-label, single-center, phase i/ii study to determine the safety and efficacy of cd19 car-t(sscart-19) combined with autologous t cells engineered to express cd19, namely cd19+ feeding t cells (ftcs), as consolidation therapy in patients diagnosed with de novo philadelphia chromosome-positive cd19+ b-all. the study will contain the following sequential phases: screening, lymphocyte apheresis, induction, and consolidation chemotherapies combined with tyrosine kinase inhibitors. once in complete response, patients will receive two to four cycles of sscart-19s, namely one cycle of sscart-19 infusion (car-t1) followed by one to three cycles of sscart-19 and cd19+ ftc infusion (car-t2-4). the role of cd19+ ftcs is to mimic leukemia cells. therefore, they are expected to stimulate in vivo expansion and persistence of sscart-19. considering the limited number of lymphocytes obtained by a single apheresis from patients and cost-efficacy, in addition to safety, we will explore the range of biologically active doses of ftcs in a phase i study. based on preclinical data, ftcs' stimulation of sscart-19 at a ratio of 1:1 could achieve the best activation response, so a 5×10\^6/kg dosage of ftcs was set as the initial dosage in the study, and lower doses were also evaluated. in phase i, ftcs will be administered at the dose of 5×10\^6/kg, 3.25×10\^6/kg, or 2×10\^6/kg two hours after sscart-19 infusion on day 1 and once again administered at the same dose on day 8. after sscart-19 and ftcs infusion, adverse events (aes) as the primary endpoints will be recorded for 6 months; efficacy as the secondary endpoint will be assessed by detecting molecular response for 6 months, pfs, and os for 2 years. in phase ii, we will expand the study at optimal biological doses of ftcs and further evaluate the efficacy and safety of the innovative combination therapy of sscart-19 and ftcs. the primary endpoint was the complete molecular response (cmr). the secondary endpoints were rfs, os, and adverse events (aes) of the patients.


Eligibility criteria:
inclusion criteria: * 15-65 years of age at the time of signing informed consent * diagnosed as de novo philadelphia chromosome-positive cd19+ b-all * karnofsky performance status ≥ 60 or eastern cooperative oncology group (ecog) performance status ≤ 2 * unable to find a suitable donor or for other reasons to undergo allogeneic hematopoietic stem cell transplantation during the study * ability and willingness to adhere to the study visit schedule and all protocol requirements * voluntarily sign informed consent forms exclusion criteria: * unable to tolerate any kind of tkis (including the first- and second-generation tyrosine kinase inhibitors) for a long period. * subjects who have positive mutation(s) of the abl kinase domain and require the third-generation tyrosine kinase inhibitors for long-term therapies. * inadequate hepatic function defined by aspartate aminotransferase (ast) and/or alanine aminotransferase (alt) \> 3 × upper limit of normal (uln) and direct bilirubin \> 1.5 × uln * inadequate renal function defined by serum creatinine \> 1.6 mg/dl * international ratio (inr) or partial thromboplastin time (ptt) \> 1.5 x uln * left ventricular ejection fraction \< 50% * ongoing treatment with chronic immunosuppressants * significant comorbid conditions or diseases which, in the judgment of the investigator, would place the subject at undue risk or interfere with the study; examples include, but are not limited to, cirrhotic liver disease, sepsis, recent significant traumatic injury, and other conditions * known human immunodeficiency virus (hiv) positivity * subjects with a history of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or mechanical control * subjects with second malignancies in addition to all * pregnant or lactating women, or subjects refusing to take effective contraception measures * other contraindications that are considered inappropriate to participate in this trial

Keywords: feeding t cell cd19 car-t therapy