CD19 CAR-T Consolidation Therapy for Acute Lymphoblastic Leukemia

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.

Sex

All

Minimum age

15 Years

Maximum age

65 Years

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

• DERIVEDChen LY, Gong WJ, Li MH, Zhou HX, Xu MZ, Qian CS, Kang LQ, Xu N, Yu Z, Qiao M, Zhang TT, Zhang L, Tian ZL, Sun AN, Yu L, Wu DP, Xue SL. Anti-CD19 CAR T-cell consolidation therapy combined with CD19+ feeding T cells and TKI for Ph+ acute lymphoblastic leukemia. Blood Adv. 2023 Sep 12;7(17):4913-4925. doi: 10.1182/bloodadvances.2022009072. PMID 36897251