A Phase I/II Single-center Study Evaluating the Safety and Efficacy of BCOR and ZC3H12 Genes Knock-out CD19-targeting CAR-T Cell Therapy in Adults With Refractory/Relapsed Refractory/Relapsed B-cell Lymphoma
In this single-center, single-arm, prospective, Phase 1/2 study, the safety and efficacy of autologous BCOR and ZC3H12 genes knock-out CD19-targeting chimeric antigen receptor (CAR) T-cell therapy will be evaluated in patients with refractory/relapsed (r/r) B-cell Lymphoma. For simplicity, we have termed these CD19 CAR T cells lacking ZC3H12A and BCOR as CAR19TIF( immortal-like and functional CD19 CAR T ) cells, reflecting their immortal-like and functional characteristics. In phase 1, 3 eligible patients will be enrolled and receive CAR19TIF cells at a initial dose of 5×10\^5 cells/kg. Based on the results, subsequently an additional 3-15 patients will be enrolled in a 3+3 dose-escalation/decline design to adjust the dose of CAR19TIF cells to achieve optimal safety and efficacy. The recommended Phase 2 dose (RP2D) will then be established. 10 to 12 subjects will be enrolled and receive CAR19TIF cells infusion at dose of RP2D.
• Age 18-70 (inclusive).
• Subjects who meet the following requirements:
‣ 1 Histologically confirmed refractory/relapsed B cell Non-Hodgkin's lymphomas (NHL), including the following types defined by World Health Organization (WHO) 2016:
⁃ Diffuse large B-cell lymphoma not otherwise specified (DLBCL NOS);
⁃ Primary mediastinal (thymic) large B-cell lymphoma (PMBCL);
⁃ Transformed follicular lymphoma (TFL);
⁃ High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBCL);
⁃ Follicular lymphoma (FL);
⁃ Mantle cell lymphoma (MCL) (pathologically confirmed, with documentation of monoclonal B cells that have a chromosome translocation t(11;14)(q13;q32) and/or overexpress cyclin D1);
⁃ Marginal zone lymphoma (MZL), including nodal or splenic marginal zone B-cell lymphoma and mucosa-associated lymphoid tissue (MALT) lymphoma.
‣ 2 Relapsed disease is defined as disease progression (PD) after achieving disease remission (including CR and PR) with the latest standard regimen.
‣ 3 Refractory disease is defined as no CR to first-line therapy: Evaluation of PD (never reached response or SD) after standard first-line treatment, or
⁃ SD as best response after at least 4 cycles of first-line therapy (eg,4 cycles of R-CHOP), or
⁃ PR as best response after at least 6 cycles and biopsy-proven residual disease or disease progression ≤ 6 months of therapy, or
⁃ Refractory post-autologous stem cell transplant (ASCT): i. Disease progression or relapsed less than or equal to 12 months of ASCT (must have biopsy proven recurrence in relapsed individuals); ii. If salvage therapy is given post-ASCT, the individual must have had no response to or relapsed after the last line of therapy.
‣ 4 Individuals who are intolerant to standard treatment can also be included in the study in the investigator's judgment.
• Individuals must have received adequate prior therapy:
‣ 1 For MCL, prior therapy must have included:
⁃ Anthracycline or bendamustine-containing chemotherapy and
⁃ Anti-CD20 monoclonal antibody (unless investigator determines that tumor is CD20-negative) and
⁃ Bruton's tyrosine kinase inhibitor (BTKi). 3.2 For other types, prior therapy must have included:
⁃ Anti-CD20 monoclonal antibody (unless investigator determines that tumor is CD20-negative) and
⁃ Anthracycline containing chemotherapy regimen. 3.3 For individual with transformed FL must have relapse or refractory disease after transformation to DLBCL.
• At least 1 measurable lesion: lymph node site with a long axis \>1.5cm, extranodal site with a long axis \>1.0cm (according to the Lugano2014 criteria). Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy.
• CD19 positive (detected by immunohistochemistry \[IHC\]).
• Toxicities due to prior therapy must be stable and recovered to ≤ Grade 1 (except for hematological toxicities and clinically non-significant toxicities such as alopecia).
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
• Absolute neutrophil count (ANC) ≥ 1 x 10\^9/L, Platelet count ≥50 x 10\^9/ L, hemoglobin (Hgb) ≥ 80g/L (hemocytopenia caused by lymphoma invasion of bone marrow is not subject to conditions above).
• Adequate renal, hepatic, pulmonary and cardiac function defined as:
‣ 1 Serum creatinine≤1.5 upper limit of normal (ULN) or creatinine clearance (as estimated by Cockcroft Gault) ≥ 60 mL/min.
‣ 2 Serum alanine aminotransferase / aspartate aminotransferase (ALT/ AST) ≤ 3 upper limit of normal (ULN); Total bilirubin ≤ 1.5 ULN, except in subjects with 3) Gilbert's syndrome.
‣ 3 Cardiac ejection fraction ≥ 50%, no evidence of pericardial effusion as determined by an echocardiogram (ECHO), and no clinically significant electrocardiogram (ECG) findings.
‣ 4 Coagulation Function: International Normalized Ratio (INR) ≤ 1.5 times the upper limit of normal (ULN), and Activated Partial Thromboplastin Time (APTT) ≤ 1.5 times ULN.
‣ 5 Baseline oxygen saturation \>91% on room air.
⁃ Subjects of both genders who are willing to practice birth control from the time of consent through 6 months after the completion of conditioning chemotherapy. Females of childbearing potential must have a negative serum or urine pregnancy test (females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential).
⁃ Voluntarily participate in this clinical trial and sign an informed consent form.