A Phase 1/2 Single-center Study Evaluating the Safety and Efficacy of TRAC and Power3 (SPPL3) Genes Knock-out Allogeneic CD19-targeting CAR-T Cell (ATHENA) Therapy in Adults With Refractory/Relapsed B-cell Non-Hodgkin Lymphoma
ATHENA chimeric antigen receptor (CAR)-T, a CD19-directed CAR-T cell immunotherapy comprised of allogeneic T cells prepared for the treatment of relapsed or refractory (r/r) B-cell non-Hodgkin's lymphoma (NHL). The cells are from healthy adult volunteer donors that are knocked out of TRAC and Power3 (SPPL3) genes ex vivo using CRISPR-Cas9 gene editing components. In this study, a second-generation anti-CD19 CAR prototype was constructed, bearing murine FMC63 single-chain variant fragment (scFv) together with intracellular CD28 co-stimulatory and CD3ζ signaling domains linked by a CD28 sequence comprising the hinge and transmembrane domains. This is a single center, prospective, open-label, single-arm, phase 1/2 study. A total of around 30 patients with r/r B-cell NHL will be enrolled in the study and receive allogeneic CD19-CAR-T cell infusion. Phase 1 (n=6 to 18) is a dose escalation part, and phase 2 (n=10 to 12) is a expansion cohort part. The primary objective of this study was to evaluate the safety and efficacy of ATHENA CAR-T cell therapy in patients with r/r B-cell NHL.
• Age 18-70 (inclusive).
• Subjects who meet the following requirements:
‣ 1 Histologically confirmed refractory/relapsed B cell NHL, including the following types defined by WHO 2016:
⁃ Diffuse large B-cell lymphoma (DLBCL) not otherwise specified;
⁃ 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).
‣ 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 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 Lugano2014). 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.