A Phase 1/2 Single-center Study Evaluating the Safety and Efficacy of TCR Reserved and Power3 (SPPL3) Gene Knock-out Allogeneic CD19-targeting CAR-T Cell (ATHENA-2) Therapy in Adults With Refractory/Relapsed B-cell Lymphoma
The safety and efficacy of the chimeric antigen receptor (CAR)-T, a CD19-targeting, TRAC and Power3 (SPPL3) double genes deleted allogeneic CAR-T cell product, are undergoing rigorous evaluation in non-Hodgkin's lymphoma (NHL) subjects from our ATHENA trial (NCT06014073). Unexpectedly, expansion of the initial residual CD3-positive CAR T from products were measured in patients' peripheral blood (PB) without exception. Accompanying with host immune reconstitution and appearance of the detectable B cells, the CD3-positive allogenic CAR T cells exhibited a compelling amplification advantage over CD3-negative CAR T cells. The amplification of CD3-positive CAR T cell population dynamically suppressed host B cell recovery, and presumably surveilled the recurrence or progression of tumors, but did not induce typical Graft-versus-host-disease (GvHD). Additionally, a series of in vitro experiments illustrated that the HLA-mismatched fratricide between host T cells and TCR-reserved Power3 (SPPL3)-deleted allogenic CAR T cells was markedly slashed, which in combination with our observed clinical safety date supported the notion that only genomic deletion of Power3 (SPPL3) gene in allo-CAR T cells is sufficient to overcome GvHD and host T cell-mediated rejection response. In the ATHENA-2 study, our design is to preserve the expression of the TCR on T cells from healthy donors while selectively disabling the Power3 (SPPL3) gene to prepare ATHENA-2 CAR T cells. This approach harnesses the tonic signaling of CAR T cells, resulting in enhanced persistence and improved response to treatment. The purpose of this study is to evaluate the safety and efficacy of ATHENA-2 in 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 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).
‣ 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 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.