OncoMatch/Clinical Trials/NCT06323525
TCR Reserved and Power3 (SPPL3) Gene Knock-out Allogeneic CD19-targeting CAR-T Cell Therapy in r/r B Cell Lymphoma
Is NCT06323525 recruiting? Yes, currently enrolling (Jun 2026). This Phase 1/2 trial studies multiple treatments including TCR reserved and Power3 (SPPL3) gene knock-out allogeneic CD19-targeting CAR-T cell (ATHENA-2 CAR-T) and Fludarabine for non-hodgkin lymphoma.
Treatment: TCR reserved and Power3 (SPPL3) gene knock-out allogeneic CD19-targeting CAR-T cell (ATHENA-2 CAR-T) · Fludarabine · Cyclophosphamide — 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.
Check if I qualifyExtracted eligibility criteria
Treatments studied
Chemotherapy
Other
Cancer type
Non-Hodgkin Lymphoma
Biomarker criteria
Required: CD19 positive (detected by immunohistochemistry [IHC]) (positive)
CD19 positive (detected by immunohistochemistry [IHC])
Allowed: BCL2 rearrangement
High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBCL)
Allowed: BCL6 rearrangement
High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBCL)
Allowed: MYC rearrangement
High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBCL)
Allowed: CCND1 overexpression
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)
Allowed: IGH translocation t(11;14)(q13;q32)
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)
Performance status
ECOG 0–2(Ambulatory, capable of self-care)
Demographics
Prior therapy
Must have received: anthracycline-containing chemotherapy — MCL or other types
Anthracycline or bendamustine-containing chemotherapy (MCL); Anthracycline containing chemotherapy regimen (other types)
Must have received: anti-CD20 monoclonal antibody — MCL or other types
Anti-CD20 monoclonal antibody (unless investigator determines that tumor is CD20-negative) (MCL and other types)
Must have received: Bruton's tyrosine kinase inhibitor — MCL
Bruton's tyrosine kinase inhibitor (BTKi) (MCL)
Cannot have received: autologous stem cell transplant
Exception: within 3 months of planned ATHENA-2 CAR-T infusion
Autologous stem cell transplant with therapeutic intent within 3 months of planned ATHENA-2 CAR-T infusion
Cannot have received: allogeneic stem cell transplantation
History of allogeneic stem cell transplantation
Cannot have received: immunocellular therapy
Exception: within 3 months before enrollment
Patients who received any immunocellular therapy within 3 months before enrollment
Cannot have received: chemotherapy
Exception: within 2 weeks prior to lymphodepletion
Received any chemotherapy drugs or small molecule targeted drugs within 2 weeks prior to lymphodepletion
Cannot have received: monoclonal antibody
Exception: within 3 weeks prior to lymphodepletion
Received any monoclonal antibodies, antibody drug conjugates (ADCs), or bispecific antibodies within 3 weeks prior to lymphodepletion
Cannot have received: radiation therapy
Exception: within 6 weeks prior to lymphodepletion; exception if disease progressed at site or positive lesions detected by PET-CT at non-radiotherapy sites
Received radiotherapy within 6 weeks prior to lymphodepletion. However, if disease progressed at the site of radiotherapy, or if there are positive lesions detected by PET-CT at non-radiotherapy sites, enrollment is allowed.
Lab requirements
Blood counts
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)
Kidney function
Serum creatinine≤1.5 upper limit of normal (ULN) or creatinine clearance (as estimated by Cockcroft Gault) ≥ 60 mL/min
Liver function
Serum alanine aminotransferase / aspartate aminotransferase (ALT/AST) ≤ 3 upper limit of normal (ULN); Total bilirubin ≤ 1.5 ULN, except in subjects with Gilbert's syndrome
Cardiac function
Cardiac ejection fraction ≥ 50%, no evidence of pericardial effusion as determined by an echocardiogram (ECHO), and no clinically significant electrocardiogram (ECG) findings
Adequate renal, hepatic, pulmonary and cardiac function defined as: Serum creatinine≤1.5 upper limit of normal (ULN) or creatinine clearance (as estimated by Cockcroft Gault) ≥ 60 mL/min. Serum alanine aminotransferase / aspartate aminotransferase (ALT/AST) ≤ 3 upper limit of normal (ULN); Total bilirubin ≤ 1.5 ULN, except in subjects with Gilbert's syndrome. Cardiac ejection fraction ≥ 50%, no evidence of pericardial effusion as determined by an echocardiogram (ECHO), and no clinically significant electrocardiogram (ECG) findings. 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. Baseline oxygen saturation >91% on room air.
Structured fields extracted by AI. May contain errors — verify against the official protocol.
Frequently asked questions
Is NCT06323525 currently recruiting?
Yes, this trial is currently recruiting patients.
Are there prior therapy exclusions?
Yes. Prior autologous stem cell transplant, allogeneic stem cell transplantation, immunocellular therapy disqualifies patients from enrollment.
Does this trial require CD19?
Yes, CD19 positive (detected by immunohistochemistry [IHC]) is a required biomarker for enrollment.
Is there an age limit?
Yes. Patients must be 70 years or younger.
Could you qualify for this trial?
Enter your biomarker results to see how this trial's eligibility criteria match your specific cancer profile.
Check if I qualifyRelated pages