TCR Reserved and Power3 (SPPL3) Gene Knock-out Allogeneic CD19-targeting CAR-T Cell Therapy in r/r B Cell Lymphoma

Recruiting now · Phase 1/Phase 2

Conditions studied: Non-hodgkin Lymphoma

In brief

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.

Key facts

Study ID: NCT06323525
Run by: Chinese PLA General Hospital
People needed: 30
Starts: 2024-04-17
Expected to finish: 2027-04-25
Last updated by the study team: 2025-05-25

Who can join

Age: 18 and older, up to 70. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

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.

You may not qualify if…

Expected survival time < 3 months per Principal Investigator's opinion.
History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast) or follicular lymphoma unless disease free for at least 3 years.
Autologous stem cell transplant with therapeutic intent within 3 months of planned ATHENA-2 CAR-T infusion.
History of allogeneic stem cell transplantation.
Patients who received any immunocellular therapy within 3 months before enrollment.
Patients who have used any of the following agents or treatments within a specific period of time:
1 Received any chemotherapy drugs or small molecule targeted drugs within 2 weeks prior to lymphodepletion;
2 Received any monoclonal antibodies, antibody drug conjugates (ADCs), or bispecific antibodies within 3 weeks prior to lymphodepletion;
3 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.
Subjects with detectable cerebrospinal fluid malignant cells, or brain metastases, or with a history of central nervous system (CNS) lymphoma or primary CNS lymphoma.
Presence of donor-specific anti-HLA antibodies directed against ATHENA-2 CAR-T.
History of severe, immediate hypersensitivity reaction attributed to lymphodepletion drugs or any component of ATHENA-2 CAR-T.
Presence or suspicion of fungal, bacterial, viral, or other infection that is uncontrolled or requiring intravenous (IV) antimicrobials for management.
Uncontrolled or active infectious diseases, such as human immunodeficiency virus (HIV) infection, acute or chronic active hepatitis B or C, epstein-barr virus (EBV), and cytomegalovirus (CMV) infection.
History or presence of CNS disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement.
Subjects with cardiac atrial or cardiac ventricular lymphoma involvement.
History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months of enrollment.
Expected or possible requirement for urgent therapy within 6 weeks due to ongoing or impending oncologic emergency (eg, tumor mass effect, tumor lysis syndrome).
Primary immunodeficiency.
History of autoimmune disease (e.g. Crohn's, rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years.
History of symptomatic deep vein thrombosis or pulmonary embolism requiring systemic anticoagulation within 6 months of enrollment.
Any medical condition likely to interfere with assessment of safety or efficacy of study treatment.
History of severe immediate hypersensitivity reaction to any of the agents used in this study.
Vaccine ≤ 6 weeks prior to planned start of conditioning regimen.
In the investigator's judgment, the subject is unlikely to complete all protocol-required study visits or procedures, including follow-up visits, or comply with the study requirements for participation.

Where it is running

Biotherapeutic Department of Chinese PLA General Hospital — Beijing, Beijing Municipality, China (enrolling)
Biotherapeutic Department of Chinese PLA General Hospital — Beijing, China (enrolling)
School of Life Sciences, Peking University — Beijing, China (enrolling)

Full record on ClinicalTrials.gov

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