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

NCT06323525 | Recruiting Phase 1

• 1 other identifier: CHN-PLAGH-BT-083
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 3

Brief Summary

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.

Conditions

Non-hodgkin Lymphoma

Outcome Measures

Primary Outcomes (7)

• Phase 1: Incidence of adverse events (AEs) defined as DLT

  DLT is defined as any AE related to the investigational drug that occurs within 28 days after administration of the ATHENA-2 CAR-T and meets any one of the criteria listed in the DLT criteria. The severity of AE will be assessed according to NCI-CTCAE v5.0. Cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome (ICANS) will be evaluated according to the standards released by ASTCT in 2019. GvHD according to criteria defined by the Mount Sinai Acute GVHD International Consortium. * Grade 3 acute GVHD (aGVHD) that is not resolved to Grade 1 or 2 within 7 days, with the exception of isolated skin involvement aGVHD; * Grade 4 CRS or grade 3 CRS that is not resolved to grade 2 or lower within 2 weeks; * Grade 3 ICANS lasting for ≥7 days or Grade 4 ICANS; * Any other Grade ≥4 and Grade 3 AEs related to the ATHENA-2 CAR-T that lasts for ≥14 days, except hematology toxicity.

  First infusion date of CAR-T cells up to 28 days

• Phase 1: Recommended phase 2 dose (RP2D)

  The RP2D will be determined based on the maximum tolerated dose, occurrence of dose-limiting toxicity, the obtained efficacy results, pharmacokinetics/pharmacodynamics and other data according to the phase 1.

  12 months

• Phase 2: 3-month objective response rate (ORR)

  ORR is defined as the proportion of patients who have achieved complete response (CR) and partial response (PR) assessed by investigators.

  3 months

• Phase 2: Complete response (CR) rate

  CR is assessed by investigators and based on the Lugano 2014 assessment criterion. CR rate is defined as the proportion of patients who have achieved CR assessed by investigators.

  24 months

• Phase 2: Duration of Response (DOR)

  DOR is defined as the date of their first CR or PR (which is subsequently confirmed) to PD assessed by investigators, or death regardless of cause.

  24 months

• Phase 2: Overall Survival (OS)

  OS is defined as the time from CAR-T cells infusion to the date of death. Subjects who have not died by the analysis data cutoff date will be censored at their last contact date.

  24 months

• Phase 2: Progression Free Survival (PFS)

  PFS is defined as the time from the CAR-T cells infusion date to the date of disease progression assessed by investigators, or death any cause. Participants not meeting the criteria for progression by the analysis data cutoff date were censored at their last evaluable disease assessment date.

  24 months

Secondary Outcomes (7)

• Phase 1 and phase 2: Pharmacokinetics: Level of ATHENA-2 CAR-positive T cells circulating in blood over time

  12 months

• Phase 1 and phase 2: Pharmacodynamics: Level of CD19+ cells in peripheral blood

  12 months

• Phase 1 and phase 2: Level of serum cytokines in peripheral blood

  Up to 28 days after infusion

• Phase 1: 3-month ORR

  3 months

• Phase 1: OS

  24 months

Other Outcomes (2)

• Phase 1: Level of donor-specific antibody (DSA) in blood.

  12 months

• Phase 1: Level of human anti-mouse antibodies (HAMA)

  12 months

Study Arms (1)

Patients with refractory or relapsed B-cell lymphoma

EXPERIMENTAL

A conditioning chemotherapy regimen of fludarabine and cyclophosphamide will be administered followed by investigational treatment, Power3 (SPPL3) gene knock-out allogeneic CD19-targeting CAR-T.

Biological: TCR reserved and Power3 (SPPL3) gene knock-out allogeneic CD19-targeting CAR-T cell (ATHENA-2 CAR-T); Drug: Fludarabine; Drug: Cyclophosphamide

Interventions

TCR reserved and Power3 (SPPL3) gene knock-out allogeneic CD19-targeting CAR-T cell (ATHENA-2 CAR-T) BIOLOGICAL

Phase 1 dose escalation (3+3): dose 1 (1 × 10\^6 cells/kg), dose 2 (3 × 10\^6 cells/kg), dose 3 (6 × 10\^6 cells/kg); Phase 2: dose of RP2D.

Patients with refractory or relapsed B-cell lymphoma

Fludarabine DRUG

Intravenous fludarabine 30\~50 mg/m\^2/day on days -5, -4, and -3.

Also known as: Fludarabine Phosphate for Injection

Patients with refractory or relapsed B-cell lymphoma

Cyclophosphamide DRUG

Intravenous cyclophosphamide 500\~1000 mg/m\^2/day on days -5, -4, and -3.

Also known as: Cyclophosphamide for Injection

Patients with refractory or relapsed B-cell lymphoma

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18-70 (inclusive).
• Subjects who meet the following requirements:
• 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.
• Relapsed disease is defined as disease progression (PD) after achieving disease remission (including CR and PR) with the latest standard regimen.
• 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

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:
• Received any chemotherapy drugs or small molecule targeted drugs within 2 weeks prior to lymphodepletion;
• Received any monoclonal antibodies, antibody drug conjugates (ADCs), or bispecific antibodies within 3 weeks prior to lymphodepletion;
• 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.

Sponsors & Collaborators

• Chinese PLA General Hospital: lead

Study Sites (3)

Biotherapeutic Department of Chinese PLA General Hospital

Beijing, Beijing Municipality, 100853, China

RECRUITING

Biotherapeutic Department of Chinese PLA General Hospital

Beijing, China

RECRUITING

School of Life Sciences, Peking University

Beijing, China

RECRUITING

MeSH Terms

Conditions

Lymphoma, Non-Hodgkin

Interventions

fludarabine; fludarabine phosphate; Injections; Cyclophosphamide

Condition Hierarchy (Ancestors)

Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Drug Administration Routes; Drug Therapy; Therapeutics; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Central Study Contacts

Weidong Han, Ph.D

CONTACT

+86-010-55499341; hanwdrsw@sina.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of Biotherapeutic Department

Study Record Dates

• First Submitted: March 8, 2024
• First Posted: March 21, 2024
• Study Start: April 17, 2024
• Primary Completion: April 25, 2026
• Study Completion (Estimated): April 25, 2027
• Last Updated: May 25, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

CN (3)