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652 A Novel and Successful Patient or Donor-Derived CD7-Targeted CAR T-Cell Therapy for Relapsed or Refractory T-Cell Lymphoblastic Lymphoma (R/R T-LBL)

Program: Oral and Poster Abstracts
Type: Oral
Session: 704. Cellular Immunotherapies: Allogeneic CARs and CARs for T Cell Lymphomas
Hematology Disease Topics & Pathways:
Clinical Trials, Biological, Lymphomas, Clinical Research, Chimeric Antigen Receptor (CAR)-T Cell Therapies, T Cell Lymphoma, Diseases, Therapies, Immunotherapy, Lymphoid Malignancies, Infusion
Monday, December 13, 2021: 11:15 AM

Junfang Yang1,2*, Xiao Yang1*, Ying Liu3*, Qinglong Wang3*, Hui Wang, MD1,2*, Jianqiang Li, PhD3 and Peihua Lu, MD1,2,4

1Beijing Lu Daopei Institute of Hematology, Beijing, China
2Hebei Yanda Lu Daopei Hospital, Langfang, China
3Hebei Senlang Biotechnology Co., Ltd., Shijiazhuang, China
4Department of Oncology, Capital Medical University, Beijing, China

Background

T-cell lymphoblastic lymphoma is an aggressive hematological malignancy, often presenting with bulky mediastinal masses or diffuse extramedullary disease (EMD). There is evidence that T-LBL differs in various aspects from T-cell acute lymphoblastic leukemia in addition to differences in clinical presentation of diseases. To date, there are only a few clinical case reports of CAR-T therapy for T-LBL. Here, we explored the efficacy and safety of CD7-targeted CAR-T cells (CD7CAR) for R/R T-LBL in a phase I clinical trial (NCT04916860).

Methods

Eligible R/R T-LBL patients were enrolled between November 2020 and May 2021. Peripheral blood (PB) mononuclear cells were collected from either the donor (n=1) or patients (n=7) by leukapheresis. The CD7-CAR gene was obtained by gene synthesis and then ligated into a lentiviral vector by molecular cloning. We developed second-generation CAR-T cells with an intracellular co-stimulatory domain of 4-1BB and CD3ζ targeting CD7. Intravenous fludarabine (30 mg/m2/d) and cyclophosphamide (300 mg/m2/d) were given to all patients on Day -5 to Day -3 prior to CD7CAR infusion.

Results

Patient characteristics are summarized in Table 1. Eight R/R T-LBL patients were enrolled with a median age of 37 years (14-47 years) and a median of 5 prior lines of therapies (2-10 lines). Two patients had a history of central nervous system involvement. Two patients relapsed from a previous allogenic (N=1) or autologous (N=1) hematopoietic stem cell transplantation (HSCT). Four patients expressed high-risk genotypes including TP53, EZH2 and RUNX1. At enrollment, 7 patients had EMD relapse (diffuse involvement, N=5; bulky mediastinal masses, N=2). One patient had no EMD involvement at enrollment due to a prior palliative mediastinal radiotherapy, but relapsed with bone marrow (BM) blasts up to 87.27%. A total of 5/8 patients had BM blasts at enrollment with median BM blasts of 17%.

Both patient- and donor-derived CD7CAR-T cells were successfully generated with a transfection efficiency of 86.55% (27%-98%). A single dose of CD7CAR-T cells was infused to patients at low dose (5x105 cells/kg, N=1), medium dose (1x106 cells/kg, N=6) or high dose (2x106 cells/kg, N=1). The median follow-up time was of 93 days (55-166 days) by July 18, 2021, the cutoff date.

Following CD7CAR infusion, 5/5 patients who had prior BM blasts achieved minimal residual disease negative (MRD-) complete remission with incomplete hematologic recovery (CRi) on Day 28, among whom 3 had already achieved MRD- CRi on Day 14. The 3 patients who did not have BM blasts prior to CAR-T infusion maintained zero BM blasts post infusion. Of the 7 patients who had EMD involvements, 4 achieved EMD CR on Day 28, and 1 on Day 51. Of the 2 patients who had bulky mediastinal masses (~7 or 6 cm), 1 had partial response and 1 had stable disease on Day 28, respectively. Of all patients, 6 subsequently underwent allo-HSCT following CD7CAR-T infusion with a median time of 54 days (42-56 days), without relapse or progression. One patient with an allo-HSCT prior to CD7CAR infusion died after receiving a second haploidentical allo-HSCT due to acute graft-versus-host disease. The other 2 patients who did not receive a transplant were on Day 55 and 73 post CD7CAR infusion with ongoing remission by the cutoff date. Mild cytokine release syndrome (CRS, ≤Grade 2) was observed in 7/8 patients. Only 1/8 patient had Grade 3 CRS and Grade 1 neurotoxicity. The median onset of CRS was 1 day post infusion (0-15 days) with a median duration of 16 days (5-19 days).

CD7CAR expansion in vivo occurred as early as 3.5 days (0-11 days) post infusion and reached a median peak of 2.07x105 copies/ug DNA (0.75-5.36 x105 copies/ug DNA) at a median of 19 days (13-28 days), and was still detectable up to the last follow-up, with a median duration of 50 days (26-120 days), as measured by qPCR (Figure.1).

Conclusion

Our clinical trial showed that CD7CAR-T cells derived either from the patients or the donor have a high initial efficacy and a good safety profile in R/R T-LBL patients. Initial high CR could be achieved both intramedullary and extramedullary in the majority of patients, even among those who harbored with high-risk features or had diffuse extramedullary lesions. However, patients with bulky mediastinal masses may require more than one-month time to achieve remission. Long-term observation and more patients are needed to further evaluate the safety and efficacy of CD7CAR.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH