Low-dose CD7 chimeric antigen receptor T cells for relapsed/refractory T-cell lymphomas: single-arm, open-label, phase I study

doi:10.21203/rs.3.rs-7957221/v1

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Low-dose CD7 chimeric antigen receptor T cells for relapsed/refractory T-cell lymphomas: single-arm, open-label, phase I study

https://doi.org/10.21203/rs.3.rs-7957221/v1

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CD7-directed chimeric antigen receptor (CAR)-T cell therapy has shown early efficacy in patients with refractory or relapsed T cell acute lymphoblastic leukemia (r/r T-ALL). However, manufacturing difficulties remain key challenges. We conducted a phase I study (ChiCTR2200058969) with 3 + 3 low dose-escalation followed by cohort expansion was designed in r/r T-cell lymphoma patients. CD7 CAR-T cells were isolated from patients or from previous stem-cell transplantation donors. The phase Ia study is being conducted with the following dose levels (DL): 1×10⁴, 5×10⁴, and 1×10⁵ (± 30%) CAR-T cells/kg. Of 40 patients enrolled, 31 received the recommended phase Ib dose of 1×10⁵ (± 30%) CAR-T cells/kg.The most common treatment-related adverse event (AE) within 30 days included cytokine release syndrome (CRS) (92.5%;5% grade 3–4), neutropenia (100%; 97.5% grade 3–4), thrombocytopenia (100%; 85% grade 3–4).In the Ib phase (n = 31), the ORR was 93.5% (29/31) and the CR rate was 80.6% (25/31). For responders in phase Ib (n = 29), patients who received allo-HSCT consolidation (n = 16) had superior 2-year OS compared to patients without allo-HSCT consolidation (n = 13) [54.1% (95% CI: 26.7–75.2) vs. 23.1% (95% CI:5.6–47.5) (P = 0.038)].low-dose CD7 CAR-T cell therapy is effective against r/r T-NHL, and allo-HSCT after achieving remission with CD7 CAR-T therapy can significantly prolong survival.

Health sciences/Diseases/Haematological diseases/Haematological cancer/Lymphoma/Non-hodgkin lymphoma/T-cell lymphoma

Health sciences/Medical research/Clinical trial design/Clinical trials/Phase I trials

Refractory/relapsed T-cell lymphoma

Autologous

CD7 CAR-T cell Therapy

Low dose

CRS

Cytopenias

Patients with relapsed/refractory T cell lymphomas (r/r TCL), including T cell acute lymphoblastic leukemia/lymphoma (T-ALL), anaplastic large cell lymphoma (ALCL), peripheral T-cell lymphoma (PTCL), and various subtypes of non-Hodgkin lymphomas (NHLs), often have poor prognosis, with a 3-year event-free survival of < 30% across all subtypes despite intensive chemotherapies and targeted therapies [1, 2]. Hematopoietic stem cell transplantation (HSCT) is often only recommended for the first relapse [3]. However, current salvage regimens generally fail to induce the responses required to allow patients to undergo HSCT, and those who relapse after allogeneic HSCT (allo-HSCT) have a very poor prognosis.[1]

Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a highly personalized and promising therapeutic modality for r/r T cell lymphoma. CD7, a transmembrane protein expressed on the surface of a subset of lymphoblastic lymphoma (LBL) and peripheral lymphoma T cells [4, 5], has emerged as a viable target for CAR-T cell therapy against r/r T cell lymphomas. Nevertheless, procuring sufficient autologous (auto) functional T cells to engineer CD7-targeted CAR-T cells remains challenging [9–12]. Previous studies have documented the use of CD7 CAR-T cells on smaller T-LBL/ALL patient populations [6–8], often reporting high short-term response rates and manageable safety profiles. Furthermore, CAR-T cells generated from the T cells harvested from donors enrolled in our trial have been used to treat children and young patients with T-ALL [6, 9]. The target dose of 1×10⁶ (± 30%) CAR-T cells per kg of patient weight achieved favorable efficacy and safety findings [6, 9]. Although donor-derived CD7 CAR-T cell therapy demonstrates excellent efficacy and circumvents issues such as tumor contamination and lymphocyte dysfunction, it presents two significant challenges: severe cytopenia and delayed blood cell recovery after CAR-T cell infusion, as well as mandatory allo-HSCT for patients receiving donor-derived CAR-T cells, especially from new donors. Furthermore, autologous T cells often have quantity and quality issues such as insufficient cell yield, culture failure, or fratricide.

To address these limitations, we conducted this phase Ia/Ib study using a low-dose infusion of autologous CD7-CAR T cells, and evaluated the efficacy and safety [6]. The aim was to determine whether reduced cell doses can mitigate hematologic toxicity and accelerate recovery. Moreover, our study enrolled a more diverse patient population, including patients with T-LBL and mature TCL, thus allowing for a broader assessment of the therapeutic potential of CD7 CAR-T cells.

Patients and study design

A single-cohort, phase Ia study of CD7 CAR-T cell therapy was designed for patients with r/r T-NHL (ChiCTR2200058969). The inclusion criteria of the patients were as follows: 1) age ≥ 18 years, 2) diagnosis of CD7-positive (CD7+) r/r T-NHL, 3) Eastern Cooperative Oncology Group status 0–2, and 4) absence of uncontrollable infections, intracranial hypertension, or organ failure. The protocol was approved by the Institutional Review Board and Medical Ethics Committee of Beijing Gaobo Boren Hospital (see the Supplementary materials for further details).The study was performed in accordance with the principles of the Declaration of Helsinki. All patients provided written informed consent before screening.

Patients received one infusion of CD7 CAR-T cells after standard lymphodepletion chemotherapy (fludarabine at 30 mg/m2/d and cyclophosphamide at 300 mg/m²/d conducted on days − 5, -4, and − 3 before infusion). A dose-escalation strategy was employed to strike a balance between efficacy and safety (Fig. 1). The eligible subjects are successively divided into single-dose groups of 1×10⁴, 5×10⁴ and 1×10⁵ (± 30%) cells per kilogram body weight. The dose-escalation study followed a “3 + 3”design, whereby 3–6 subjects in each group completed a single dose (Supplementary Fig. 1). The objective was to determine the optimal biological dose for phase Ib, an extended sample study with single-dose infusion. Post-remission consolidative allo-HSCT was allowed 28 days after CD7 CAR-T cell infusion at the physician’s discretion (see the Supplementary materials for further details).

Construct design and manufacture of CD7 CAR-T cells

Peripheral blood mononuclear cells (PBMNCs) were isolated from patients without peripheral tumor cells who had not yet undergone allo-HSCT, or from previous SCT donors who had already received allo-HSCT. The CD3 + T lymphocytes were separated using antigen-coated immunomagnetic beads. To prevent tumor contamination, the cells were continuously monitored at apheresis, and on the penultimate and final day of culture. Products were free of replication-competent lentivirus. The median culture time was 7 days (range, 6–8 days) and the CAR-T cells were approved for infusion only after confirming the absence of tumor cells. All manufacturing procedures were performed according to the good manufacturing practices (GMP) laboratory. The protocol and CD7 CAR-T products has been described in the Supplementary materials and Table S2 [6, 9, 10].

Endpoints and related assessments

The primary endpoints were the incidence of dose-limiting toxicities (DLTs) in the dose-escalation phase Ia, and the incidence of adverse events (AEs) within 30 days or between day 30 and final follow-up date. DLTs were determined within 14 days and defined as (1) any CAR T-related cytokine release syndrome (CRS) ≥ grade 3 or neurotoxicity lasting more than 7 days, or (2) ≥ grade 3 organ toxicity or anaphylactic reaction associated with CAR-T infusion therapy (see Data Supplement). Patients who developed DLT were considered off-study, and given clinical interventions until the AEs subsided to grade ≤ 2, or death. CRS and neurotoxicity were graded according to the American Society of Transplantation and Cellular Therapy (ASTCT) consensus [11]. Other AEs were graded as per the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 [12]. Graft-versus-host disease (GVHD) was graded according to European Bone Marrow Transplantation consensus [13]. Any CAR T cell-related toxicities were managed according to institutional standards.

Secondary end points were objective overall response rate (ORR) after CD7 CAR-T cell infusion, duration of overall response (DOR), progression-free survival (PFS), and overall survival (OS). Objective response was defined as the achievement of complete response (CR) or partial response (PR). Treatment efficacy was evaluated on the basis of the National Comprehensive Cancer Network (NCCN) Guidelines 2021 [14]. Minimal residual disease (MRD) was assessed by flow cytometry (sensitivity of threshold was 1×10^− 4). Response of extramedullary disease (EMD) was assessed by PET-CT and/or contrast CT and MRI. The involvement of central nervous system (CNS) was assessed with lumbar puncture, and the morphological and flow cytometric analyses of the cerebrospinal fluid (CSF). Extramedullary and intramedullary disease were evaluated on day 28 after CAR-T cell infusion, and every 3 months thereafter. PFS was defined as the time from the first infusion of CD7 CAR-T cells in patients who achieved objective remission to the date of disease progression, or last follow-up, or death from any cause. In HSCT was performed after CD7 CAR-T cell infusion during remission, the date of recurrence or death after HSCT was the last timepoint in the calculation of PFS. OS was defined as the time from infusion to the date of last follow-up or death from any cause, or in case of HSCT, the date of death due to any cause after HSCT.

The proliferation and persistence of CD7 CAR-T cells in the peripheral blood were tested by qPCR and FCM at baseline, and on days 3, 7, 10, 15, 21, and 30 (± 3 days) post-infusion, and monthly thereafter or as clinically indicated. In addition, CAR transgene copies in the peripheral blood were quantified by polymerase chain reaction (PCR) at the same timepoints. The CSF was analyzed for the presence of CAR-T cells and tumor cells in patients exhibiting CNS disease burden or epileptic seizures. The variations in cytokines within 30 days in all patients, and in the non-malignant CD7 T cell subpopulations within 90 days in patients who underwent non-allo-HSCT and were in remission in phase Ib were detected by cytometric bead array (CBA)-based FCM (see the Supplementary materials for further details).

Statistical analysis

Time-to-event endpoints survival rate and curves were generated by the Kaplan-Meier method. Hazard ratio and Wald 95% confidence interval were calculated using Cox proportional-hazards model, and the Breslow approach was used to handle tied events. Competing-risk survival analysis was used to compute the non-parametric estimate of the cumulative relapse incidence function, and Gray’s (1988) test was used to calculate p value for the difference between groups. The individual and mean CAR-T load-time curves were plotted based on the results of flow cytometry (linear scale) and PCR (semi-logarithmic scale). Four parameters were summarized, including maximum observed concentration (Cmax), time of maximum observed concentration (Tmax), last observed (quantifiable) concentration (Clast) and time of last observed (quantifiable) concentration (Tlast). All statistical analyses were performed with SAS (version 9.4) and R (version 4.3.3).

For OS analysis, data of patients for whom death had not been confirmed were censored as of the last known date they were alive. Censoring for PFS was performed based on the last adequate disease status assessment or the last clinical visit.

A total of 48 patients were observed between August 2020 and April 2024, and 40 were enrolled and received CAR-T cell infusions. At data cutoff on June 1, 2025, the median follow-up duration was 30 (range, 14–58) months.

Patient characteristics

The median age of the cohort was 32 years (18–72), and 87.5% of the patients (35/40) were diagnosed with T-LBL. The remaining patients had rare TCL subtypes (Table 1 and Table S1). All patients had relapsed or were refractory to their most recent treatment before enrollment. The median number of prior therapies was 3 (2–4), and 55% of the patients (22/40) had previously undergone HSCT, including 5 who underwent autoHSCT and 17 who underwent allo-HSCT. In addition, 27.5% patients (11/40) exhibited > 25% bone marrow (BM) blasts as per morphological assessment, while 25% (10/40) showed CNS involvement. Furthermore, 10% patients (4/40) presented with mediastinal masses, 10% (4/40) had bulky disease, and 62.5% (25/40) demonstrated diffuse disease.

Safety

No DLTs were observed in the phase Ia cohort (n = 9), while 31 patients were treated in the phase Ib cohort expansion with 1×10⁵ (± 30%) CAR-T cells/kg following lymphodepletion (Fig. 1). Among the 9 patients in stage Ia, none experienced grade 3 or higher CRS reactions. In addition, no incidence of immune effector cell-associated neurotoxicity syndrome (ICANS) or GVHD was recorded. The most common adverse reaction was cytopenia, with 8 patients developing grade 4 neutropenia and 7 patients presenting grade 4 thrombocytopenia. There were no treatment-related deaths (Table 2).

CRS occurred in 92.5% of all patients (37/40), with grades 3 documented in 5.4% (2/37) of the patients. None of the patients exhibited grade 4 CRS (Table 2). The median time to onset of CRS was one day (1–7) and the median duration was seven days (5–12 days). Fever and hypoxia were common symptoms of CRS. All patients with grade 1–2 CRS received low flow oxygen and steroids, and none received tocilizumab. In the two patients with grade 3 CRS, the symptoms resolved completely within 7 and 13 days respectively. The median time to onset of CRS in these patients was 48 hours and the median duration was seven days, and the treatment consisted of antipyretics, tocilizumab and corticosteroids.

ICANS-related events were observed occurred in two patients (7.7%) – one with grade 1 and one with grade 4. The patient with a pre-infusion tumor burden of 4.32% in CSF and 65.5% in BM experienced grade 4 neurotoxicity, which manifested as seizures or cerebral edema. The time to onset of neurotoxicity was 10 days and the duration was seven days. The patient was transferred to the intensive care unit and underwent antiepileptic therapy, intracranial pressure lowering therapy and methylprednisolone pulse therapy. The patient was successfully cured.

Grade ≥ 3 cytopenias occurred in 97.5% of the patients (39/40) after infusion, although 67.5% (27/40) exhibited grade ≥ 3 cytopenia prior to the lymphodepletion chemotherapy (Supplementary table 3). Of the 39 patients with grade ≥ 3 neutropenia, 56.4% (22/39) recovered to grade 2 within 1 month, with 18.2% (4/22) recovering after infusion of CD34 + donor stem cells. 10.3% (4/39) did not recover until bridging allo-HSCT. 7.7% (3/39) had unresolved neutropenia despite receiving G-CSF and supportive care. Of the 34 patients who experienced grade ≥ 3 thrombocytopenia, 64.7% (13/34) recovered to grade 2 within 1 month, with 15.4% (2/13) receiving CD34 + donor stem cell infusion.11.8% (4/34) did not recover to grade 2 until bridging allo-HSCT. However, 20.6% (7/34) did not recover from thrombocytopenia despite receiving TPO (7/7) or purified stem cells without preconditioning (2/7) (Table S3).

Infections occurred in 30% (12/40) of the patients within 1 month, of whom 58.3% (7/12) had grade 3 infections. All were effectively treated with antimicrobial therapy. Grade 3 bacterial and viral infections were detected in 57.1% (4/7) and 42.9% (3/7) of these patients respectively. Grade 3 viral activation included one case of Epstein-Barr virus (EBV) activation and two of CMV reactivations. Grade 3 CMV reactivation was treated with ganciclovir and CMV-specific immunoglobulin. One patient developed EBV-associated lymphoproliferative disease after B-cell transplantation and was treated with ganciclovir, rituximab, and immunoglobulin, and recovered (Table 2).

Acute GvHD grade 1 occurred in 23.5% (4/17) of the patients who had received prior HSCT, and all were in Ib phase. The symptoms occurred after a median duration of 12 days (range 10–21) and lasted for a median of seven days (range 4–16), and were manageable with steroids until complete resolution. Immune effector cell-associated hemophagocytic lymphohistiocytosis (HLH)-like syndrome (IEC-HS) occurred in 5% of the patients (2/40), and were of grade 2 severity and resolved with ruxolitinib and steroids. In addition, one patient developed grade 2 capillary leak syndrome that was resolved with steroids (Table 2).

Long-term (> 30 days post-infusion) safety was evaluated for 37 responding patients (Table 2). Monitoring was discontinued for 19 patients after bridging allo-HSCT. Chronic GVHD (cGVHD) was observed only in the 13 patients who received prior SCT and non-bridging second allo-HSCT. Infections and cGVHD were the major long-term adverse events. In addition, 38.9% (7/18) of the deaths were attributed to infections, including two cases of COVID-19 pneumonia, four of bacterial infection, and one of fungal infection. Chronic GVHD occurred in 30.8% (4/13) of the patients, with one case being of grade 3 (extensive type involving the skin and liver), which improved after corticosteroid and supportive therapy (Table 2).

Efficacy

Disease response

CD7 CAR-T cells showed increased anti-tumor activity at each dose level (Fig. 2). Across all dose levels with 40 response-evaluable patients, the ORR at 30-day post-infusion was 92.5% (37/40), with a CR rate (MRD-) of 77.5% (31/40). In the Ib phase (n = 31), the ORR was 93.5% (29/31), and the CR rate was 80.6% (25/31) (Fig. 3). Fig. S2A and S2B demonstrate a representative patient who was treated at the recommended phase 2 dose (RP2D) and achieved CR.

All five patients with mature TCL achieved an ORR (two with PR and three with CR) at one month post-infusion. Seventeen patients who received donor-derived CD7 CAR-T cells during post-HSCT relapse showed 100% ORR (14 with CR and three with PR).The remission rates for extranodal lesions and CNS involvement were 90.6% (29/32) (CR: 23, PR: 6) and 90%(9/10) (CR: 9) respectively. All four patients with bulky disease achieved remission (two cases of CR and two cases of PR).

PFS and OS

Of the 37 patients who achieved an ORR, 51.4% (19/37) underwent bridging allo-HSCT, including 16 who progressed to the phase Ib trial. Allo-HSCT was performed two months (median, 1–8 months) after infusion; 78.9% patients (15/19) received cells from haploidentical donors and 21.1% (4/19) from matched unrelated donors.

At the time of this analysis (June 1, 2025), the median follow-up duration was 30 months (14–58 months) after CAR-T cell infusion. Among the responders, 35.1% (13/37) had durable CR, including 52.6% (10/19) who underwent bridging HSCT (one case in stage Ia and nine cases in stage Ib) and 16.7% (3/18) who did not undergo bridging HSCT (two case in stage Ia and one in stage Ib). One patient discontinued follow-up at 17.9 months post-infusion. The swimmer plot of duration of response (DOR) is shown in Fig. 4 (also see Table S4). In phase Ib (n = 31), the median DOR in the 29 responders was 6 months (0.5–43 months).The median PFS (mPFS) duration of responders was 7.05 months (95% CI: 3.42-NE), and the median OS (mOS) duration in 31 patients was 16.34 months (95% CI: 4.47-NE). The 2-year PFS rate of the responders and OS rate of 31 patients were 40.1% (95% CI, 22.2–57.5%) and 36.9% (95% CI, 20.0-53.9%) respectively (Fig. 5A, B). For responders in phase Ib (n = 29), patients who received allo-HSCT consolidation after CAR-T cell therapy (n = 16) had superior OS compared to those who did not undergo allo-HSCT (n = 13) [mOS NR (95% CI:8.05-NE) vs. 4.47 months (95% CI:3.09–17.72); 2-year OS 54.1% (95% CI: 26.7–75.2) vs. 23.1% (95% CI:5.6–47.5) (P = 0.038)]. Likewise, the mPFS duration in the allo-HSCT group was 34.68 m (95% CI: 3.42-NE) compared to only 3.98 months (95% CI: 2.43–5.88) in the non-allo-HSCT group, and the respective 2-year PFS rates were 54.1% (95% CI: 26.7–75.2) and 23.1% (95% CI: 5.6–47.5) (P = 0.063; Fig. 5C, D).

All three refractory patients (NO.003, 011, 025) experienced early mortality. Furthermore, 29.7% of the responders (11/37) relapsed (31% [9/29] in the Ib phase), and the rates were higher for the non-allo-HSCT group (38.9%, 7/18) compared to the allo-HSCT group (21.1%, 4/19). The median time to relapse was one month (0.5–16 months). Among the 11 relapsed patients, 72.7% (8/11) showed CD7-negative (CD7-) relapse, 18.2% (2/11) showed CD7 + relapse, and 9.1% (1/11) had reduced CD7 antigen expression (33.8%). For Ib-phase responders (n = 29), the 2-year cumulative relapse rate among patients who underwent allo-HSCT was 25.5% (95% CI: 7.4–48.9) compared to 64.3% (95% CI: 21.2–88.2) in the non-allo-HSCT group (P = 0.149). Non-relapse mortality (NRM) rate was 20.9% (95% CI: 4.5–45.3) with allo-HSCT compared to 30.8% (95% CI: 8.7–56.6) without allo-HSCT (P = 0.369; Fig. 5E, F). By the end of the follow-up end, 62.5% (25/40) patients had died (52% recurrence-related, 44% infection-related, and 4% bleeding-related).

CD7 CAR T-cell expansion and persistence

The amplification of CD7 CAR-T cells in the peripheral blood of all nine patients in stage Ia was detected by flow cytometry and PCR. The median time to peak CD7 CAR-T cell count at stage Ib was 14 (7–30) days post-infusion, and the median count was 82.1×10⁶/L (0.643-734) in the peripheral blood. The CAR transgene was detectable in all patients (Fig. 6A, B). The longest period of time that the CAR-T cells were detected was 180 days post-infusion with a count of 0.19×10⁶/L, and the CAR transgene was persistent till day 396 post-infusion. Monitoring was discontinued after HSCT. Nevertheless, CAR T-cell expansion did not appear to differ in terms of therapeutic efficacy or the origin of T cells (Fig. S3 and Fig. S4). CD7 CAR-T cell expansion was detectable in three refractory patients (NO.003, 011, 025) (Fig. S5). Among 10 patients with CNS involvement, seven tested positive for CAR gene copy number in the CSF. Neither of the two patients with ICANS had detectable CAR copies in the CSF (Fig. 6C). Serum biomarkers including interleukin (IL)-2, IL-6, IL-10, tumor necrosis factor (TNF)-α, and interferon (IFN)γ increased in most patients in phase Ib (Fig. S6).

T cell aplasia

Although CD7 + normal T cells were cleared within a median duration of 10.5 (7–14) days after infusion, the CD7- T cells expanded in all patients and began to recover at a median duration of 10.5 (7–21) days post-infusion (Fig. S7). The median count of CD7- normal T cells was 98.8 cells (95.5–99.7) per µL. We also observed changes in CD7 + and CD7- T lymphocyte subsets from reinfusion to day + 90 in stage Ib patients who achieved 90-day remission without bridging to allo-HSCT.

This study reports the results of a phase I study on low-dose CD7 CAR-T cell therapy for patients with r/r T-NHL, including T-LBL and r/r TCL. The CAR-T cells were engineered using the IntraBlock technology. The low-dose infusion (1×10⁵ ±30% /Kg) of CD7 CAR-T cells expanded efficiently and achieved a high CR rate with a manageable safety profile in patients with r/r T-NHL, regardless of whether the CAR-T cells are patient-derived (autologous) or donor-derived (allogeneic). The patients were followed up for a median duration of 30 months to obtain reliable data on survival outcomes. Compared to previous studies, this extended follow-up allowed calculation of PFS, and provided new insights into the treatment landscape.

CD7-targeting immunotherapies may be compromised by T-cell fratricide and extermination [15–17]. Pan et al. reported successful expansion of donor-derived CD7 CAR-T cells with the same CAR construct as in our study [6]. However, after five days of culture, four out of the 16 patients received a lower dose than the predetermined trial dose due to sub-optimal CAR T-cell expansion. Our data demonstrate that CD7 CAR-T cells, whether patient- or donor-derived, expand robustly with low-dose infusion without intensive preconditioning. Low-dose cell reinfusion avoids culture failure caused by insufficient cell numbers in high-dose protocols, reduces the cost of in vitro culture, and expands the possibilities for the use of CAR-T cells, especially for patients who do not have a suitable donor or are not eligible for transplantation. Furthermore, the low-dose CD7-CART cell therapy showed manageable adverse effects with a lower incidence of grade ≥ 3 CRS compared to that reported previously [6]. In contrast to the findings reported by Pan et al. [6], both Ia and Ib phase patients receiving CAR-T cell infusion showed significantly accelerated neutrophil and platelet recovery. However, hematological toxicity and delayed hematopoietic recovery remain critical safety issues following CD7 CAR-T cell therapy. Therefore, improved prevention of infections, promotion of hematopoietic recovery and proactive supportive care are essential.

In earlier studies, the CD7 CAR-T cells were primarily obtained from donors (6,13,22). Therefore, the improvement in long-term survival was associated with consolidation allo-HSCT in later phases [18]. There is a lack of comparative data on the long-term survival of these patients and those who have received a bridging HSCT. Our study is the first to directly compare these two cohorts within a single study. The results showed that patients who switched to allo-HSCT achieved better long-term survival and a significantly lower relapse rate within 2 years, although non-relapse mortality did not improve. To further improve survival in the bridging cohort, future research should focus on reducing transplant-related mortality through less intensive conditioning or other strategies. In particular, a novel "all-in-one" strategy entailing sequential CD7 CAR T-cell therapy and haploidentical HSCT could be promising in patients with relapsed or refractory CD7 + leukemia or lymphoma [19]. Our findings also suggest that CD7 CAR-T cell therapy is a promising option for mature TCL. Nevertheless, despite universal initial response (5/5), 80% of the patients (4/5) relapsed. The sole survivor, who remained disease-free for 39.6 months, received bridging allo-HSCT, thereby supporting its integration as a consolidation therapy for TCL after CAR-T cell infusion.

Unlike other published studies [7, 8, 19, 20], we observed a higher proportion of CD7- relapse cases (72.7%, 8/11). It remains unclear whether clonal escape is more frequent in T-ALL patients who undergo anti-CD7 CAR-T cell therapy. Frameshift or missense mutations may be the main cause of CD7 loss in tumor cells [9]. The impact of these factors needs to be clarified in more extensive studies.

This study has several limitations. First, it was a phase I trial with a small sample size; a larger study is therefore needed to confirm the findings. In addition, the high-risk profile of the enrolled population may limit the generalizability of these findings. Due to the lack of sufficient samples, future research is needed to evaluate immunodeficiency associated with the long-term depletion or impairment of normal B, T, and NK cells after CD7 CAR-T cell therapy, as well as mechanisms of relapse due to CD7 antigen loss. The results will be pivotal for optimizing consolidation therapy decisions after CD7 CAR-T cell therapy. While initial results are promising, further research is needed to optimize manufacturing methods, address safety concerns, and determine the optimal patient populations for each approach.

In conclusion, low-dose CD7 CAR-T cell therapy is effective against r/r T-NHL, and allo-HSCT after achieving remission with CD7 CAR-T therapy can significantly prolong survival.

Ethics approval and consent to participate

Approval of the research protocol by an Institutional Reviewer Board. The study was approved by the Ethics Committee at the Beijing Gobroad Hospital in Beijing Informed Consent. The study adheres to the Declaration of Helsinki.

Consent for publication

Not applicable.

Conflicts of interest

The authors confirm that there are no conflicts of interest.

Funding

None.

Author contributions

Conception and design: Kai Hu.

Acknowledgements

We are grateful to the patients and their families who participated in this study. We also thank all the physicians, nurses and other patient caregivers who participated in the study.

Availability of data and materials

All the data and materials are included in the manuscript and supplemental materials. The detailed and original data can be accessed by contacting the corresponding author’s email.

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Table 1 and 2 are available in the Supplementary Files section.

There is NO conflict of interest to disclose.

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Supplementary materials
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Supplementary Tables
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Supplementary Figs
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Table2
Table1Table1.pdf
Table1

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Low-dose CD7 chimeric antigen receptor T cells for relapsed/refractory T-cell lymphomas: single-arm, open-label, phase I study

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Abstract

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Background

Methods

Patients and study design

Construct design and manufacture of CD7 CAR-T cells

Endpoints and related assessments

Statistical analysis

Results

Patient characteristics

Safety

Efficacy

Disease response

PFS and OS

CD7 CAR T-cell expansion and persistence

T cell aplasia

Discussion

Declarations

Consent for publication

Funding

Author contributions

Acknowledgements

Availability of data and materials

References

Tables

Additional Declarations

Supplementary Files

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