CD7-directed chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a promising cellular immunotherapy for patients with relapsed or refractory T-cell acute lymphoblastic leukemia and lymphoma (T-ALL/LBL), a population with limited treatment options and poor prognosis. While early clinical outcomes have demonstrated strong antitumor activity, the process of immune reconstitution following CD7 CAR-T therapy remains insufficiently understood, particularly in relation to infection risk and disease relapse.

To address this knowledge gap, GoBroad Healthcare Group investigators conducted an open-label phase I CAR-T clinical trial to evaluate the safety, efficacy, and immune recovery dynamics of donor-derived CD7 CAR-T cells in patients with relapsed or refractory T-ALL/LBL. This study represents an important step toward optimizing CAR-T treatment strategies for aggressive T-cell malignancies.

All treated patients achieved complete remission within 28 days after CD7 CAR-T infusion, highlighting the potent antileukemic efficacy of CD7-targeted CAR-T therapy in this high-risk setting. Robust in vivo expansion of CAR-T cells was observed in all patients, confirming effective target engagement and cellular persistence. As expected, CD7-positive T cells were rapidly eliminated following infusion, while CD7-negative T cells expanded markedly in peripheral blood, becoming a dominant component of post-treatment T-cell immunity.

To better characterize post–CAR-T immune reconstitution, single-cell RNA sequencing was used to profile immune cell populations at high resolution. The analysis revealed that CD7-negative T cells exhibited enhanced immunologic activity compared with pre-infusion T cells, with upregulation of T-cell functional pathways and immune activation signatures. Notably, autoimmune-related pathways were also enriched, suggesting that immune homeostasis after CD7 CAR-T therapy is reshaped rather than simply restored.

Despite encouraging efficacy, infectious complications remained a significant clinical concern. Hematologic toxicities such as leukopenia, neutropenia, and thrombocytopenia were common, and infections occurred in the majority of patients. Importantly, loss of monocytes was identified in patients who developed fatal infections, indicating that impairment of innate immunity may be a key driver of infection risk after CAR-T therapy. These findings underscore the importance of close immune monitoring and supportive care during immune recovery following cellular immunotherapy.

In addition to immune reconstitution, this study provided insights into relapse biology after CD7 CAR-T treatment. The inflammatory proteins S100A8 and S100A9 were found to be significantly upregulated in leukocyte populations from patients who experienced relapse, suggesting their potential role as biomarkers for early relapse detection. Identification of such biomarkers may improve post–CAR-T surveillance and guide timely therapeutic intervention.

Overall, this study delineates the cellular and molecular dynamics of immune recovery after CD7 CAR-T therapy for relapsed or refractory T-ALL/LBL. By integrating clinical outcomes with single-cell immune profiling, the findings offer valuable guidance for improving CAR-T therapy safety, managing infection risk, and refining long-term disease monitoring. This work highlights GoBroad Healthcare Group’s commitment to advancing innovative CAR-T research and translating cutting-edge immunotherapy into meaningful clinical benefit for patients with aggressive T-cell leukemias and lymphomas.

 

Refer to the original:https://doi.org/10.1158/1078-0432.CCR-22-2924

In recent years, Chimeric Antigen Receptor T-cell (CAR-T) therapy has garnered significant attention for its remarkable efficacy, especially in treating patients with relapsed or refractory lymphoma. In this issue, we invited Dr. Hu Kai, Director of the Lymphoma and Myeloma Department at GoBroad Healthcare Group-Beijing GoBroad Hospital, to explain the principles, therapeutic effects, and groundbreaking progress of CAR-T therapy in depth.

 

CAR-T Therapy: From “Reprogramming Immune Cells” to Precision Anti-Cancer Treatment

 

1. Engineering Immune Cells for Tumor Recognition and Killing

T cells play a central role in the immune system by monitoring and eliminating cancerous cells and combating external pathogens. However, in cancer patients, T cells often lose their ability to identify and kill tumor cells due to dysfunction.

CAR-T therapy involves extracting a patient's T cells and genetically modifying them in a lab to express a Chimeric Antigen Receptor (CAR) on their surface. This receptor enables T cells to recognize specific antigens on tumor cells, thereby restoring their tumor-killing function. Once engineered, the T cells are reinfused into the patient's body, where they actively seek out and destroy cancer cells.

 

2. Precision Therapy with Advantages over Conventional Treatments

Unlike traditional chemotherapy, which non-selectively kills both cancerous and healthy cells, CAR-T therapy targets tumor-specific antigens, thereby minimizing damage to normal cells and reducing side effects. It also overcomes drug resistance seen in chemotherapy and has shown efficacy in relapsed and refractory cases. Moreover, CAR-T cells exhibit persistence and immune memory, offering patients longer remission periods.

 

3. Manageable Adverse Effects with Growing Clinical Experience

CAR-T cells may cause Cytokine Release Syndrome (CRS) and neurotoxicity during tumor cell destruction, manifesting as fever, fatigue, or altered mental status. However, with accumulating clinical experience, these effects are now effectively managed with medications. As tumor burden decreases, acute toxicity symptoms generally subside.

Long-term toxicities like immunodeficiency may occur but can be mitigated with immunoglobulin infusions and timely interventions, greatly improving treatment safety.

 

CAR-T: A New Hope for Curing Relapsed/Refractory Lymphoma and Myeloma

 

CAR-T therapy has been well established for diseases such as B-cell lymphoma, B-cell acute lymphoblastic leukemia (B-ALL), and multiple myeloma, with abundant clinical data supporting its safety and efficacy.

 

1. CD19 CAR-T for B-cell Lymphoma: A Classic Targeting Success

B-cell lymphoma was one of the first indications for approved CAR-T therapy. In relapsed/refractory cases, CAR-T has shown superior efficacy over traditional therapies and has become the recommended first-line salvage therapy in global guidelines.
CD19, a highly expressed B-cell surface marker, was one of the earliest CAR targets. CD19 CAR-T has delivered excellent outcomes in DLBCL, mantle cell lymphoma, and B-ALL. Data from our center shows an overall response rate of 70–80% in relapsed/refractory B-cell lymphoma, with 40–50% achieving progression-free survival of over five years—meeting the criteria for clinical cure.

 

2. CD19 CAR-T for B-ALL: Outstanding Short-term Efficacy

CD19 CAR-T therapy yields ~90% overall response rate and 60–70% complete remission in relapsed/refractory B-ALL. However, its long-term efficacy remains a challenge, especially for high-risk patients or those with residual disease post-treatment, where allogeneic hematopoietic stem cell transplantation may still be needed.

 

3. BCMA CAR-T Brings New Hope to Myeloma Patients

For heavily treated, refractory myeloma patients, BCMA CAR-T therapy shows ~80% response rate and ~60% complete remission. Although remission often lasts 1–2 years, CAR-T offers hope where conventional therapies have failed.

 

4. Emerging Targets, Multi-targeted & Enhanced CAR-T Products

To overcome tumor escape and improve outcomes, researchers are developing CAR-Ts targeting CD22, CD20, and dual-target formats (e.g., CD19/CD22), as well as enhanced CAR-Ts with cytokine-modulating properties. “Relay-style” multi-target strategies are explored to extend remission, such as switching from CD19 to CD22 CAR-T after relapse.

In multiple myeloma, GPRC5D has emerged as a promising target beyond BCMA, with early clinical data showing good efficacy and safety.

 

5. Universal CAR-T: A Breakthrough for Cell Source Limitations

Traditional CAR-T relies on patient-derived T cells, which may be dysfunctional after extensive chemotherapy. Universal CAR-T uses healthy donor cells, enabling “off-the-shelf” production for wider access. Despite some immunologic and expansion challenges, universal CAR-T continues to improve in feasibility and safety.

 

CD7 CAR-T: Breakthrough in T-cell Lymphoma

 

T-cell lymphoma is rare, heterogeneous, and difficult to treat. Our center has developed CAR-T therapies targeting CD7 and CD5 for these challenging diseases.

1. Challenges in T-cell CAR-T Therapy

• Cell sourcing: Many patients lack viable T cells for CAR-T manufacturing.
• Fratricide: T-cell CAR-Ts may attack each other during expansion. This issue is being technically addressed.
• Prolonged immune suppression: T-cell depletion post-therapy may require stem cell transplantation to restore immunity.

2. Clinical Strategies for T-cell CAR-T

• Early treatment before excessive chemotherapy damage is critical.
• Plan for hematopoietic stem cell transplant post-CAR-T, especially in aggressive subtypes.
• Treat during low tumor burden to enhance response and reduce toxicity.
• Use allogeneic or universal CAR-T when autologous cells are unavailable.

Despite challenges, with proper patient selection and timing, T-cell CAR-T offers a hopeful option with superior outcomes over repeated chemotherapy.

 

Toward Personalized & Comprehensive Care for Maximal Benefit

The rapid evolution of CAR-T therapy is transforming the landscape of hematologic malignancies—from B to T cells, from single to multi-targets, from autologous to universal formats.

In addition, therapies like bispecific antibodies and antibody-drug conjugates (ADCs) are enriching the treatment toolbox across disease stages.

Ultimately, tailoring treatment plans to the patient's disease biology, tolerance, and prognosis is key to maximizing therapeutic efficacy and improving survival outcomes.

 

The 67th Annual Meeting of the American Society of Hematology (ASH) was held in Orlando, USA, showcasing the latest research and clinical advances in the field of hematology. At this year’s meeting, the team led by Professor Kai Hu from GoBroad Healthcare Group had seven studies accepted for presentation. These studies focused on CAR-T therapy in various types of relapsed/refractory lymphoma, including B-cell lymphoma, central nervous system lymphoma (CNSL), T-cell lymphoma, as well as combined strategies integrating CAR-T therapy with hematopoietic stem cell transplantation. Professor Hu provided a systematic interpretation of these research findings.

Q1. What were the main studies presented by your team at this year’s ASH meeting, and which “key clinical questions” did they aim to address?

All seven studies we presented this year revolve around a single core objective: to make CAR-T therapy more effective, more predictable, and more actionable in high-risk patient populations, with clear strategies for subsequent treatment steps.

Overall, these studies can be summarized into three main lines of investigation.

First, prospective studies targeting key refractory disease subtypes, resembling rigorously designed clinical trials. These include:

• A phase I study of CD19 CAR-T therapy in relapsed/refractory central nervous system lymphoma (CNSL)
• A phase I study of CD7 CAR-T therapy in T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (T-ALL/LBL), with long-term follow-up

Both disease entities have limited treatment options and are particularly difficult to manage after relapse, making prospective evidence essential to address fundamental questions such as feasibility, efficacy, and safety.

Second, what should be done after failure of CD19 CAR-T therapy?
CAR-T therapy is not effective for all patients. We explored salvage strategies using hematopoietic stem cell transplantation after CAR-T failure and compared outcomes between autologous and allogeneic transplantation cohorts, aiming to provide evidence-based guidance for post–CAR-T treatment decision-making.

Third, can treatment response be predicted earlier, and are there actionable biomarkers?
We investigated several potential biomarkers associated with treatment outcomes, including:

• The presence of TP53 mutations in tumor cells
• Dynamic changes in PD-1 expression on CAR-T cells and their in vivo exhaustion status

The goal is clear: to move CAR-T management from experience-based decision-making toward biomarker-assisted precision management.

Q2. In molecularly high-risk B-cell lymphoma, what new hope does CAR-T therapy offer, and can we assess efficacy at an earlier stage?

We observed two particularly noteworthy findings.

First, patients with TP53 mutations may still derive meaningful benefit from CAR-T therapy.
In the chemotherapy era, TP53 mutations were well established as an adverse prognostic factor and were associated with poor outcomes in diseases such as CNSL and diffuse large B-cell lymphoma (DLBCL). Our data suggest that CAR-T therapy may, to some extent, mitigate the negative prognostic impact of TP53 mutations, offering new therapeutic value for molecularly high-risk patients—although further studies are needed to refine risk stratification strategies.

Second, dynamic changes in PD-1 expression may help predict treatment trajectories at an early stage.

We found that a rising trend in PD-1 expression—from low to higher levels—may reflect more robust in vivo activation of CAR-T cells, and this dynamic pattern was associated with better clinical outcomes. This observation not only aids early efficacy assessment, but also provides a rationale for exploring combination strategies involving CAR-T therapy and PD-1 inhibitors.

Overall, CAR-T management is evolving from meticulous clinical observation alone toward precision management that integrates laboratory and molecular biomarkers.

Q3. Given the limited treatment options for CNSL, what are the latest advances in CAR-T therapy, and which factors most strongly influence efficacy?

Our prospective phase I study in CNSL was selected for oral presentation at ASH. While real-world data had previously suggested some therapeutic activity, prospective evidence remained limited. Our study provides more systematic and structured data in this field.

The results indicate that CD19 CAR-T therapy demonstrates meaningful antitumor activity in relapsed/refractory CNSL. We also found that treatment outcomes may be influenced by multiple factors, including patient age, disease stage, and pre-treatment clinical status.

One clear clinical implication is that maximal tumor burden reduction prior to CAR-T infusion—in other words, effective debulking—may be a critical prerequisite for optimizing CAR-T efficacy.

Q4. T-cell lymphoma is particularly challenging. What are the key innovations and long-term benefit signals from CD7 CAR-T therapy?

T-cell lymphoma represents one of the most challenging frontiers for CAR-T therapy. Although short-term response rates can be relatively high, achieving durable long-term benefit remains difficult. Our phase I study of CD7 CAR-T therapy highlighted three important points.

First, a broader eligible population. In addition to T-ALL/LBL, we included patients with certain subtypes of mature T-cell lymphoma, expanding the potential application boundaries of CD7 CAR-T therapy.

Second, high response rates can be achieved even with low-dose infusion. Our data showed that overall response rates exceeded 80% despite the use of low-dose CAR-T strategies, suggesting that high doses may not be necessary to achieve antitumor activity.

Third, long-term follow-up underscores the value of bridging to allogeneic transplantation. Patients who achieved durable responses or potential cure were more frequently those who subsequently underwent allogeneic hematopoietic stem cell transplantation, whereas long-term outcomes were less favorable in patients who did not proceed to transplant.

These findings suggest that when CD7 CAR-T is used as salvage therapy, early evaluation and planning for allogeneic transplantation as consolidation should be considered in eligible patients to maximize long-term benefit.

Q5. CAR-T therapy combined with transplantation: which patients may benefit most, and what are the future directions?

Combination strategies integrating CAR-T therapy and transplantation are gaining increasing attention. This year, we focused particularly on a highly challenging population: patients who fail CD19 CAR-T therapy. These patients often exhibit both chemotherapy resistance and CAR-T resistance and can be considered “double refractory,” with very limited treatment options.

Our findings suggest that if patients can still achieve some degree of response after debulking chemotherapy (including targeted combinations), consolidation strategies may be considered, such as:

• Autologous transplantation combined with CAR-T targeting alternative antigens
• Allogeneic transplantation combined with donor-derived CAR-T therapy

The overarching goal is to achieve improved disease control and more durable long-term outcomes.

In summary, the success of combination strategies depends on understanding the complementary mechanisms of CAR-T therapy and transplantation, as well as precise patient selection, ensuring that those most likely to benefit can do so from intensified therapeutic approaches.