I. Introduction

Refractory diffuse large B-cell lymphoma is a clinical problem with high unmet medical needs. Existing high-intensity salvage therapies, such as autologous stem cell transplantation, cure a small number of patients, so new treatment modalities are urgently needed. Tumor immunotherapy has become an exciting new frontier in the treatment of malignant tumors. As a unique type of immunotherapy, CAR-T cells have special efficacy in hematological cancers and can exploit the cytolytic ability of the patient's own T cells to find and eradication of tumor cells that have proven resistant to more conventional methods.

2. Pharmaceutical research on CAR-T

A related concept is the length of time that CAR-T cells remain in the circulation after infusion, often referred to as persistence. Data on the role of long-term persistence in durable remission are inconclusive. Studies have shown that CD19-positive chronic lymphocytic leukemia cells were completely eliminated, and normal B cells were also eliminated, but spontaneous repopulation of normal B cells was only observed in one patient 13 months after infusion, and chronic lymphocytic leukemia cells continued to be lost for more than 23 months.

Conversely, in patients receiving CAR T-cell therapy for acute lymphoblastic leukemia (ALL), the restoration of normal B cells may signal impending disease relapse. Ultimately, for durable disease control, the requirements for long-term CAR-T persistence and sustained B cell regeneration may prove to be disease and/or CAR specific.

3. CAR-T and B cell aplasia

Because CD19 is the target of CAR-T and several other leading CAR-T cell therapies under investigation to treat B-cell malignancies, and CD19 is expressed on malignant and healthy B cells, so-called on-target, off-tumor toxicity Risk is limited to normal B cell aplasia. Patients lacking B cells after CAR-T therapy may require immune globulin supplementation. The length of time that anti-CD19D CAR-T cells remain in circulation affects the duration of normal B-cell aplasia, as active anti-CAR-T cells can target B cells, thereby impeding B-cell recovery and prolonging the need for immunoglobulin therapy .

However, indefinite normal B cell aplasia does not appear to be a prerequisite for sustained disease remission. There is a report of a patient who sustained remission from chronic lymphocytic leukemia for 23 months after CAR-T cell therapy. The patient had polyclonal CD19 or B cell recovery 10 months after CAR-T cell infusion. There was no evidence of disease recurrence.

4. Reduce toxicity and improve efficacy

The antigen specificity of T cells can be redirected by cancer-specific CARs, and nearly 25 years later, it is likely that CD19-targeting CAR-T cells will be available as a treatment option for patients with refractory B-cell malignancies in the not-too-distant future. Multiple teams have made impressive progress not only by studying and optimizing CAR construct design, but also by developing key tools and technologies, such as developing efficient gene transfer technologies and improving manufacturing processes, to create accessible treatments.

Future efforts will further improve the benefit-risk ratio by mitigating toxicity while maintaining or even improving efficacy. Several approaches are being investigated, including CAR-T cells with additional functions, novel CAR-T dosing strategies, and mechanistic studies of the clinical relevance of observed safety and efficacy.

5. Future Direction

Preclinical research results show the feasibility of various conversion mechanisms of CAR-T cells. Switch technology can provide clinicians with real-time adjustable control of CAR-T cell activity and can broaden the CAR-T treatment window. Additionally, engineering CAR-T cells to express more than one CAR may reduce the ability of tumor cells to downregulate surface proteins targeted by monospecific CAR therapy.

The development of bispecific CAR-T cells, such as cells that recognize both CD19 and CD20 (another surface antigen typically specific to B cells), may increase response rates and improve the response potential through tumor escape mechanisms that prevent antigen loss. Persistence. Improved dosing, especially repeated dosing of human (or humanized) CARs, may be effective in improving response rates.

6. Discussion

A more detailed understanding of efficacy and toxicity mechanisms through further biomarker analysis may enable rational, targeted, and prospective safety management and may provide new ways to improve CAR efficacy while maintaining efficacy. -T cells are reprogrammed away from toxicity-related immune programs.