Science: New CAR-T therapy with 100% effective

Science: New CAR-T therapy with 100% effective.  Science journal: 100% effective, Shanghai Jiaotong University‘s Yang Xuanming team develops new CAR-T therapy.

Chimeric antigen receptor T cell immunotherapy (CAR-T) has achieved significant effects in the treatment of patients with malignant hematological tumors, and it has also brought great breakthroughs and successes in the field of adoptive cell therapy. However, this method is effective for entities.

The curative effect of tumor patients is limited. In order to improve the curative effect, researchers have made various improvements to the CAR structure, including two costimulatory molecules in series, and the introduction of CD40L, IL-12, anti-PD-1 immunomodulatory molecules and other strategies. In traditional CAR design, usually only the intracellular domain of the costimulatory receptor is used. When the CAR binds to the tumor antigen, the integrated costimulatory receptor signal is activated.

In the natural T cell activation process, the activation signal of the costimulatory receptor mainly comes from the costimulatory ligand expressed by the antigen presenting cell, not the tumor antigen. This separate activation strategy of tumor antigen-first signal, costimulatory ligand-second signal provides the unique temporal and spatial specificity required for T cell activation.

Recently, Yang Xuanming’s team from the School of Life Sciences and Technology of Shanghai Jiaotong University and others published a research paper titled: A chimeric antigen receptor with antigen-independent OX40 signaling mediates potent antitumor activity in Science Translation Medicine, a subsidiary of Science.

This study found for the first time that the antigen is independent of OX40 signal, and on this basis, a new type of CAR-T cell with independent costimulatory signal was designed to simulate the second signal of natural T cell activation. This new type of CAR-T cell culture model in vitro, Tumor-bearing mouse models and clinical patient trials have shown stronger expansion capabilities and tumor killing capabilities.

This research provides a new strategy for improving the anti-tumor activity of CAR-T cells and breaking through the challenges of solid tumor treatment.

The researchers chose to add a full-length costimulatory receptor to the CD3ζCAR (20BBZ CAR) vector with the costimulatory molecule 4-1BB, which is currently the most widely used clinically. A new type of CAR-T cell that stimulates molecules. By comparing 12 costimulatory receptors, the researchers found that 20BBZ-OX40 CAR-T cells containing the OX40 costimulatory receptor have better expansion and anti-tumor capabilities.

The researchers tested the therapeutic effect of 20BBZ-OX40 CAR-T cells in Raji and Daudi leukemia models derived from human B cells. It was found that compared with the traditional 20BBZ-CAR-T cells, the survival time of leukemia tumor-bearing mice was prolonged after 20BBZ-OX40 CAR-T cell treatment. This is closely related to the better expansion of 20BBZ-OX40 CAR-T cells in vivo.

The survival time of mice in the 20BBZ-OX40 CAR-T treatment group is prolonged

In view of the excellent anti-tumor effect of 20BBZ-OX40 CAR-T cells in mouse models, in order to continue to explore the safety and effectiveness of 20BBZ-OX40 CAR-T cells as clinical anti-tumor treatments, the researchers cooperated with the Affiliated Hospital of Xuzhou Medical University A preliminary clinical trial was conducted on patients with refractory, relapsed and metastatic B-cell lymphoma. A total of 5 patients were recruited, all of whom completed 20BBZ-OX40 CAR-T cell therapy, with an effective rate of 100%, of which 2 cases were completely remitted and 3 cases Partial relief.

20BBZ-OX40 CAR-T has a very strong expansion ability in patients. In one patient, its CAR-T cells accounted for more than 80% of T cells in the peak value of proliferation. At the same time, the CAR-T has good safety characteristics, the patient has no CAR-T-related neurotoxic side effects, and no serious cytokine storm (CRS).

Amplification of 20BBZ-OX40 CAR-T in patient #2 (top) and anti-tumor ability (bottom)

This new CAR structure with constitutive costimulatory receptor OX40 has improved proliferation ability, anti-apoptosis ability, anti-depletion ability and tumor killing ability compared with BBZ CAR-T cells that are widely used in clinical treatment. These characteristics have led to enhanced therapeutic efficacy in preclinical mouse leukemia and lymphoma models and clinical patients. This research provides new ideas for improving the efficacy of CAR-T cells and breaking through the challenges of CAR-T therapy for solid tumors.

(source:internet, reference only)

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