February 24, 2024

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CAR-T therapy cured another autoimmune disease and fully recovered in 6 months!

CAR-T therapy cured another autoimmune disease and fully recovered in 6 months!



 

Lancet: CAR-T therapy cured another autoimmune disease and fully recovered in 6 months!

Antisynthetase antibody syndrome , a serious autoimmune inflammatory muscle disorder, can be fatal if diagnosed too late, or if the patient does not respond adequately to drugs that suppress the immune system.

The disease iscaused by the erroneous attack of aminoacyl-tRNA synthetase , which is involved in the synthesis of amino acids in the body, by the immune system, thereby affecting the functions of various cells, involving muscles, joints, skin and lungs.

 

Last year, a 41-year-old man developed anti-synthetase antibody syndrome. Unfortunately, all of the conventional treatments used to suppress his immune system failed to work for him.

Fortunately, the CAR-T cell therapy originally used for cancer treatment saved him, and 6 months after treatment, he fully recovered from the autoimmune disease.

 

Recently, researchers from the University of Erlangen-Nuremberg in Germany published a paper titled “CD19-targeted CAR-T cells in refractory antisynthetase syndrome” in The Lancet .

Researchers successfully treated a male patient with anti-synthetase antibody syndrome using CAR-T cell therapy .

Six months after CAR-T cell therapy, the patient fully recovered from the autoimmune disease and did not need to use Immunosuppressive drugs .

This is the world’s first patient with anti-synthetase antibody syndrome successfully treated with CAR-T cell therapy , and also the second autoimmune disease cured by CAR-T after systemic lupus erythematosus .

 

CAR-T therapy cured another autoimmune disease and fully recovered in 6 months!

 

 

Starting in 2023, CAR-T cell therapy can be described as mixed. “The Lancet” reported that CD19 CAR-T successfully treated patients with autoimmune disease-anti-synthetase antibody syndrome .

But in the market, sales of the world’s first CAR-T therapy fell by 9%.

 

 


Application of CAR-T in hematological tumors

 

CAR-T therapy utilizes the specificity and persistence of the killing effect of immune cells to provide a more precise and long-term treatment mode for tumor patients, and has significant anti-tumor activity in various hematopoietic malignant tumors.

A number of cell products targeting CD19 and BCMA have been launched in the world.

 

CAR (Chimeric Antigen Receptor) is a recombinant transmembrane molecule composed of single-chain antibody variable regions, hinge transmembrane regions and intracellular signaling domains targeting antigen-binding antigens.

CAR genes can be passed through a variety of viral or non-viral vectors Transduced into T cells in vitro, the prepared CAR-T cells can migrate, redirect to tumor cells and proliferate extensively to exert cytotoxicity after reinfusion.

From the official website of clinical trials in the United States, the CAR-T for lymphoma is the most, followed by acute lymphoblastic leukemia (ALL) , multiple myeloma (MM) , chronic lymphocytic leukemia (CLL) , acute myeloid cell leukemia (AML) .

 

 

 

 


Limitations of CAR-T Therapy

 

Some bottlenecks of CAR-T therapy limit its wide application, such as severe side effects, antigen escape, treatment persistence, heterogeneity, etc., especially in solid tumors where the therapeutic effect is limited. There are:

 

First, CAR-T cell exhaustion. For example, some patients’ own T cells cannot successfully produce CAR-T cells, or the generated CAR-T cells are not sufficiently expanded.

Limited persistence in some patients is a potential factor for disease recurrence.

 

Second, antigen regulation. For example, the loss or downregulation of CD19 or CD22 on malignant B cells causes antigen escape and resistance to CAR-T therapy.

 

Third, CAR-T therapy toxicity, mainly severe cytokine release syndrome (CRS) and neurotoxicity. Whether the treatment of CRS interferes with the durable effect of CAR remission is still under investigation.

 

Fourth, unknown disease mechanisms, which are the focus of ongoing research efforts to optimize the clinical application of CAR-T cell therapy.

 

 

 


Optimization of CAR Design

 

CAR is mainly composed of components: antigen binding domain, hinge, transmembrane domain and intracellular signaling domain.

Each part has different functions, and the diversified combination of components can realize the optimal design of CAR molecules.

The antigen-binding domain is usually a single-chain antibody (scFv) , which is responsible for recognizing and binding the target antigen.

The hinge and transmembrane domain anchor the scFv to the cell membrane. The intracellular signaling domain consists of co-stimulatory factors and the CD3 signaling domain.

When the antigen is recognized and combined, a stimulating signal is generated and transmitted to the intracellular signaling domain, and T cells are activated and exert effector functions.

 

 

CAR-T therapy cured another autoimmune disease and fully recovered in 6 months!CAR-T molecular structure (from reference)

 

 

 


More solutions

 

For the cytokine storm and neurotoxicity that occur during CAR-T therapy, it is mainly to interfere with the secretion of cytokines or control the excessive activation of T cells, such as blocking IL-1, IL-6 and GM-CSF by antibodies, thereby blocking Excessive inflammatory response.

In the face of the problem of resistance during treatment, it can be improved by designing multi-targeted CAR molecules or increasing the expression of target antigens, or improving the affinity of scFv to target antigens, which may also help CAR-T cells recognize low density of target antigens.

 

At present, the manufacture of CAR-T mostly uses the patient’s heterogeneous T cells.

CAR-T cells modified by certain specific T cell subsets may produce better results.

Making universal cells is the direction of future development. One form is that the antibody is tagged with biotin and other tags, and after binding to the antigen, the tumor cells are labeled, and then the CAR-T cells developed for this tag will be activated to exert cell killing function.

 

CAR-T cell research trials revolve around efficacy, toxicity, and drug resistance. Based on the search for new targets and the elucidation of signaling mechanisms, combined with the application of new technologies, through continuous research on CAR design, transduction methods, and optimal cell types, It will definitely improve the therapeutic effect of CAR-T and be applicable to the treatment of more types of cancer patients.

 

 

 

 

 

 

 

 

 

 

 

references:

1. Xiaoyu Wang, et al. Recent advances in lentiviral vectors for gene therapy.

2. Natalia Elizalde and Juan Carlos Ramírez. Lentiviral vectors: key challenges and new developments.

3. Michael C. Milone and Una O’Doherty. Clinical use of lentiviral vectors.

4. David Escors, Karine Breckpot. Lentiviral vectors in gene therapy: their current status and future potential.

5. Merten OW, Hebben M, Bovolenta C. Production of Sakuma,T.,Barry, MA and Ikeda, Y. Lentiviral vectors : basic to translational.

6. Fabian, et al. CD19-targeted CAR-T cells in refractory antisynthetase syndrome.

CAR-T therapy cured another autoimmune disease and fully recovered in 6 months!

(source:internet, reference only)


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