How should the four major challenges of CAR-T therapy be optimized?

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How should the four major challenges of CAR-T therapy be optimized?

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How should the four major challenges of CAR-T therapy be optimized?

 CAR-T immunotherapy refers to the engineering of human T cells so that T cells can specifically target and eliminate tumor cells, so as to achieve the purpose of precise cancer treatment.

Which tumors can CAR-T treat?

CAR-T is currently mainly used to treat relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) in children and young adults and certain types of B-cell non-Hodgkin’s lymphoma (B-NHL) in adults. Including relapsed/refractory diffuse large B-cell lymphoma (DLBCL), relapsed/refractory mantle cell lymphoma (MCL) and relapsed/refractory follicular lymphoma (FL).

With the development of clinical research, related CAR-T cells targeting different targets are also expected to be applied to B-NHL, multiple myeloma (MM), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), T Cellular lymphoma and solid tumors and other fields.

Challenges encountered in CAR-T cell therapy

Challenge one:

Overcome the off-target problem of CAR-T and improve the specific recognition ability.

Only by specifically recognizing tumor surface antigens can CAR-T cells ensure that they only attack tumor cells without causing damage to normal tissues.

Studies have shown that tumors can escape the recognition of the immune system by down-regulating or losing surface antigens.

In solid tumors, due to the heterogeneity and tumor microenvironment, it is difficult for CAR-T to find a therapeutic target with strong specificity, high safety and not easy to off-target.

These reasons will lead to more application of CAR-T in solid tumors. for difficult.

Challenge two:

Ensure the safety of CAR-T applications. There are two main types of CAR-T toxicity: cytokine release syndrome (CRS) and neurotoxicity (NTX) or CAR-T cell-related encephalopathy syndrome (CRES).

CRS is a systemic inflammatory response, including fever, fatigue, headache, rash, arthralgia, and myalgia. It is common within a few days after the first infusion of CAR-T cells, and in severe cases, it manifests as tachycardia, hypotension, Pulmonary edema, cardiac insufficiency, hyperthermia, hypoxia, renal impairment, liver failure, coagulation disorders, and irreversible organ damage are the hallmarks.

NTX occurs in more than 40% of patients, usually within 1 to 3 weeks after the infusion, and is characterized by confusion, dullness, tremors, delirium, difficulty finding words, and headache.

Challenge three:

Maintain the persistence of CAR-T cells in vivo. Although the complete remission rate of CAR-T cell therapy is high, a considerable number of patients relapse within a few years. Taking B-ALL as an example, the relapse rate ranges from 21% to 45%.

The cause of disease relapse is CAR-T cell exhaustion, resulting in the loss of antigen-specific T cells due to continuous antigen stimulation, increased expression of costimulatory domains of CAR structures and inhibitory receptors.

Challenge four:

Graft-versus-host disease (GVHD) and graft rejection in allogeneic CAR-T therapy.

Most of the current CAR-T is prepared from the patient’s own T cells, which is prone to poor therapeutic effect due to poor quantity (in patients receiving lymphodepletion and/or chemotherapy) and poor quality.

Therefore, allogeneic CAR-T therapy has become an attractive alternative therapy.

The application of allogeneic CAR-T cell therapy is accompanied by challenges of graft-versus-host disease (GVHD) and graft rejection.

Strategies to improve the efficacy of CAR-T therapy

At present, the treatment of CAR-T still faces many challenges, including the difficulty in identifying the ideal target antigen in some tumors, drug resistance, antigen escape, decreased persistence and expansion of CAR-T cells, and the effect of CAR-T cells on immune suppression.

Environmental susceptibility and life-threatening toxicity associated with CAR-T cells during treatment.

These problems have affected the expected efficacy and durability of CAR-T.

However, CAR-T related research on these issues is developing rapidly, and scholars at home and abroad have proposed various strategies to solve these treatment obstacles.

Optimization and improvement of CAR-T technology

Enhanced CAR Targeting Specificity

1. Optimizing scFv and designing it to target two antigens or even more than three antigens may solve the escape problem of antigen-negative cancer cells.

2. The use of bispecific CD20/CD19 CAR-T can treat patients with relapsed B-cell malignancies. In addition, it has been proved that tri-specific CD19-CD20-CD22 targeting CAR-T cells can rapidly eliminate B-cell lymphoma in preclinical studies , BAFF ligand-based CAR-T cells simultaneously target three receptors, including BAFF-RBCMA and TACI.

3. In the field of solid tumors, use GD2 as the target antigen, and use the second-generation CAR to modify EBV-specific T cells to treat children with neuroblastoma.

In addition, representative antigenic targets include mesothelin, used for the treatment of mesothelioma, pancreatic cancer, ovarian cancer, and lung cancer; CEA, used for the treatment of lung cancer, colon cancer, gastric cancer, breast cancer, and pancreatic cancer; MUC-1, used for For the treatment of liver cancer, lung cancer, pancreatic cancer, colon cancer, gastric cancer;

GPC3, for the treatment of liver cancer; EGFRvIl, for the treatment of glioma, head and neck tumors; PSMA, for prostate cancer, etc.

Enhanced persistence of CAR-T cells

There are many strategies to improve the persistence of CAR-T cells, such as optimizing the structure of CAR-T cells, using memory T cells, and rationally designing the ratio of CD4/CD8 CAR-T cells.

CD28 and 4-1BB are the most common co-stimulatory molecules in CAR-T cell products Compared with CD28 co-stimulation, 4-1BB co-stimulation can improve CAR-T cell exhaustion, and the combination of CD28 and 4-1BB can simultaneously enhance the anti-tumor effect And increase the persistence of CAR-T cells. Personalized CAR design helps to improve persistence.

For example, CD4+ CAR-T cells show excellent persistence. The ratio of CD4/CD8 CAR-T cells may affect the therapeutic effect. The current 1:1 ratio of CD4/CD8 CAR -T cells have been proven to have excellent anti-tumor effects.

Enhancing the safety of CAR-T therapy

At present, CRS is mainly treated clinically by reducing the dose of CAR-T, using steroid therapy or blocking IL-6R antibodies. Since IL-6 is associated with severe CRS, 1 Tocilizumab, as an IL-6 receptor antagonist, has been approved by the US FDA for the treatment of CRS in CAR T cell patients. Another CRS management strategy being explored is to block IL-1.

Given that overexpansion of CAR-T cells may lead to life-threatening CRS, it is necessary to regulate the expansion and persistence of CAR-T cells by adding a safety switch to mitigate unexpected or severe toxicity.

FDA-approved small-molecule drugs act as key switches to specifically modulate antigen recognition or deplete CAR-T cells, such as lenalidomide, methotrexate, alemtuzumab, rituximab, and cetuximab, as well as positive Hand in IL-2.

Outlook

Some scholars believe that the development trend of CAR-T technology in the future will be multifunctional smart T cells, which can generate complex immune responses and reshape the tumor microenvironment so that they can be active in every tumor type.

As research advances, more and more CAR-T cell products are entering the investigational new drug stage of therapy development; however, in terms of target optimization, precise regulation, functional enhancement, synthetic biology, and general CAR-T cell therapy design Challenges remain.

In addition, the tumor microenvironment in solid tumors hinders the widespread application of CAR-T cell therapy. The mechanism behind adverse reactions and the risk of relapse after CAR-T cell therapy also need to be further explored.

How should the four major challenges of CAR-T therapy be optimized?

(source:internet, reference only)

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