CAR T-cell Therapy

Dr Emma Zhao details a new era in cancer treatment

Cancer is a growing global health problem. Cancer immunotherapy has recently emerged as a promising new treatment option for various types of cancer. Chimeric antigen receptor T-cell therapy is a revolutionary new pillar of cancer treatment because it produces significant and durable clinical responses. Chimeric antigen receptors (CARs, also known as chimeric immune receptors) are receptor proteins modified to give T-cells new abilities to target specific proteins. These receptors are chimeric because they combine antigen binding and T-cell activation functions in a single receptor.

CAR T-cells have undergone four iterations. The first CAR T-cells were developed in 1987 by Kuwana et al., followed by the second, third and fourth-generation compositions.

Anti-tumour activity, effector function and in vivo persistence with expanded improvement modifications on these generational compositions allow enzymatic degradation of the extracellular matrix by solid tumours and co-stimulation of various receptors with additional ligands. Accordingly, two landmark events for CART-cell therapy occurred in 2017: the Food and Drug Administration (FDA) approved two anti-CD19 CART-cells to treat acute lymphoblastic leukaemia (ALL) and relapsed or refractory large B-cell lymphoma, respectively. There are currently six products of CAR T-cell therapies that have been approved by the FDA (Table 1).

CAR T Therapy In Tumours

Through genetic modification technology, CART-cell immunotherapy has higher targeting, killing activity, and persistence of effector T-cells than conventional immune cells. It can also overcome the tumour’s local immunosuppressive microenvironment and break the host immune tolerance state, showing great application potential and development prospects in the clinical treatment of tumours. However, there are also risks of cytokine storm, off-target effect, insertion mutation and other clinical applications.

Car T-Cell Therapy In Haematologic Cancer

CAR T-cell therapy has gained an initial foothold in bloodborne cancers. CAR T-cell-based therapies with high efficacy are widely used in haematological cancers such as acute and chronic forms of leukaemia, lymphoma and myeloma.

Anti-CD19 CAR T-cells are effective for treatingR/R (relapsed or refractory) B-cell malignancies, such as B-cell non-Hodgkin lymphoma (NHL), ALL and chronic lymphocytic leukaemia in both paediatric and adult patients. CD19, a member of the immunoglobulin superfamily expressed on the surface of B cells, serves as an ideal target for car-targeted therapy. Phase 2 of the multicentre ELIANA trial saw a complete remission rate of 60% in 75 children and young adults, an overall remission rate of 81%, a durable remission rate of 80%, and a six-month relapse-free survival associated with prolonged CAR T-cells in peripheral blood samples and sustained B-cell proliferation.

The CD22-CAR T-cell can target another overexpressed antigen on B-cell tumours, CD22. The impressive antitumor function of CD22-CAR T cell was reported in relapsed cancer after CD19-CAR T-cell therapy or in an era directing all tumour cells. Moreover, several studies have confirmed the safety and efficacy of CD20-CAR T-cells in R/R NHL, follicular and set-in-cell lymphoma.

Sino Biological provides several recombinant haematologic tumour target proteins, ELISA kits and more. Various methods have validated these high-quality reagents and will provide consistent and reproducible results.

Car T-Cell Therapy In Solid Tumours

Targeting solid tumours is more complex than targeting hematologic cancers, and CAR T-cells have a set of challenges to address. The genetic instability of tumour cells means that they can stop expressing the antigens targeted by T-cells or lack the mechanism to present these antigens.

Solid tumours in clinical trials are growing, including CAR T-cells targeting carcinoembryonic antigen, mesothelin, interleukin 13 receptor alpha(IL-13Ralpha), human epidermal growth factor receptor 2(HER2), fibroblast activation protein(FAP), L1 cell adhesion molecule(L1CAM) and epidermal growth factor receptor.

HER2, a tyrosine kinase receptor, is overexpressed in many cancers and approximately 80% of glioblastoma. HER2 plays a crucial role in development, cell proliferation and differentiation. The HER2 gene has been associated with malignancy and a poor prognosis in many carcinomas, including breast, prostate, ovarian, lung cancers, etc. It has been shown that third-generation HER2 CAR T-cells can target and kill glioblastoma cells. Efficacy was significantly improved when combined with PD-1 blockade. Sino Biological provides broad CAR T-cell therapy targets with high activity and purity (Fig. 1).

CAR T-cells were one of the popular critical advances in cancer immunotherapy at the beginning of this century. They will be an essential immunological technology in the 21st century, ultimately defeating fatal diseases such as cancer.

Dr Emma Zhao is with Sino Biological

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