CAR-T FOR CARCINOMA- THE GAME CHANGER IN CANCER TREATMENT

PRIASHA DUTTA, AMITY UNIVERSITY KOLKATA, WEST BENGAL

One of the leading causes of mortality in the present-day world is cancer. Whenever we think of cancer treatment, the two words that are immediately synonymous are chemotherapy and radiation therapy. Although, due to limited efficacy based on the heterogeneity factor of cancer cells, there is a constant search for alternative therapeutic methods that are more effective and come with lesser of the severe side-effects. Because of the complex behaviour that tumours showcase, coupled with added genetic and cellular factors of tumorigenesis and metastasis, the development of promising immunotherapy that targets tumours at both cellular and genetic levels, has become important. 

CAR (Chimeric Antigen Receptor)-T cell therapy is where T cells derived from a patient’s blood are engineered in vitro to express artificial receptors targeted to a specific tumour antigen. Direct recognition of the tumour antigen is observed, without any involvement of the MHC. Following are the steps of CAR-T cell therapy– 

STEP 1: Leukapheresis: 

(Leukapheresis: A process where WBCs or components of it are separated from a blood sample for collection and study). In this case, autologous T cells are isolated from the patient’s blood. Cell collection might be challenging if the patient has an underlying disease or is seeking treatment for one. This could lower WBC count thereby affecting the functionality of other lymphocytes as well. Records mention chemotherapeutic cycles potentially harm T cell expansion, depicting poorer development with an increase in the number of cycles. Thus, the timing of cell collection is quite crucial for CAR-T cell production. 

STEP 2: Cryopreservation: 

(Cryopreservation: A process where biological compounds are preserved at sub-freezing temperatures, below −80°C and typically below −140°C). Shortly after the collection, the samples are cryopreserved, allowing storage for up to a month. CAR-T cells show the highest activity in case of samples that are freshly collected and cryopreserved at the possible. 

STEP 3: Reprogramming: 

T cells are reprogrammed in a lab with all of the information needed for them to have a CAR on their surfaces. The reprogrammed T cells can then continue to produce CARs by themselves. They are then multiplied in the lab.

STEP 4: Infusion: 

Finally, the CAR-T cells are infused back into the patient, which then begin identifying and destroying the cancer cells! 

The speciality of chimeric receptors in their ability to fuse or split discrete functions like recognition, co-stimulation and activation, in different chains of a receptor molecule by mimicking the complexity of the native T cell receptor (TCR) structure. 

The basic structure of a chimeric antigen receptor consists of the ectodomain, transmembrane domain, and endodomain; each having a specific

Function:

1.  Ectodomain: 

• The ectodomain comprises of a targeting domain and a spacer. 
• The targeting domain is derived from monoclonal antibodies, which recognizes specific antigens. A single-chain variable fragment (scFv) is generated by linking the variable region’s heavy and light chains. This domain allows the T cell to bind to the antigen, thereby triggering the T-cells’ activity. 
• A small hinge-like part called ‘spacer’ connects the extracellular targeting element to the transmembrane domain and plays a role in the functionality of CAR and scFv flexibility.

2. Transmembrane domain: Within the membrane of that particular cell lies the transmembrane domain which affects CAR stability on the T cell surface: 
3. Endodomain: 

• This has two parts- a costimulatory domain and a signalling domain.
• The costimulatory domain provides the co-stimulatory signal needed for full activation of the T cell. Some evidence suggests that co-stimulatory domains may increase CAR-T cell antitumor activity, cytokine production and longevity, facilitate T cell replication and even reduce CAR-T cell exhaustion. 
• The intracellular portion usually has the signalling domain– TCR complex CD3 zeta. After antigen recognition, the receptors’ cluster activates and relays the signal to the T cell.

Advantages:

CAR-T cells can remain stable as long term memory cells for many years in the body. Thus, they can recognize and kill cancer cells encountered during circulation, if relapse occurs. Another advantage of CAR-T cells is that they specifically target only tumour cells and not auto antigens and hence are safe to host cells. This form of combined gene therapy and immunotherapy has been proven to treat hematopoietic malignancies, especially various forms of Non-Hodgkin’s lymphoma. However, there is still a long way to go in the treatment of other cancer types and solid tumours. 

Also read: Chapare virus: A new Arenavirus threat to mankind

References-

1. Cheng Zhang, Jun Liu, Jiang F. Zhong, Xi Zhang- “Engineering CAR-T cells”; Biomarker Research, June 2020 DOI: 10.1186/s40364-017-0102-yhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482931/2. Rimjhim Mohanty, Chitran Roy Chowdhury, Solomon Arega, Prakriti Sen- “CAR T cell therapy: A new era for cancer treatment (Review)”; ResearchGate, September 2019 DOI: 10.3892/or.2019.7335https://www.researchgate.net/publication/336027608_CAR_T_cell_therapy_A_new_era_for_cancer_treatment_Review

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