Cancer immunotherapy has progressed tremendously in recent years, with the emergence of innovative approaches like chimeric antigen receptor (CAR) T-cell therapy and T-cell receptor (TCR) T-cell therapy. Both strategies involve harnessing the power of the immune system to fight cancer, but there are some key differences between them.

In CAR T-cell therapies, T cells are taken from the patient’s blood, genetically engineered to produce the chimeric antigen receptor, and the resultant CAR T-cells are then given back to the patient. The CAR helps the T cells recognise a specific cancer cell antigen and activate the T cells to kill these cancer cells.

TCR-T therapy works similarly to CAR T-cell therapy, but instead of using a chimeric antigen receptor, TCR therapy modifies a patient’s T-cells to express a T-cell receptor (TCR) that recognises a specific antigen on cancer cells. Once the modified T-cells are infused back into the patient, they can also seek out and destroy cancer cells expressing the targeted antigen.

Differences Between CAR T-Cell Therapy and TCR-T Therapy

Structurally, CAR T-cells and TCR-engineered T-cells are different. CAR-T Cell structures are composed of engineered intracellular and extracellular domains. The extracellular domain is composed of a single-chain variable fragment (consisting of antigen binding domain of the antibody) to recognise specific antigens on the surface of cells to trigger intracellular signalling leading to T-cell activation. The maintenance of T-cell activation and survival of CAR T-cells are further enhanced by the addition of costimulatory domains to the intracellular portion of the CAR T-cell.

TCR-engineered T cells, on the other hand, use naturally occurring (or minimally modified) TCR receptors to recognise tumour antigens presented by the major histocompatibility complex (MHC) molecules. The other major difference is the targets. CAR T-cells only recognised specific antigens on the surface of the cancer cells, and these surface antigens are commonly not expressed on solid tumours. In contrast, TCR-engineered T cells not only target surface antigens but also targets intracellular targets. Therefore, TCR therapy has broader applicability, as there are far more tumour-specific sequences within a cell and presented in the MHC than there are tumour-specific proteins on the surface.

Credit: Ivica, N.A.; Young, C.M. doi.org/10.3390/healthcare9081062 reproduced under the Creative Commons license

A Brief Overview of CAR T-Cell Therapy

CAR T-cell therapy was developed and pioneered to treat blood cancers, specifically B-cell malignancies such as acute lymphoblastic leukaemia (ALL) and non-Hodgkin’s lymphoma. These types of cancer are often difficult to treat with traditional chemotherapy and radiation therapy, and CAR T-cell therapy has shown promising results in clinical trials.

While CAR T-cell therapy has shown great success in treating blood cancers, researchers are also exploring its potential applications in other types of cancer, including solid tumours. However, the development of CAR T-cell therapy for solid tumours is presented with several challenges. One such challenge is the complex microenvironment and fewer specific antigens on the surface of these solid tumours. The lack of specific antigens on the solid tumours makes it difficult to target the tumour cells without harming healthy tissue. In addition, as solid tumours are highly heterogeneous, this makes it difficult to identify and target the tumour cells with CAR T-cells. The immunosuppressive tumour microenvironment in the solid tumours can also inhibit the function of T cells and make them less effective. CAR T-cells designed to target antigens expressed on solid tumour cells may also recognise and attack healthy cells that express similar or identical antigens, resulting in off-target toxicities. It can also be challenging for the CAR T-cells to traffic and infiltrate the tumours limiting their ability to target and kill tumour cells.

Credit: Mehrabadi AZ, Ranjbar R, Farzanehpour M, et al. doi:10.1016/j.biopha.2021.112512 reproduced under the Creative Commons license

A Brief Overview of TCR-T Therapy

Unlike CAR T-cells, TCR-engineered T cells recognise MHC-presented peptides derived from proteins of all cellular compartments. Many solid tumours do not express surface antigens but rather, they express the tumour antigens intracellularly. As such, TCR-T therapy may be better suited than CAR T-cell therapy for treating solid tumours, which make up the vast majority of all malignancies. 

The clinical trials for TCR treatment of solid tumours were first performed for patients with melanoma. Since then, there have been many clinical trials for the treatment of different cancers including sarcoma, renal cell carcinoma, bladder, lung, oesophagal, metastatic, pancreatic, and liver cancer.

One of the challenges of TCR-T therapy is identifying the right antigen to target. This requires a deep understanding of the specific cancer being targeted, as well as the antigen expression patterns on the cancer cells. Additionally, there is a risk of off-target effects, where the modified T cells attack healthy cells in addition to cancer cells. Despite these challenges, TCR-T therapy has shown promising results in early clinical trials. TCR-T therapy is still a relatively new approach to treating cancer, and more research is needed to fully understand its potential benefits and limitations.

Differences between CAR T-cell therapy and TCR-T therapy

	CAR T-Cell Therapy	TCR-T Therapy
Constructs	– Engineered receptors consisting of intracellular and extracellular domains	– Native or minimally engineered TCR
Targets	– Targets cell surface antigens only	– Targets both cell surface and intracellular antigens presented by the MHC class molecules
Advantages	– Cellular targets not restricted by MHC complex. – Great therapy outcomes on haematological cancers	– Enable a greater diversity of targets as it can target intracellular antigens – Permits highly sensitive binding interactions with MHCEncouraging outcomes in the therapy of solid tumours
Disadvantages	– Little effect on solid tumours – Side effects like cytokine release syndrome and neurotoxicity	– Restricted by MHC compatibility – Side effects like cytokine release syndrome and neurotoxicity
FDA Status	– Approved therapy for multiple forms of cancers	– Under the clinical trials phase

Overall, both CAR T-cell therapy and TCR-T therapy represent exciting developments in the field of cancer immunotherapy, offering the potential to treat a wide range of cancers and improve outcomes for patients. While there are some key differences between the two approaches, both have their own unique strengths and challenges, and both have the potential to make a significant impact on the treatment of cancer. Though there are challenges that need to be addressed, researchers are continuing to explore the potential of these innovative therapies. We can expect to see significant advances in the fight against cancer in the years to come.

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References:

Ivica, N.A.; Young, C.M. Tracking the CAR-T Revolution: Analysis of Clinical Trials of CAR-T and TCR-T Therapies for the Treatment of Cancer (1997–2020). Healthcare 2021, 9, 1062. https://doi.org/10.3390/healthcare9081062

Mehrabadi AZ, Ranjbar R, Farzanehpour M, et al. Therapeutic potential of CAR T cell in malignancies: A scoping review. Biomed Pharmacother. 2022;146:112512. doi:10.1016/j.biopha.2021.112512

Shafer P, Kelly LM, Hoyos V. Cancer Therapy With TCR-Engineered T Cells: Current Strategies, Challenges, and Prospects. Front Immunol. 2022;13:835762. Published 2022 Mar 3. doi:10.3389/fimmu.2022.835762

Zhang, Y., Liu, Z., Wei, W. et al. TCR engineered T cells for solid tumor immunotherapy. Exp Hematol Oncol 11, 38 (2022). https://doi.org/10.1186/s40164-022-00291-0