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Chimeric Antigen Receptor (CAR) T-cell Therapy has been hailed as the next frontier of oncology, as it is an innovative and revolutionary approach to treating cancers. Here is a look at how the treatment has evolved from the past into the present, and towards the future.

As its name suggests, CAR T-cell Therapy is a type of immunotherapy that harnesses the body's immune system to target cancer cells.

Specifically, it genetically engineers T-cells, a type of white blood cells, to form CARs, which possess a unique ability to bind to cancer-related proteins.

The most frequent protein targets are the CD-19 that is highly expressed on B-cell leukaemia and lymphomas¹, or the B-cell maturation antigen (BMCA), which is present on the surface of mature B-cells, another type of white blood cells that forms antibodies. Once CARs are bound to these proteins, T-cells will then initiate a series of immune responses against the cancer cells.

This innovative therapy has shown the potential for efficacy against haematological malignancies, such as B-cell lymphoma. For example, a two-year follow up study from a trial involving patients with relapsed or refractory large B-cell lymphoma (R/R LBCL) showed a median overall survival of greater than two years².

CAR T-cell Therapy is targeted to treat diseases with a significant unmet medical need, such as for individuals with aggressive blood cancers who do not respond to several lines of treatments, including chemotherapy, radiotherapy and surgery.

Progress so far

The first CAR was designed in 1993³. Following three decades of innovation, it has evolved to include more effective structures, so they can better exert its anti-tumour activity and is less challenging for patients.

In 2011, a landmark achievement was met as researchers in the University of Pennsylvania first administered the therapy to patients with chronic lymphocytic leukaemia (CLL)⁴.

In 2012, a seven-year-old with acute lymphoblastic leukaemia (ALL) received CAR T-cell Therapy and she was eventually cured⁵. During her treatment process, she experienced several side effects unknown at the time, but later discovered as cytokine-release syndrome, which is the overstimulation of the immune response. Side effects such as cytokine release syndrome and neurotoxicity continue to occur and can be managed with clinical interventions.

CAR T-cell Therapies

Currently, there are two types of CAR T-cells under development, either autologous or allogeneic.

In autologous treatment, the cells are taken from the same patient that is receiving treatment, which minimises the chances of an immune host response once the modified cells are reintroduced into the body.

Alternatively, in allogeneic treatment, large batches of modified cells are manufactured from a single healthy donor.

At the time of writing, there are two autologous CAR T-cell Therapies that have received approval from the Health Sciences Authority (HSA) in Singapore⁶. These therapies are only approved to treat a limited set of B-cell malignancies, including certain non-Hodgkin lymphomas (NHL) and B-cell acute lymphoblastic leukaemia (ALL).

Navigating the complex manufacturing process

While clinical studies have demonstrated efficacy in treating certain cancers, there are considerations, such as a complex and carefully controlled manufacturing procedure.

The process starts with leukapheresis, where blood is drawn and separated so that white blood cells can be collected. The cells are further distilled down to extract T-cells and transported under strict temperature control and monitoring, and sometimes across different countries, so they can be engineered in the laboratory.

A new gene is then introduced, so the T-cells produce CARs, and they are expanded in the laboratory for several days to produce the treatment quantity required, with quality checks to ensure it is ready for patient use.

After being transported in an uninterrupted cold chain and ensuring the T-cells are viable, they can then be infused into the patient's body. The patient will then be monitored closely in the hospital for any potential side effects and if the cancer is responding to the therapy.

Looking ahead to future innovations

As CAR T-cell Therapy is expected to be widely administered in hospitals, a sustainable ecosystem must be in place to collect, transport, manufacture and infuse the engineered cells to patients. This requires a trained multidisciplinary team of specialists and support staff.

Currently, many of the clinical trials that investigate CAR T-cell Therapy are in the United States, Europe and China to study its use against B-cell malignancies, and several studies are assessing long-term effects in patients⁷. As researchers continue to improve on the technology by altering the composition of the target protein and CAR gene, we can expect more breakthroughs in the years to come, such as enhanced efficacy and reduced side effects, including cytokine release syndrome.

Beyond B-cell malignancies, CAR T-cell Therapy is also being studied for different cancer types, including solid tumours—however, the therapy is more complicated than in haematological malignancies, as the T-cells have to persist in the tumour for a prolonged time to mount an antitumour response.

In addition, off-the-shelf allogeneic CAR T-cell Therapy has also attracted increasing attention, as it provides patients with immediate access to treatment when needed. Early clinical trial data is promising for the treatment of relapsed or refractory B-cell acute lymphoblastic leukaemia using healthy donors⁸. However, more research is needed to consider the long-term successes of this mode of therapy, such as ensuring the host does not reject the donor cells.

Three decades have passed since the development of CAR T-cell Therapy and the pace of its innovation and success have continued to bring hope to clinicians and patients who may benefit from it. The challenge now is to take learnings and work in a concerted effort to manage the possible risks associated with this revolutionary therapy.

¹Subklewe M, Bergwelt-Baildon MV & Humpe A. Chimeric antigen receptor T cells: A race to revolutionize cancer therapy.

²Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): A single-arm, multicentre, phase 1-2 trial. The Lancet: Oncology. 2018;20(1):31-42.

³Eshhar Z, Waks T, Gross G, et al. Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the γ or ζ subunits of the immunoglobulin and T-cell receptors. Proc Natl Acad Sci USA. 1993;90:720-724.

⁴Styczynski J. A brief history of CAR-T cells: From laboratory to the bedside. Acta Haematologica Polonica. 2020;5(20):2-5.

⁵Rosenbaum L. Tragedy, perseverance, and chance — The Story of CAR-T therapy. New England Journal of Medicine. 2017;377(14):1313-1315.

⁶Health Sciences Authority. (2023). Register of Class 2 cell, tissue or gene therapy products. [Online]. Available at: https://www.hsa.gov.sg/ctgtp/ctgtp-register. [Accessed date: 04 April 2023].

⁷Charrot S & Hallam S. CAR-T cells: Future perspectives. HemaSphere. 2019;3(2):e188.

⁸Benjamin R, Jain N, Maus MV, et al. UCART19, a first-in-class allogeneic anti-CD19 chimeric antigen receptor T-cell therapy for adults with relapsed or refractory B-cell acute lymphoblastic leukaemia (CALM): a phase 1, dose-escalation trial. The Lancet: Haematology. 2022;9(11):E833-843.