Writers: Patrick Toh & Celine Tedja
Editor: Ayotenu Dosumu
Cancer is well known to be highly complex and diverse, which makes it difficult to combat with conventional methods such as surgery, chemotherapy, and radiation. Thanks to advancements in gene-editing technology and ongoing efforts to explore new treatment modalities, scientists have successfully developed a ‘living drug’ in which a person’s immune cells are genetically engineered to fight cancer cells. This is known as CAR T-cell therapy. Recently, a team led by Professor Waseem Qasim at UCL and Great Ormond Street Hospital (GOSH) made headlines for reversing an aggressive blood cancer with CAR T-cell therapy, with the first treated patient having been cancer-free for 3 years now. This story has sparked even greater interest in this novel treatment, which is considered a major leap in cancer research. UCL, in fact, has been at the forefront of CAR T-cell therapy research, having established its own CAR T-cell program.
The science behind CAR T-cells
CAR T-cell therapy is a type of adoptive transfer therapy, a form of immunotherapy that collects immune cells from a patient, grows them in a laboratory, and returns them to the patient. CAR T-cell therapy involves T cells, immune cells that recognise foreign pathogens or particles that are not normally found in our bodies. T cells have been shown to kill cancer cells; however, they struggle to recognise cancer cells because cancer cells can ‘hide’ from them in various ways, such as losing key antigens that allow immune cells to recognise them or releasing signals that prevent anti-tumour activity. This is where chimeric antigen receptors (CARs) come into the picture. Engineering T cells to express these receptors on their surface enables them to recognise specific antigens on cancer cells, therefore activating T cells to kill cancer cells.
To engineer T cells to make them express CARs, blood is first collected from the patient of interest. T cells are isolated from the blood, and the remaining blood is returned to the patient. This process is known as leukapheresis. Next, the collected T-cells are genetically altered by inserting the gene encoding the CARs using a viral vector. The edited T cells are then grown in the lab until there are millions of them – enough to target cancer cells effectively. Finally, the products are returned to the patient’s bloodstream as an infusion. Currently, this entire process takes about 3-5 weeks.
Advantages and limitations
What has made CAR T-cell therapy a spotlight in cancer research? The answer lies in its strengths compared to conventional treatments. CAR T-cells are ‘living drugs’, as they are made of cells. These cells persist long-term in the body, so even a single infusion can result in remission that lasts for years, as shown in previous clinical trials. Moreover, CAR T-cells are designed for precision targeting – their chimeric antigen receptors (CARs) make them highly selective for cancer cells, unlike chemotherapy or radiotherapy, which also damage healthy cells.
However, CAR T-cell therapy poses several drawbacks. In some cases, it was shown to lead to toxicities, namely cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). They are inflammatory responses caused by the surge of cytokines, a group of signalling molecules that activate other cells along the immune response pathway. To manage this side effect, drugs that inhibit IL-6, a major cytokine, can be administered. Another point is that CAR T-cell therapy currently appears to have limited efficacy in solid tumours, such as lung cancer, as the microenvironments can prevent CAR T cells from accessing them.
Brief history
Despite the relatively recent success of CAR T-cell therapy, the development of T-cell editing dates back to the 1980s. The concept of adoptive transfer therapy was first described by Dr Steven Rosenberg, but it wasn’t until 1989 that the first generation of CAR T cells was developed by immunologist Dr Zelig Eshhar. His team developed chimeric T cells known as ‘T-bodies’, which are essentially simple T cells fused with antibodies. In 1993, Dr Eshhar collaborated with Dr Rosenberg and Dr Patrick Hwu to develop receptors to be engineered onto tumour-infiltrating lymphocytes, and Dr Hwu later showed that these cells could kill ovarian cancer cells in mouse models in 1995. Ever since, new generations of CAR T cells have been developed, each time introducing new features to enable them to recognise and fight against cancer cells more effectively. As of now, six CAR T-cell therapies have been approved by the FDA for treating various forms of blood cancer, such as acute lymphoblastic leukaemia (ALL), diffuse large B-cell lymphoma, and multiple myeloma.
Scientists are now engineering ‘off-the-shelf’ allogeneic CAR T cells, in which the T cells are collected from healthy donors rather than patients. This method offers the advantages of reduced cost, improved efficacy, and enhanced safety. One such off-the-shelf CAR T-cell is base-edited CAR T-cell therapy developed by Professor Waseem Qasim and his team at UCL and Great Ormond Street Hospital (GOSH) to treat T-cell ALL, which commonly affects children. They used gene-editing technology to remove a CD7 marker that causes CAR T-cells to recognise and kill one another. In its phase 1 clinical trial involving eight children and two adults, 82% of patients achieved remission, and 64% remained disease-free three years after administration.
Future direction
Given the optimistic results of CAR T-cell therapy trials, this innovative treatment has significant potential to be implemented more widely, subject to regulatory approval. One particular challenge in translating CAR T-cell therapy from bench to bedside is the high manufacturing cost; however, this has been addressed by developing off-the-shelf allogeneic CAR T cells, which can be manufactured in large quantities and stored until needed. Another challenge is that progress in CAR-T cell development against solid tumours has stalled, so research on CAR- T cells has been primarily focused on blood cancers. This highlights an unmet need and an exciting question to be explored further, with the hopes of increasing the variety of cancers treatable by CAR T-cell therapy.
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