The story so far: The three major forms of treatment for any cancer are surgery (removing the cancer), radiotherapy (delivering ionising radiation to the tumour), and systemic therapy (administering medicines that act on the tumour). Surgery and radiotherapy have been refined significantly over time – whereas advances in systemic therapy have been unparalleled. A new development on this front, currently holding the attention of many researchers worldwide, is CAR T-cell therapy.
Chemo and immunotherapy
Systemic therapy’s earliest form was chemotherapy: when administered, it preferentially acts on cancer cells because of the latter’s rapid, unregulated growth and poor healing mechanisms. Chemotherapeutic drugs have modest response rates and significant side-effects as they affect numerous cell types in the body.
The next stage in its evolution was targeted agents, a.k.a. immunotherapy: the drugs bind to specific targets on the cancer or in the immune cells that help the tumour grow or spread. This method often has fewer side-effects as the impact on non-tumour cells is limited. However, it is effective only against tumours that express these targets.
What are CAR T-cells?
Chimeric antigen receptor (CAR) T-cell therapies represent a quantum leap in the sophistication of cancer treatment. Unlike chemotherapy or immunotherapy, which require mass-produced injectable or oral medication, CAR T-cell therapies use a patient’s own cells. They are modified in the laboratory to activate T-cells, a component of immune cells, to attack tumours.
These modified cells are then infused back into the patient’s bloodstream after conditioning them to multiply more effectively.
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The cells are even more specific than targeted agents and directly activate the patient’s immune system against cancer, making the treatment more clinically effective. This is why they’re called ‘living drugs’.
How does it work?
In CAR T-cell therapy, the patient’s blood is drawn to harvest T-cells – immune cells that play a major role in destroying tumour cells. Researchers modify these cells in the laboratory so that they express specific proteins on their surface, known as chimeric antigen receptors (CAR): they have an affinity for proteins on the surface of tumour cells. This modification in the cellular structure allows CAR T-cells to effectively bind to the tumour and destroy it.
Conventional chemotherapy or immunotherapy comprises molecules that bind to the tumour or block chemical pathways that allow the tumour to grow or multiply – but don’t directly affect the immune system.
The final step in the tumour’s destruction involves its clearance by the patient’s immune system.
When there are abnormalities in the immune system or when the tumour finds a way to evade it, the cancer resists these drugs. In CAR T-cell therapy, the immune system is activated when the modified T-cells are reintroduced into the body, which allows a gradual and sustained tumour kill as these cells multiply.
Where is it used?
As of today, CAR T-cell therapy has been approved for leukaemias (cancers arising from the cells that produce white blood cells) and lymphomas (arising from the lymphatic system). These cancers occur through unregulated reproduction of a single clone of cells: following the cancerous transformation of a single type of cell, it produces millions of identical copies. As a result, the target for CAR T-cells is consistent and reliable.
CAR T-cell therapy is also presently used among patients with cancers that have returned after an initial successful treatment or which haven’t responded to previous combinations of chemotherapy or immunotherapy.
Its response rate is variable. In certain kinds of leukaemias and lymphomas, the efficacy is as high as 90%, whereas in other types of cancers it is significantly lower. The potential side-effects are also significant, associated with cytokine release syndrome (a widespread activation of the immune system and collateral damage to the body’s normal cells) and neurological symptoms (severe confusion, seizures, and speech impairment).
How widespread is its use?
The complexity of preparing CAR T-cells has been a major barrier to their use. The first clinical trial showing they were effective was published almost a decade ago; the first indigenously developed therapy in India was successfully performed only in 2021.
The technical and human resources required to administer this therapy are also considerable. Treatments in the US cost more than a million dollars. Trials are underway in India, with companies looking to indigenously manufacture CAR T-cells at a fraction of the cost. The preliminary results have been encouraging.
The Indian perspective
In India, introducing any new therapy faces the twin challenges of cost and value. Critics argue that developing facilities in India may be redundant and/or inappropriate as even when it becomes cheaper, CAR T-cell therapy will be unaffordable to most Indians. Those who are affluent and require the therapy currently receive it abroad anyway.
While this is true, it may be the right answer to the wrong question. Having access to the global standard of care is every patient’s right; how it can be made more affordable can be the next step. A significant fraction of the Indian population incurs out-of-pocket expenses for their treatment since state and private insurance coverage is minimal.
Investments in developing these technologies in India represent the hope that, as with other initially expensive treatments like robotic surgery, we will be able to provide economies of scale: the sheer volume of patients in India has the potential to drive the cost of treatment down.
Evolution of ‘cell therapies’
The interest in the technology goes beyond providing a new lease of life to people with leukaemias and lymphomas. For solid tumours – like those of the prostate, lung, colon, and some other organs – CAR T-cell therapy has been shown to be able to cure patients with tumours that have recurred or have evaded multiple lines of treatment.
The challenge with harnessing these techniques for solid tumours remains significant. These are highly heterogeneous cancers that lack a consistent target with which CAR T-cells can bind.
Progress in the field, however, has the potential to unlock a host of newer treatments on the horizon called cell therapies. They include personalised anti-cancer vaccines and tumour infiltrating lymphocyte therapies (where white blood cells that attack the tumour are extracted, modified, and reintroduced into the patient).
Cancer constantly evolves to evade treatment; similarly, we need to develop more sophisticated therapies with as few-side effects as possible. Cell therapies hold this promise and will also help us understand this dreaded disease and its complexities better.
Dr. Narayana Subramaniam is head of the department of Head and Neck Oncology, Sri Shankara Cancer Hospital and Research Centre, Bengaluru.
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