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Innovations in Oncology 2019

I couldn’t have imagined the successes we are seeing from immunotherapy

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Professor Alan Melcher

Professor of Translational Immunotherapy, The Institute of Cancer Research, London, The Royal Marsden NHS Foundation Trust

Scientists are further exploring checkpoint inhibitors and cell therapies as ways to use immunotherapy more widely in the fight against cancer.

The way we treat cancer has progressed over recent years and immunotherapy has had a big impact in allowing patients’ immune systems to uncover and attack cancers that may have previously gone undetected.

When I first started researching the potential of immunotherapy as a cancer treatment, I don’t think I could ever have imagined how much of a difference immunotherapy would be making for people with cancer now.

Cancers that were considered incurable are now being so successfully treated with immunotherapy that patients who have had multiple, widely-spread tumours of some types, are now living for many years with no evidence of active disease.

Our immune system is good at killing cancer in theory, but cancer has evolved many different ways to evade and hide from the body’s natural defenses; what is clever and different about immunotherapies is that they are designed to help unmask the cancer and encourage the immune system to attack.

How do the checkpoint inhibitors and cell therapies work?

So-called ‘immune checkpoint inhibitors’ are examples of this kind of treatment.

The immune system has ‘on’ and ‘off’ switches to make sure it is effective against infection, but does not become so uncontrollably overactive that it ends up harming the body’s own healthy tissue. Cancer has found ways to stimulate the off switches (or negative immune checkpoint proteins), to help the cancer hide in plain sight.

The checkpoint inhibitor treatments work by inhibiting these off switches co-opted by the cancer – cancer then has nowhere to hide. And the results of clinical trials of many of these treatments have been remarkable.

Checkpoint inhibitor treatments made their breakthrough in melanoma, but are now also available and effective in, for example, lung, head and neck cancer and bladder cancer, and are being trialled in other tumour types.

CAR-T cell therapy is more personalised, complex and expensive, but can be very effective

The other headline-grabbing form of immunotherapy is cell therapies such as ‘CAR-T cells’. The early trials were in some ways as impressive as the checkpoint inhibitors. However, such cell therapy is also far more complex and personalised than checkpoint inhibitors – a patient’s own immune cells must be extracted, trained to spot cancer cells by genetic alteration, and then put back so they can hunt down and kill the cancer.

In addition, this treatment is only effective in, and available for, some forms of blood cancer – we are yet to see it work on solid tumours. But it is so effective that, despite its very high cost, NHS England has agreed to pay for CAR-T in the small number of children and young people with acute lymphoblastic leukaemia, when chemotherapy has not worked.

As with all immunotherapies, but particularly for CAR-T, it is early days – we do not yet have long-term survival data and do not know whether there are any later side effects.

Despite all the headline-grabbing clinical trial results and the amazing stories of individual people’s treatment, we still don’t really know exactly how immunotherapies such as checkpoint inhibitors work, the ways patients could benefit most and, importantly, how to get them to work in more tumour types.

So what do we need to do next to make immunotherapy a viable treatment for many more patients?

Combination strategies, combining immunotherapies with other, more traditional, cancer treatments, complicate things further. Radiotherapy and chemotherapy, can, in some circumstances, trigger an immune response that helps immunotherapy work. However, an almost infinite number of combinations are possible, and we need to develop informed, scientifically validated strategies, which may particularly help in tumour types in which immunotherapy has not yet proved successful.

While we are making great strides in treating patients with the new generation of immunotherapies, and immuno-oncology is evolving into a completely new cancer treatment paradigm, we, as doctors and researchers, want to see these treatments benefit as many patients as possible. And, with further research, working together as laboratory and clinical scientists, the future looks bright.

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