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In 1893, the American Journal of the Medical Sciences reported on ten patients whose large and hitherto incurable cancers had been injected with bacteria taken from skin infections. In every case, striking improvement was seen, marking the birth of “cancer immunotherapy” – using the power of the immune system to attack cancer.
The immune system is the body’s most powerful weapon against cancer and infection. For a cancer cell, surviving long enough to divide and eventually form a lump or tumour is the result of a brutal Darwinian process. To reach this point, cancer must adapt, hiding from immune detection and co-opting patients’ immune machinery to betray its original programming and instead protect the cancer.
Immunotherapy – which really started to take off just over a decade ago – is an attempt to artificially tip the balance back in favour of tumour elimination. Sometimes this can be done by taking off the brakes from immune cells already in the cancer.
This works because cancers have fooled the body by using its own natural safety switches, or “checkpoints”, that usually keep our immune systems under control. Blocking these switches using specially chosen antibodies – biological drugs – turns the immune response back on. This approach is called “immune checkpoint blockade”.
Mutations are alterations in genetic code that can lead to cancer. All cancers fall on a spectrum, depending on how many mutations the cells have. Typically, cancers caused by exposure to toxic or harmful things have higher numbers of mutations than those which are not – examples include melanoma, a type of skin cancer, and some types of colon cancer.
From the perspective of the immune system, the more mutations there are, the “hotter” the cancer is. This may make a cancer more aggressive, but it also increases the chances that the immune system will have detected it and mounted a response. This is why immune checkpoint blockade therapy works well for these high-mutation cancers, but less well for others.
The other type of immunotherapy does not rely on the natural activity of the immune system. This approach uses immune machinery that is designed in a laboratory, a bit like biological Lego. Scientists take pieces of existing immune mechanisms and combine them to make new ones, which enhance the way the body’s defence system responds.
When put into the patient’s T-cells (a type of immune cell that usually fights viruses), this machinery allows them to attack and kill cancer. Called cell therapy, this approach has cured patients with previously incurable leukaemia.
The new machinery, called a “chimeric antigen receptor” or “Car”, transforms a diverse T-cell population into Car-T, where the engineered cells all respond to the same cancer-associated marker.
Victims of their own success
Both types of immunotherapy have been victims of their own success. This has led to the replication of existing technology rather than riskier diversification. Of 11 immune checkpoint blockade treatments approved by American regulators, nine target the same immune interaction. And of the Car-T cell treatments approved in the US since their debut in 2017, all target one of two markers found exclusively on blood cancers.
Substantial effort has been spent on iterative developments of the existing Car concept. Examples include changing the target or tuning the signals that stimulate the T-cells.
This has yielded important advances, but the saturation of both academic and commercial research space has contributed to a diminishing appetite for funding more cell therapy programmes.
Success against solid cancers has also been extremely low. The Darwinian adaptiveness shown by cancer creates a suppressive environment in a cancer lump, where it is hard for Car-T to work properly. So, reliance on a single technology has not delivered on its initial promise.
Given that Car-T costs around £282,000 per patient in the UK, and the patient’s disease often worsens in the two-to-three weeks it takes to manufacture them, confidence is waning.
This phenomenon is not new. In the 1950s, confidence in chemotherapy was low because single drugs failed to produce lasting cures. But by the 1960s, combination chemotherapy began to deliver durable patient benefit, and multi-drug regimens now form a mainstay of cancer therapy.
Immunotherapies that use combination approaches are now emerging. Recent research from University College London demonstrated how engineered immune cells called gamma-delta T-cells could act as delivery vehicles for anti-cancer antibodies.
In this approach, not only did the engineered cells kill cancer in mice, they also empowered other cells to join the fight. Also, gamma-delta T-cells can be safely taken from a healthy donor and given to several patients.
So there is hope.
Cell therapies that can be made beforehand from healthy donor cells and then stored, ready to use, are receiving more interest. For example, the number of trials using gamma delta T-cells doubled between 2022 and 2023, the fastest-growing area of activity.
This could remove the waiting time for treatment manufacture, reducing the chance of disease worsening in the interim. A move away from reliance on single-axis immune interventions, such as immune checkpoint blockade or Car-T in isolation, should yield better outcomes.
The immune system is highly complex. Our attempts to manipulate it must live up to this complexity if we are to deliver lasting patient benefit.
Jonathan Fisher works for University College London and is an inventor on patents pertaining to gamma-delta T cell immunotherapy. In the past 5 years he has received research funding from UKRI, the Academy of Medical Sciences, Cancer Research UK, CCLG, and the UCL Technology Fund.
