Artwork from the Print edition by Allanah Booth.
This article was originally published in the Oxford Scientist’s Print edition, Barriers, in Michaelmas Term 2022, under the title ‘Checkpoints: challenges and solutions in cancer immunotherapy’. You can read more of our Print articles here.
In the fight against cancer, our strongest weapon is ourselves. Or rather, our immune systems. Since William Coley, the father of immunotherapy, first noted that patients with post-operative infections appeared to be cured of bone cancer, studying how the immune system responds to cancer has revolutionised our understanding of how tumours develop, evolve, and die. As research progressed, it was found that the pharmaceutical inhibition of “immune checkpoints”—markers on white blood cells (such as T-cells) that downregulate immune responses and reduce inflammation—not only promotes autoimmunity but also induces a potent response against cancer cells.
It is now over ten years since this discovery and still only 15-25% of patients will respond to the two most common checkpoint inhibitors, drugs targeting the T-cell checkpoints PD-L1 or CTLA-4. Furthermore, only a small percentage of patients given any kind of cancer immunotherapy will experience significant prognostic improvement. Cancer is complex, with multi-step pathways acting redundantly and interconnectedly to promote uncontrollable growth.
Targeting a single checkpoint or pathway inevitably leads to resistance and disease progression, as the cancer cells mutate in a desperate fight for survival, driving the growth of the tumour unrelentingly forward. Furthermore, it is hard to describe cancer by a single definition as it varies hugely both between and within patients, with different gene mutations, variable tumour microenvironments (the surrounding immune cells, blood vessels and molecules), and differing immune states. The battle for successful immunotherapies appears doomed to fail, which invites the question of whether it is worthwhile for scientists to invest their research efforts into such a complicated problem. This article explores the challenges facing immunotherapy today and their potential solutions.
The high attrition rates of immunotherapeutics in clinical trials is testament to the difficulty of developing and marketing effective cancer drugs. Many immunotherapies only offer promise for certain patients with distinct tumour types, due to tumour heterogeneity, treatment history, and variability in cancer stage and genotype. Furthermore, clinical endpoint criteria for immunotherapy clinical trials need to be different to that of trials evaluating the efficacy of other chemotherapeutics. Because immunotherapies work indirectly by activating the immune system to kill cancer, rather than killing the cancer themselves, it may take longer than in conventional drug trials to observe a positive clinical response. For example, one clinical trial for the anti-CTLA-4 inhibitor developed by AstraZeneca was terminated prematurely due to a lack of visible effects. After follow-up, it was found that patients did start improving after 24 months. This drug is now approved for melanoma treatment in the US.
Tumour heterogeneity is also a key challenge when evaluating the efficacy of anti-cancer drugs. Cancer cells display a high level of genetic instability, meaning they rapidly generate new mutations. Within a single area of a tumour, thousands of different mutations may be present with each cell having diverged down a slightly different evolutionary pathway. Such a high level of genetic diversity makes it difficult to target tumours with a single drug. Crucially for combatting this, researchers have found that cancer cells share some genetic similarity in the form of “driver” mutations. These are mutations that occur early in the development of cancer and give rise to the oncogenic properties of cells. Identifying these genetic changes and formulating treatment strategies to specifically target them is key to increasing the efficacy of cancer immunotherapies in the face of tumour heterogeneity.
A further problem in the development of these treatments is acquired resistance—cancer cells can become drug resistant in a similar manner to bacteria gaining antibiotic resistance. Secondary mutations in the drug target can reactivate cancer pathways or alternative mechanisms that allow cancer cells to evade the action of drugs. Identifying these resistance pathways will be important in improving current therapies so that they are robust against evasive cancer cells. For example, a study of patients with checkpoint-inhibitor-resistant melanoma discovered resistance mutations in two genes, JAK1 and JAK2, which disrupted the signalling pathway for interferon-gamma, a key immune system chemical messenger, and prevented T-cells from recognising the tumours.
Now, the scientists who made this discovery are evaluating the effects of checkpoint inhibitor combination therapies in cell lines and mouse models containing these resistance mutations. Taking biopsies of tumours, as was done in this study, is essential in finding the right mutations to target. This isn’t always easy as taking a tissue biopsy is both invasive and can increase morbidity. One alternative is liquid biopsy, which involves analysing circulating DNA from the blood to identify tumour mutations. The introduction of liquid biopsies in a clinical setting to analyse the genetic landscape of a tumour could be revolutionary—a workable method of characterising the mutations and pathways that lead to resistance is vital in improving the prognostic outcome of patients on immunotherapies.
Financial sustainability for healthcare systems is an important consideration when evaluating new therapies. Immunotherapy drugs are particularly expensive due to their personalised nature—a recent study demonstrated that the cost per year per patient for one immune checkpoint inhibitor, Pembrolizumab, was around $140,000. In addition to this, the cost per year worldwide for this drug, used to treat lung cancer, was $83.9 billion. With an increasingly stretched NHS, and prohibitive costs in countries like the USA where healthcare is not free at the point of delivery, immunotherapy is not available to everyone. Perhaps counterintuitively, one way to improve its accessibility is to be more selective in the groups of patients it is being offered to. High-throughput genetic screening and identification of novel biomarkers can be used to find patients who would benefit from the drug, therefore reducing expenses for individuals who may not see any prognostic improvement—along with saving time and quality of life for those patients who may then be able to pursue alternative options.
Cancer immunotherapy may have revolutionised how we treat tumours, but this is yet to be translated into the ever elusive “cure for cancer”. The truth is that “cancer” is not one uniform disease, as it varies significantly both between people and individual cells. Importantly, the power of immunotherapy is found in its personalised approach. Ensuring that the right therapies are targeted to certain patients with a specific pattern of mutations, and that this is practically and financially accessible to everyone, will bring markedly better outcomes for cancer patients.
