Cancer therapy to order

Immunotherapy is fast becoming the go-to treatment for many cancers. But are we any closer to realising the holy grail of personalised cancer medicine? Katrina Megget reports

Tapping into the power of our immune system has spearheaded a drive in an exciting new therapeutic class to treat cancer known as immunotherapies. The first such drug only hit the scene in 2011, yet by December 2021 there were more than 30 approved immunotherapies on the market and, according to the US-based Cancer Research Institute, more than 7270 immunotherapy clinical trials under way worldwide. These drugs are fast becoming the standard of care for many cancers and market research firm Precedence Research estimates the market could be worth $277.1bn by 2030.

‘Immunotherapy for cancer has made a tremendous difference to patients’ outcomes across a number of cancer types,’ says Karla Lee, oncologist and clinical research fellow at King’s College London, UK. ‘Ten years ago, a diagnosis of metastatic melanoma carried a dismal prognosis, even with treatment. Today, approximately half of the patients who took part in one of the key [immunotherapy] studies are alive six and a half years later and we are hopeful the majority of these patients are probably “cured”.’

Immunotherapy works by harnessing the body’s immune system to recognise and attack cancer cells rather than relying on toxins to directly kill the tumour.

Cancer’s ability to grow and spread comes down partly to its built-in ability to escape detection and evade immune attack. But this cloaking mechanism can be thwarted by stimulating the immune system to target cancer in one of two ways: either by making cancer cells more recognisable to the immune system – seen with checkpoint inhibitor drugs such as Keytruda; or by super-charging immune cells to be more potent, such as cell therapies and vaccines.

Increasingly there is a push for more personalised drugs unique to the individual patient and their cancer, and immunotherapy is on a path to making this a reality. ‘Optimising individual tumour response while reducing side effects is the goal of personalised medicine,’ says Santosh Kesari, Professor of neuro-oncology at the Pacific Neuroscience Institute in California, US. ‘Personalised medicine in cancer has the potential to replace toxic treatments such as radiation and chemotherapy and may even obviate the need for more extensive surgeries.’

Personalised medicine in cancer has the potential to replace toxic treatments such as radiation and chemotherapy and may even obviate the need for more extensive surgeries.
Santosh Kesari Professor of neuro-oncology, Pacific Neuroscience Institute, US

Engineered immunity

In many senses, personalised immunotherapy is already here with the advent of adoptive cell therapies such as CAR-T. Code for Chimeric Antigen Receptor Therapy, this form of immunotherapy involves removing T-cells from the patient’s body. These cells are then engineered with CAR proteins which, once injected back into the patient, allows the T-cells to target specific cell-surface proteins on cancer cells and launch an immune response. CAR-T has been particularly effective in blood cancers but is still struggling with solid tumours because these tumour microenvironments can supress T-cell immune activity.

It’s for this reason that another type of personalised adoptive cell therapy is stoking interest. T-cell receptor (TCR) T-cell therapy again involves removing a patient’s T-cells and engineering them but this time with T-cell receptors, which recognise a wider array of tumour-associated antigens than CARs, notably intracellular proteins presented to T-cells as peptides on the cancer cell surface. This gives TCR therapy an advantage over CAR-T, with the added bonus of potentially reduced toxicity and enhanced personalisation to the specific tumour.

TCR therapies are still in clinical trials, being investigated for leukaemia, melanoma, head and neck cancers, cervical cancer, pancreatic cancer among others. A team of scientists from the Fred Hutchinson Cancer Research Centre in Seattle, US, for instance, was able recently to tailor a TCR therapy to a patient who, despite being treated with an initial TCR therapy, developed recurrent acute myeloid leukaemia. They found the patient’s cancer had developed a novel way to avoid detection. By targeting a different subtype of antigen, the new TCR therapy successfully killed leukaemia cells from the relapsed patient in lab dishes. The team also found the new treatment could reduce the growth in solid tumour cell lines of pancreatic and breast cancer that expressed the antigen.

The downside with these personalised cell therapies is cost. ‘A one-time infusion of Kymriah costs $475,000 and the total cost for Kymriah or Yescarta treatment is nearly $1m/patient,’ says Mike Ward, Global Head of life sciences and healthcare thought leadership at London-headquartered analytics firm Clarivate. Many companies are looking to counter this by developing off-the-shelf therapies using a source of T-cells from healthy donors, which could lower treatment per dose to the low thousands of dollars. But Ward says these products would no longer be personalised and, as a result, ‘there are still some concerns about response durability, T-cell persistence and graft-versus-host-disease’.

A cheaper alternative to T-cell therapies are therapeutic cancer vaccines. ‘We can use vaccines to educate the immune system to see, recognise and eliminate cancer in an adaptive immune response,’ says Christian Ottensmeier, Professor of immuno-oncology at the University of Liverpool, UK, who is overseeing a trial in the UK of a personalised vaccine for head and neck cancer and ovarian cancer developed by the French biotech Transgene.

Ottensmeier says despite one cancer vaccine on the market – Provenge (sipuleucel-T) for prostate cancer – most attempts over the past few decades have had limited success. That, however, is starting to change as scientists better understand how cancer works to evade the immune system and how to tune it for optimal and personalised anti-cancer results, he says. ‘What’s beginning to emerge is that, while it’s critical to tune immune cells to recognise the difference in cancer cells, that tuning may not be sufficient to turn a possible immune response into an effective immune response,’ he adds.

Tumour-associated antigens (TAAs), for example, are the target of choice for cancer vaccines to date. Found in both healthy and malignant cells, they are expressed at higher rates in cancer cells. The problem, Ottensmeier says, is the immune system is taught to ignore what is ‘healthy’ – so boosting the immune system to recognise TAAs could have unintended side effects. For this reason, targeting TAAs makes developing an effective vaccine more difficult.

Over the past seven to eight years, it has become clear that cancer cells are genetically different to healthy cells, which allows cancer to grow and metastasise. Many, but not all, of these genetic abnormalities can be detected by the immune system as ‘foreign’ peptides that are present on cancer cells. These mutant gene products are tumour-specific antigens known as neoepitopes or neoantigens and are only found in cancer and are often unique to individual patients. ‘We can now read the abnormal genes and predict which peptides might be visible to T-cells. The desire is to turn these molecules into cues for T-cells to recognise,’ he says. The result would be a vaccine personalised to target the individual tumour’s neoepitopes.

Most cancer vaccines are still in clinical trials and Ottensmeier says ‘there is currently a bun fight as to who will get a clinically viable vaccine first’. At the end of 2021, Transgene released Phase 1 results for the TG4050 personalised neoepitope vaccine – demonstrating its ability to prime the immune system by inducing a robust anti-tumour cell response against multiple neoantigen targets. No serious adverse events were reported.

Looking ahead, Ottensmeier says: ‘I’m confident vaccines will play a role in cancer treatment with the first ones four or five years away from licence approval.’

Indeed, the University of Arizona Health Sciences, US, expanded a study after releasing positive Phase 1 results in 2020. Sponsored by US biotech Moderna, the trial combined a personalised mRNA vaccine with Keytruda. Five of the 10 patients with head and neck cancer experienced a clinical response and two patients showed no detectable disease after treatment. The 50% preliminary response rate of the combined treatment is notable given that a positive response for Keytruda alone is around just 15%.

This latter statistic highlights the challenge of the checkpoint inhibitor drugs approved in recent years; on average, only about a quarter of patients respond to them. These off-the-shelf drugs work by blocking the cancer’s cloaking mechanism that allows it to evade the immune system. When patients are responders, checkpoint inhibitors can be highly effective.

According to Jill O’Donnell-Tormey, CEO at the Cancer Research Institute (CRI), New York, US, numerous studies are now under way to understand why only some patients respond, making it one of the major areas of current immunotherapy research. The hope is there might be a personalised approach to boost response rates or at least identify those patients who are and aren’t responders.

Biomarker development

One way is by identifying biomarkers. These could include molecular markers such as genetic mutations, expression of certain cell surface proteins such as PD-L1, the density of tumour-infiltrating lymphocytes, or the quantity of mutation-related neoantigens, says Ward. Research into the cellular clocks of tumours – a dysfunction of the circadian clock – could also point to future biomarkers.

Because anti-cancer immune responses vary from patient to patient, personalised biomarkers could potentially determine the likelihood of a particular patient’s tumour responding to immune checkpoint inhibitor treatment or possible toxicity. ‘Development of clinical tests using potential markers will enable a personalised immunotherapy approach for a wide variety of cancers,’ Ward says.

In February 2022, for example, a team from Wake Forest School of Medicine, US, analysed blood samples from two groups of melanoma patients – those who responded to checkpoint inhibitors and those who didn’t. They found the circulating immune cells of patients who responded to treatment had an increased extracellular acidification rate – a measure of glucose metabolism – along with structural changes to cell organelles. Responders also had elevated glucose receptors. The scientists believe these could become potential biomarkers to guide personalised treatment.

It is unlikely, though, that one biomarker will be the catch-all for personalisation – PD-L1 expression, for instance, is ‘not a black and white biomarker [for treatment response] as is the case for many other molecular markers’, says Ward. Instead, a collection of biomarkers taking into account the activity of the patient’s immune system as well as the genetic identity of their tumour is more likely. ‘Ultimately, we would like a set of biomarkers that could be used to predict what immuno-oncology treatments will be effective for any given patient,’ says O’Donnell-Tormey.

Another area of interest for improving checkpoint inhibitor treatment is research into understanding and modulating the gut microbiome, which is unique to each individual and could also act as a biomarker. Studies have already shown a link between the microbiome and response to immunotherapy but the mechanism appears to be complex, says Lee.

She was recently involved in a study investigating whether there is an association between the composition and function of the gut microbiome in patients with melanoma and response to immunotherapy. The results suggested that the presence of three types of bacteria (Bifidobacterium pseudocatenulatum, Roseburia spp. and Akkermansia muciniphila) were associated with a better immune response and that the chances of survival based on healthy microbes nearly doubled between subgroups, but it was a mixed picture and no single species stood out as a consistent biomarker.

The researchers are now trying to identify the specific features of the microbiome that could be exploited for personalised immunotherapy, although Lee notes this will be years away. That said, French biotech firm EverImmune intends to start a Phase 1 trial in Q2 2022 for its live biotherapeutic product Oncobax AK in non-small cell lung cancer and renal cell cancer. Containing the bacteria species Akkermansia, the product would be used as an oral adjuvant to checkpoint inhibitors.

Many believe it’s this sort of combination therapy that will really unlock the potential of immunotherapies and a more personalised approach to cancer treatment. Ottensmeier sees this as the case for vaccines and a recent CRI report noted the number of monotherapy checkpoint inhibitor drug trials was decreasing while the number of combination studies was on the rise. ‘Combinations of immunotherapy with other immunotherapy drugs or other forms of cancer treatment will likely prove more effective than treatment with any one drug alone,’ says O’Donnell-Tormey.

It’s for this reason she believes that not just personalised immunotherapy but personalised treatment plans for cancer will become a reality. This will gain traction as research continues into understanding individual patient response to immunotherapies. ‘Personalisation for me goes beyond using a patient’s own cells or unique tumour mutational targets,’ she says. ‘It also includes immunologically informed treatment plans customised to each patient based on the presence or absence of predictive signals.’ That’s something scientists are working to now identify.