Currently, healthcare systems worldwide are pushed to capacity, staff and resources are being redirected to COVID-19 efforts, and operating theatres among other spaces are becoming makeshift intensive care units to ventilate those suffering the more severe effects of the novel coronavirus. Many people living with cancer may be facing the possibility of delayed treatment, surgery and a worsened prognosis (BBC News, 2020; Gardner, 2020). People living with cancer also have lower immunity than the general population and will need to take extra precautions during this time (Cancer Research UK, 2020).
Encouragingly, however, there have also been some relatively recent developments in cancer therapy, some of which may contribute to a larger reframing of the way we think about treating cancer. Though still less common than surgery, chemotherapy or radiation, immunotherapies are attracting increasing interest, making use of the patient's own immune system to fight the patient's cancer. Some immune therapy developments including those novel agents that are agnostic to disease type will be explored here.
CAR-T therapy
One such therapy, first offered to patients in the UK in early 2019, is chimeric antigen receptor T-cell (CAR-T). CAR-T forms part of a newer class of medicines called advanced therapy medicinal products (ATMPs).
During CAR-T, T-cells are removed from the patient's blood via a process called leukapheresis, separated from other white blood cells, and sent to the manufacturer's laboratory to be genetically modified by adding CAR to them over a period of weeks, before being reinfused back into the patient once the new CAR-T cells have the ability to seek out and destroy the patient's exact type of cancer cells (Chappell, 2020; NHS, 2020). However, it is possible that patients may need to undergo some chemotherapy prior to having the blood reinfused, to cut down on other types of immune cells to clear the way for the CAR-T cells to multiply and attack (Martin, 2020).
Despite it being early days, one of the most encouraging aspects of CAR-T is that it results in positive disease responses in patients who previously had no treatment options (Chappell, 2020). It is developed for each individual patient, reprogramming their immune cells to target their cancer (NHS, 2020). The NHS (2020) notes that it is potentially risky but has been shown in trials to ‘cure’ some patients, some with advanced cancers where other treatments failed. They can, however, cause severe side effects in some patients, including high fever, severe low blood pressure, confusion, headaches, seizures, weakened immunity, low blood cell counts and severe infections (Martin, 2020).
The NHS is currently providing CAR-T therapies for the following patient groups (NHS, 2020):
- Children and young people (up to age 25) with B-cell acute lymphoblastic leukaemia
- Adults in England with relapsed or refractory diffuse large B-cell lymphoma and primary mediastinal B-cell lymphoma after two or more systemic therapies.
Tumour-agnostic drugs
One of the ways in which cancer takes advantage of a person's immune system is by turning on and off its molecular brakes or ‘checkpoints’, which distinguish between your own cells and foreign cells (Martin, 2020). Some novel drugs called immune checkpoint inhibitors release the brakes so that the immune system can continue to effectively do its job, and attack the cancer cells (Martin, 2020).
Pembrolizumab targets and blocks the PD-1 protein on the surface of T-cells, triggering the T-cells to locate and destroy the cancer cells (Cancer Research UK, 2019a). Nivolumab blocks a protein that stops the immune system from functioning effectively (Cancer Research UK, 2019b). Both drugs were approved for specific cancer types but it has since become clear that patients with a higher number of mutations, regardless of cancer type, benefit the most from these drugs (Gray, 2020).
Clinical senior lecturer, Matthew Krebs, from the University of Manchester, who was quoted by the Pharmaceutical Journal, notes that when pembrolizumab was approved by the US Food and Drug Administration in 2017, this was the first example of a drug approved that was not ‘agnostic’ to the type of disease, but rather based on a molecular finding (Gray, 2020). This has paved the way for the possibility of targeted drugs for all cancers with a particular biomarker, regardless of where in the body the tissue originates (Gray, 2020). However, because all biomarkers are still unknown, it is unclear why this isn't always the case, such as in the case of BRAF inhibitors, which are effective for patients with melanoma with a BRAF mutation but not in patients with colorectal cancer with the identical mutation (Gray, 2020).
The success and potential of pembrolizumab and nivolumab has prompted further research into similar agents. Late last year, larotrectinib became the first medicine developed specifically to target a mutation rather than a tumour type to be licensed for use in Europe and is currently being assessed in the UK by the National Institute for Health and Care Excellence (NICE), with a decision expected by 27 May 2020. This drug, together with entrectinib (also currently being assessed by NICE) are the newest examples of tumour-agnostic therapies for cancer and both specifically target the neurotrophic tyrosine receptor kinase (NTRK) fusion mutation, which can lead to abnormal proteins that may cause the growth of cancer cells, regardless of tumour type (Gray, 2020).
Both of these drugs received accelerated approval by the FDA for use in patients with solid tumours that harbour this mutation but early draft guidance suggests that NICE has found it too expensive to approve on the NHS (Gray, 2020). There are several theories, beyond its cost alone, for why this might be – for example, NICE uses clinical trials to assess drugs; this being a novel option that cannot be organised by tumour type makes it difficult to assess by traditional means and will be more reliant on genetic testing and genomic sequencing and technologies (Gray, 2020). Encouragingly, this will allow for these and other forms of more personalised treatments and interventions in the future (Mendes, 2019).
