For many years, improvements in the medical treatment of cancer have come in small steps, but this is now changing, says Dr Christian Rohlff, CEO of Oxford BioTherapeutics.

This highly selective approach means that normal cells are most likely not affected, resulting in little or no toxic side effects to the patient - a problem commonly encountered with conventional chemotherapeutic agents.

Following a PhD in pharmacology from Georgetown University, Dr Rohlff identified cancer as one of the biggest areas for future research and decided to devote himself to the development of a cure.

Working at the National Cancer Institute in Washington DC was a career-defining period during which he decided to consolidate his work in oncology, having been personally affected by cancer in his family. For the first 20 years of his career, he has witnessed improvements in treatments that have given patients extra weeks or months of life.

"The next decade is likely to be tremendously exciting, as we witness a larger proportion of patients with cancer being cured."

However, in the last five to seven years, new drugs are coming along that can provide benefits measured in years and, in some instances, allow patients to be cured. He describes the next decade as likely to be tremendously exciting as we witness a larger proportion of patients with cancer being cured. He attributes this shift in focus, from disease remission to complete cure, to a greater understanding of the role each individual’s immune system plays in preventing cancer cells from multiplying.

Our immune system protects us from infections and other illnesses, including those involving the abnormal multiplication of groups of cells, i.e. cancer. A compromised immune system has devastating effects, including an increased susceptibility to infections not normally known to cause harm – this is commonly seen in patients with leukemia, multiple myeloma and in the AIDS spectrum of HIV. Dr Rohlff explains that cancers flourish by both suppressing, and hiding from, the immune system.

The immune system includes CD4 and CD8 T lymphocytes and natural killer (NK) cells, which are very important for the body’s defence against pathogens, such as viruses and bacteria, and for tumour surveillance. They have proteins on their surface called checkpoints, which allow them to be turned on or off as needed. Some cancers, however, manipulate this cleverly designed system by using a molecular ‘switch’. By activating these checkpoint receptors and turning the immune cells  off, the cancer effectively ‘hides’ from the patient’s immune system and avoids its destruction by the body’s defenses.

Checkpoint inhibitors are a new class of antibody drug, which attach to the checkpoint receptor, turning the lymphocyte and NK cells back on, so that they can, once again, defend the body against the cancer. In some cases, this will allow the patient to be cured. Checkpoint inhibitors are already in use for some cancers, including blood cancers such as lymphoma and cancers of the lung and kidney.

 

Improving the success of checkpoint inhibitor drugs

 

Current checkpoint inhibitors are generally used at a late stage in treatment, commonly in patients who have either relapsed or not responded to conventional treatment. They usually only work for around one-quarter of patients on whom they are tried. To overcome this, Dr Rohlff is working on a second generation of drugs in this class, which will hopefully be effective for more patients. By activating both T-cells and NK cells, these drugs undertake a two-pronged approach to help the immune system identify and fight the cancer.

One of the benefits of this type of treatment is that the drug will only work on the immune cells that have been switched off by the cancer, and will therefore selectively target the cancer cells that are ‘hidden’ from the immune system. It is very likely that most non-cancerous cells elsewhere in the body won’t be affected and so toxicity should be limited.

This is important, as up to 7.5% of deaths in cancer patients have been attributed to severe side effects rather than the disease itself1 (O’Brien et al, British Journal of Cancer, 2006). A recent study by Public Health England and Cancer Research UK have placed 30-day treatment mortality figures for systemic chemotherapy for breast and lung cancer at 3 in 100 patients (Wallington et al, Lancet Oncology 2016).

Taken together, the benefits of checkpoint inhibitor drugs will hopefully mean that they can be used earlier in the treatment pathway, rather than as a drug of last resort.

 

Checkpoint inhibitor drugs can cost hundreds of thousands

 

Some current checkpoint inhibitor drugs are very expensive (in the hundreds of thousands of pounds) but Dr Rohlff is confident that the new generation will be deliverable at no more than the cost of current cancer therapies. Diagnostic biomarkers based on a number of patient and tumor characteristics are also being developed to identify, in advance, which patients will benefit most. This will further help drive down costs by avoiding treatment in patients for whom the drugs won’t work.

Does this mean that we can start to talk about a cure? It is always difficult to say that a disease is cured when a drug is relatively new – no one has a crystal ball. We do know that there are patients with lymphoma, for whom all other treatments had failed, who are completely free of disease six years after treatment with checkpoint inhibitors. There is every hope that the future outcome will be an effective cure for some types of cancer.

This second generation of checkpoint inhibitors is still at the research and development stage, with initial testing planned for the next three years. The relevant T lymphocytes and NK cells are being extracted from patients so that the drugs can be tested in the lab and compared to current treatments. If all goes well, they should be on the market three to five years after that, so patients could be benefiting well within a decade from now. This is a fast-moving field with the potential for exciting change in the relatively near, and increasingly optimistic, future.

 


1 Reference O’Brien MER, Borthwick A, Rigg A, et al. Mortality within 30 days of chemotherapy: a clinical governance benchmarking issue for oncology patients. British Journal of Cancer. 2006;95(12):1632-1636. doi:10.1038/sj.bjc.6603498. 

2 Source Walligton M, Saxon EB, Bomb M, et al. 30-day mortality after systemic anticancer treatment for breast and lung cancer in England: a population-based, observational study. The lancet oncology, 2016; 17(9): 1203-1216: DOI:10.1016/S1470-2045(16)30383