Immunotherapy using checkpoint inhibitors is an emerging cancer treatment that has recently had great success in treating metastatic cancer. The technique works by blocking checkpoint proteins (such as CTLA-4 or PD-1) that stop the patient’s immune system from attacking cancer cells, and reactivating the immune system to fight cancer. Unfortunately, however, only a fraction of patients respond to such immunotherapy and only certain tumour types can be treated.
To increase its potential pool of patients and cancers, immunotherapy can be combined with radiation therapy, which under certain conditions also triggers an immune response. It has also been proposed that charged particles – such as the carbon-ion beams already used clinically to treat certain cancers – could prove more effective than X-rays in this combination.
To investigate this idea further, an international research team headed up at the GSI Helmholtz Centre for Heavy Ion Research has compared the efficacy of carbon-ion radiotherapy and conventional X-ray radiotherapy in combination with checkpoint inhibitors in a mouse bone tumour model. The researchers report their findings in the International Journal of Radiation Oncology, Biology, Physics.
“There are several explanations as to why carbon ions and immunotherapy are a good match,” explains lead author Alexander Helm. “The most prominent is actually the peculiar pattern of cell death that is induced by carbon ions compared with conventional radiotherapy. It is hypothesized that this very cell death is more immunogenic, which will eventually lead to a more efficient activation of the immune response and a better elimination of metastases. These effects, nonetheless, depend on the combination with immunotherapy to boost such immune responses.”
The researchers, also from the Parthenope University of Naples and NIRS-QST in Japan, conducted their experiments at the accelerator in Chiba, Japan. They inoculated mice in both hind legs with osteosarcoma cells, a bone tumour that is generally considered radioresistant. They then treated each mouse with a 10 Gy dose of either carbon ions or X-rays, in combination with two immune checkpoint inhibitors: anti-PD-1 and anti-CTLA-4. Tumours on the animals’ left legs (representing primary tumours) were irradiated, while those on the right legs (abscopal tumours) were kept out of the radiation field.
Tumours that were directly irradiated, with either carbon ions or X-rays, demonstrated reduced growth compared with untreated mice. Tumour growth was better controlled in mice that received irradiation plus immunotherapy than in animals treated with radiotherapy alone, suggesting a synergistic effect likely based on the additional immune response boost by the checkpoint inhibitors.
In mice receiving the combination treatments, growth of the unirradiated abscopal tumours also decreased. This reduced growth was most pronounced when the animals received a combination of carbon ions plus checkpoint inhibitors.
The team also examined the effects of the various treatments on lung metastases, which form spontaneously from the bone tumours in the mice. When combined with immunotherapy, both radiation types essentially suppressed the metastases. As found previously, the combination of carbon ions plus checkpoint inhibitors had the greatest effect, resulting in the least number of metastases.
Carbon-ion irradiation alone also significantly reduced the number of lung metastases compared with the control group, comparable with results in animals that received only checkpoint inhibitors. This was not the case for mice treated with X-rays.
The team concludes that a combination of high-energy carbon-ion radiotherapy and checkpoint inhibitors has the highest potential to control distal metastases in this mouse model and could provide a potential clinical option for treatment of advanced tumours. Corresponding author Marco Durante, director of the department of biophysics at GSI, has previously demonstrated that carbon ions and protons have physical advantages over X-rays that enable drastically improved sparing of healthy tissue during radiotherapy. In fact, charged particles spare circulating immune cells in the blood much more than X-rays, which is necessary for an efficient immune response.
Immunotherapy plus radiotherapy benefits metastatic lung cancer patients
The researchers are now working to discover the mechanisms underlying these immune responses. Understanding these mechanisms should allow them to tailor radiation treatments to increase immune response activation.
“For example, the radiotherapy fractionation scheme has been shown to have a crucial role on the immunogenicity of the induced cell death,” explains Helm. “Hypofractionation, in which higher doses are applied in a shorter time span (than with conventional radiotherapy), has been reported as beneficial – and carbon ions are a perfect match for hypofractionation.”