Date: 16th April 2021
Malignant pleural mesothelioma (MPM) is an intractable, aggressive form of cancer, with an extremely poor prognosis, and is most frequently a result of inhaling asbestos. With the majority of patients dying between six and 18 months after diagnosis, treatment options are limited although, the best outcomes have been achieved by combining different treatment modalities. Now, researchers show that subablative radiotherapy (RT) combined with two immunotherapy drugs conferred long-lasting control and resistance against mesothelioma, and that further surgery to remove the remaining tumour improved response rates yet further.
From 1994-2008 there were 92,253 mesothelioma deaths recorded in the WHO mortality database of which >40% were pleura, which is the most common form. There is a great unmet clinical need for better treatments for MPM, and the long latency period of ~40 years between asbestos exposure and disease presentation coupled with its aggressive nature, results in poor prognosis.
Now, researchers led by Marc de Perrot at the Princess Margaret Cancer Centre, University of Toronto, and Toronto General Hospital Research Institute, Canada, have used a triple-modality therapy, combining an interleukin-15 (IL-15) superagonist (IL-15SA) and glucocorticoid-induced tumor necrosis factor receptor–related protein (GITR) agonist (DTA-1) with subablative RT in a mouse model of mesothelioma, to maximise antitumour responses and which generates a long-lasting in situ vaccination.
Subablative RT has already been shown to render tumour microenvironments into a more immunogenic ones, by the release of tumour-specific antigens that lead to the initiation of an anti-tumoural immune response, increasing regulatory T (Treg) cells. Together with surgery, the team had previously shown that there was a systemic anti-tumoral immune response and a generation of a long-lasting in situ vaccination in mice. However, now they wanted to explore the additional effects of immunotherapy – could it be used to optimise and enhance the immune response?
The scientists treated preclinical mouse mesothelioma models with well-tolerated, short-course radiation (consisting of three days of treatments over one week), then they administered two immunotherapy drugs. IL-15SA, a superagonist which stimulated the differentiation and proliferation of natural killer (NK) cells, NKT cells, and memory CD8+ T cells, and DTA-1, an agonist which selectively depleted intratumoral Treg cells.
The team found that the combination treatment enhanced infiltration of CD8+ T cells and decreased infiltration of Treg cells into tumours after local radiation (LRT). This was driven by a systemic antitumoral CD8+ T cell response. Tumour growth was retarded, and in 40% of the cohort a complete tumour rejection was observed.
They also observed an increased abscopal effect – this occurs on treatment of metastatic cancer whereby shrinkage of untreated tumours occurs concurrently with shrinkage of tumours within the scope of the localised treatment. Here secondary tumours away from the radiation site were also monitored, after the triple-therapy and surgical resection of the primary tumour was performed. This led to a reduction of secondary tumour growth and extended the survival of these animals.
Importantly, the anti-tumour immune response was shown to be robust. Re-injection of tumour cells, into the preclinical models up to 12 weeks after the triple-therapy and surgery, conferred long-lasting immunity against the cancer.
Finally, the team confirm a therapeutic benefit of the combination therapy on intrathoracic mesothelioma model. Although no complete rejection of tumours was seen, prolonged survival did occur.
Conclusions and future applications
The work here provides strong evidence that triple combination therapy for the treatment of mesothelioma is an effective treatment, prolonging survival, reducing tumour growth, and in some cases enabling tumour rejection. The increased ‘memory effect’ of the T-cells in the immune system effectively acted as a cancer vaccine, providing long-term protection for months possibly years after treatment.
By combining three complementary treatments the strategy takes advantage of each one, while limiting the toxicity of each. It offers a new paradigm in cancer treatment that can potentially cure even late-stage cancer.
The team are now looking to develop the combination therapy for clinical trials in MPM, and other advanced malignancies. It may also open avenues for more radical treatment options for other patients with metastatic or locally advanced cancer if amenable to surgery.
Aggressive cancers often have poor prognosis and therefore, there is great demand for new and alternative technologies to fight these diseases. We recently reported the development of a novel ionic liquid which functioned as a drug carrier to treat aggressive liver cancer. Such technologies may be adapted to carry immunotherapies, which may yet further increase efficacy in studies such as we’ve seen here. We have also seen the development of machine learning models that accurately predicts how combinations of different cancer drugs kill various types of cancer cells. Leveraging this type of technology to determine the best drug combination in addition to local radiation and surgery may provide a very powerful tool in preclinical research of aggressive cancer in the future.
For more information please see the press release from University Health Network
Murakami, J., L. Wu, M. Kohno, M.-L. Chan, Y. Zhao, Z. Yun, B. C. J. Cho and M. de Perrot (2021). “Triple-modality therapy maximizes antitumor immune responses in a mouse model of mesothelioma.” Science Translational Medicine 13(589): eabd9882.
https://doi.org/10.1126/scitranslmed.abd9882
