September is particularly significant to us here at Radyus, as it is cancer awareness month. We want to celebrate some major achievements and acknowledge ongoing frustration in two specific cancer types – lung cancer and glioblastoma.
The scientific world’s understanding and treatment of cancer has undergone a transformation over the past 10 years. We now know that harnessing the immune system to fight cancer, at this point primarily (although not exclusively) through checkpoint inhibitors, is a highly effective strategy. This realization has led to a revolution in the world of cancer, shedding new light on both cancer’s causes and its treatment. Cancer occurs when uncontrolled cell proliferation has avoided detection by the host immune response, flourishes by energizing or escaping the host anti-tumor immune response. Furthermore, all cancer treatments ultimately work by engaging the host immune system to destroy tumors.
Immunotherapy has revolutionized lung cancer treatment:
Lung cancer remains the leading cause of cancer mortality worldwide and was responsible for 1.8 million deaths in 2020 alone. Fortunately, clinicians who treat lung cancer have benefited hugely from the tumor immunology revolution. It is no longer the case that cytotoxic chemotherapy is the dominant treatment option – the advent of checkpoint blockade in lung cancer has changed the paradigm. Biologics that block PD-1 signalling have unambiguously contributed to improved overall survival and have multiple benefits over chemotherapy – a better side effect profile and an improved quality of life. However, checkpoint inhibitors do not work in a large fraction of patients and to address this deficiency, biomarkers that can identify responding patients are under investigation. What is perhaps particularly encouraging is that we are still learning which checkpoint pathways are most important since research continues to uncover other targets beyond the Programmed Death 1 (PD-1) axis. We predict that modulating these other immunoregulatory receptors will also provide clinical benefit. So, were you to be diagnosed with lung cancer, you can rest assured that the care you receive now is far better than it was even 5 years ago.
Immunotherapy is struggling with brain cancer:
Glioblastoma (GBM) is the most aggressive form of brain tumor. Unfortunately, despite extensive research, GBM remains challenging to treat. GBM is problematic for many reasons, but an important one is the blood-brain barrier (BBB) which makes it difficult for cancer treatments to get into the brain and reach their tumor target. Another challenge for GBM treatment is the brain itself. When removing brain tumors, neurosurgeons have to make the unenviable call of how much tissue to take without causing permanent disability – increasing the chances of cancerous cells being left behind. Finally, as the brain is an immune privileged organ, under normal circumstances it is immunologically quiet, creating a substantial hurdle for tumor immunologists.
As might be expected, GBM has a poor prognosis. Tragically, more than two-thirds of adults diagnosed with the condition pass away within the first two years. Checkpoint blockade initially demonstrated encouraging results, but a recent large Phase III trial revealed that monotherapy with nivolumab is no better than anti-angiogenic therapy in recurrent GBM. Nevertheless, one failed Phase III result of single agent PD-1 blockade does not mean that immunotherapy has no role to play. Multiple different immune strategies are being tested in addition to checkpoint blockade, including peptide and dendritic cell vaccines, adoptive T cell therapies, and various types of oncolytic viruses. Given a dismal history, the road ahead in GBM is filled with detours, blind alleys and blockades. However, given the relative infancy of immunotherapies in this awful disease, there is reason to believe that continued experimentation will yield limited successes. Unfortunately, cure is still likely to be far in the future.
What lies ahead:
Although the war against cancer is far from over, we have won some crucially important battles over the past decade resulting in no small part due to novel immunotherapies. With lung cancer as a beacon of hope, we can appreciate progress and work towards further improvement. However, with GBM as a reminder of intractable disease, the war continues. Now, with multiple new immune weapons at our disposal, we at Radyus continue to endeavor to identify and progress innovative cancer therapies toward clinical evaluation through our diverse pre-clinical contract research platform. Consequently, we are confident that biomedical research will continue to make progress. Indeed, given the response to the SARS-Cov-2 pandemic, we tend to agree with a recent tee-shirt worn by a colleague in the battle against cancer: science will win. We only wish the victory would come sooner.