Immunotherapy – a major breakthrough in cancer treatment

I was first introduced to the cancer immunology field in 2000 during my third-year undergraduate studies. Over a series of six lectures, I was taught that the immune system can recognise cancer cells and that immunotherapy might have the potential to help cancer patients. I really liked this concept. Our immune system protects us against various bacteria, virus and fungal infections, so if cancer is mutated self, why not also protect us against cancer?

However, over the preceding two decades, therapeutic cancer vaccines, which aim to prime and activate a patient’s endogenous tumour-specific T cells, did not demonstrate clinical activity in many cancer types. In addition, adoptive transfer of tumour infiltrating lymphocytes (TILs), while having some efficacy in melanoma, was much less impressive for other solid cancers, due in part to difficulties in isolating tumour-specific T cells for expansion and re-infusion back into patients.

I was taught that the immune system can recognise cancer cells and that immunotherapy might have the potential to help cancer patients.

The scepticism towards cancer immunotherapy at that time was therefore unsurprising. What readers today have to understand is that during this period, very few – including medical oncologists, researchers and pharmaceutical companies – believed that the immune system played any role in cancer control, except perhaps in virus-induced cancers. Instead, the focus remained to develop new therapies that directly targeted tumour cells.

Despite these generally negative sentiments, I was convinced that immunotherapy had great potential, if only we understood how to overcome the different barriers limiting an effective anti-tumour response. Over my career, my research has focused on different strategies to address this problem. My PhD studies were amongst the first to pioneer the development of second-generation chimeric antigen receptor (CAR)-T cells for cancer treatment, which is a strategy to redirect T cells with improved effector function to recognise and kill tumour cells. After my PhD, I broadened my research to investigate the mechanisms of tumour-induced immunosuppression. Using a variety of mouse tumour models, I assessed how various immunoregulatory cell types, immune checkpoint receptors, suppressive metabolites and cytokines suppressed white blood killer T cell anti-tumour responses.

I was interested in the types of tumour microenvironment where immune suppression was operating, and in its hierarchy of dominance. I thought that this would allow us to rationally design therapies to target these pathways. Excitingly, over the last two decades, the clinical success of CAR-T cells and immune checkpoint inhibitors – in particular antibodies reactive with CTLA-4 and PD1/PD-L1 – have led to a renaissance in the immuno-oncology field.

Nevertheless, the field still has much to do. Through clinical impact, we have convinced the oncology field that the immune system is involved in the control and evolution of cancer, and importantly, can be targeted with therapeutic benefit. However, there remains a significant proportion of patients and cancer types that do not respond to currently approved cancer immunotherapies. Strategies that can further improve the efficacy of immunotherapies now represent a major research focus.

I was interested in the types of tumour microenvironment where immune suppression was operating, and in its hierarchy of dominance.

To date, immunotherapies have been used to treat patients with advanced/metastatic cancers. One exciting approach involves giving immune checkpoint inhibitors before cancer surgery to patients with earlier stages of disease. Currently, patients with high-risk resectable cancers (those that can removed by surgery) are given adjuvant therapy after their surgery to lower the risk that their cancer will come back. In 2016, using a mouse model of cancer, my laboratory showed for the first time that scheduling immunotherapy before surgery (neoadjuvant immunotherapy) was more effective in curing mice of their metastases compared to giving immunotherapy after surgery (adjuvant immunotherapy).

Furthermore, our study demonstrated that one of the reasons for the efficacy of neoadjuvant immunotherapy was the rapid expansion of tumour-specific T cells in the blood and primary tumour early after treatment; this level of expansion correlated with long-term survival. Our discovery generated great excitement in the cancer immunology field, and our study was used as a rationale to set up new comparative trials of neoadjuvant and adjuvant immunotherapy in many human cancer types.

Critically, the translatability of our animal research was recently verified in neoadjuvant immunotherapy trials of human melanoma, lung and glioma (tumours of the nervous system), where expansion of tumour-reactive T cells in blood and primary tumour were observed as predicted by our pre-clinical model. Excitingly, even in cancers that generally do not respond to immune checkpoint inhibitors when given in advanced/metastatic settings, for example colorectal cancer, data from early phase clinical trials suggest they may be more effective when given in a neoadjuvant setting to treat earlier stages of disease. Currently, a phase III trial comparing neoadjuvant and adjuvant immunotherapy in high-risk stage III melanoma patients is ongoing. The standard of care for these patients is adjuvant immunotherapy following cancer surgery. If improved recurrence-free survival is observed in the neoadjuvant compared to the adjuvant setting, this will be practice-changing.  

In recognition of my team’s pioneering research into neoadjuvant immunotherapy, I was honoured with the 2021 Australian Academy of Science Jacques Miller award for research of the highest standing in the field of Experimental Biomedicine for a mid-career scientist. My research team’s success was due to the diverse experimental mouse-tumour models we had access to and expertise in.

As I wrote in an opinion piece for the journal Cancer Cell in 2020, I believe mouse models of cancer have significantly advanced cancer research. They represent a critical part of the translational pipeline from “bench to bedside”. In fact, these mouse tumour models played an important role in helping Nobel Prize Laureate Professor Jim Allison demonstrate the therapeutic efficacy of anti-CTLA4 in 1996! These findings encouraged its translation to the clinic before it was FDA-approved for advanced melanoma in 2011.

Unfortunately, in Australia, our ability to perform this type of research is fast disappearing, caused by a rapidly diminishing research investment and significant increases in monitoring, recording and reporting on animal research. Examples include the significant decline in federal and state funding for basic research and the impending closure of the Perth-based Animal Research Centre (ARC) at the end of 2022. The ARC is a main provider of mice and rats to researchers in Australia. Furthermore, a risk-averse culture applied to a tightening Animal Ethics code has resulted in a very significant new burden for researchers using these methods, compared to the past, and much of this extra compliance burden has arisen over the last decade without much rationale or researcher consultation.

I believe mouse models of cancer have significantly advanced cancer research. They represent a critical part of the pipeline from “bench to bedside”.

Medical researchers worldwide are wasting their training and time trying to comply with this ever-expanding, sometimes redundant and misguided “red tape”. I have no problem with industries being compliant with laws, but I do have a problem when the red tape is self-serving and only seems to significantly detract from the aim of benefiting human health. Consequently, researchers are abandoning this part of the translational pipeline, and my personal experience tells me Australia is now in a severe shortage of skilled workers in this area.

This emergent gap is already biting Australian medical research at a time when, more than ever, major funding bodies encourage and advocate translational research with impact for human health. Ironically, this comes at a time when big data being generated by genomics creates many questions that lack the functional proof – which animal modelling could comprehensively provide. The patients’ ability to benefit from advances (bench to bedside) has never been greater. Most sad for me is the job that others and I trained for is no longer a viable career course.

In 2013, Science magazine named cancer immunotherapy as the breakthrough of the year, and since then cancer immunotherapy has become a new pillar of cancer treatment, complementing the other pillars including chemotherapy, surgery, radiotherapy and targeted therapies. With advances in artificial intelligence, engineering capabilities and the coalescence of scientific minds from various disciplines, cancer immunotherapy is entering a golden era. Australian scientists, including my group, have contributed to its renaissance.

However, we cannot continue if Australia does not support its scientists by substantially increasing its investment and reducing regulatory burden. According to a 2020 report from the Committee for Sydney, Australia’s spending on research and development has sunk to 1.79% of GDP, well below the OECD average of 2.37%, and far below world leaders like Israel (4.94%) and South Korea (4.53%).

The Australian medical research sector is in crisis. Our state and federal leaders need to act now to ensure our current and future generations of Australian scientists can continue to make breakthrough discoveries to benefit human health.