Combination therapies are fast becoming the holy grail of immuno-oncology research and development. The past couple of years in immunotherapy have been characterised by a growing excitement in the possibilities of combination therapies for improved patient response to cancer treatment. With hundreds of combination trials starting each year, many industry leaders have increased their investments into combination strategies. It is also expected that this acceleration will soon deliver a barrage of data for advancing translational immuno-oncology. So, what is the rationale behind combination therapies and how they can improve patient response? And why is there the need for a robust body of biomarkers to make combination treatments safer?
Combination Therapies: The Rationale
Immuno-oncology therapies harness the body’s natural ability to identify, target, and destroy cancer cells. Combined immuno-oncology therapies aim to kick-start immune response, decrease immunosuppression, and target signalling and resistance pathways. According to Patrick Kaminker, Director of Translational Biology at Macrogenics, “the rationale behind combination therapy is an exciting area of the immunotherapy field”. Combination therapies offer a longer-lasting treatment option compared to traditional therapies that are based upon the patient’s tumour type such as chemotherapy, surgery, or radiation. While immunotherapy agents can be effective as a monotherapy option, they do not always work. Chief Executive Officer at Amcure, Klaus Dembowsky, even points out that “while there are some tumours that react very well, there is a large number of cancers that do not respond at all”. Owing to innate and adaptive resistance mechanisms in the body, cancer can easily evade this singular treatment strategy.
Combination therapies have the potential to reach a wider range of patients. These act synergistically, with either immunotherapy agents being paired with conventional cancer treatments such as targeted therapy and radiotherapy, or by pairing two immunotherapy treatments together. Combination therapies possess the complementary effects of more than one cancer treatment, which essentially provides a doubly powerful means of defence against an immune system attack. Approved combinations include T-Cell therapy combinations, combinations of nivolumab and ipilimumab drugs to treat liver cancer, and then chemotherapy paired with both nivolumab and ipilimumab.
Despite the rapid growth forecast, there are still a few factors restricting the field. Mahendra Deonarain, Chief Executive and Science Officer of Antikor states that “a contentious area right now is whether people can actually afford combination therapies”. Combination therapies are a lot more expensive than traditional monotherapy treatments. A single immunotherapy drug can cost over $100,000 per year, which means the cost for combining more than one is considerably elevated. Deonarain asks “what happens when you’re using expensive ADCs and checkpoint inhibitors?”. “These treatments can be a huge financial burden for healthcare systems”, he continues. In addition to this, widespread use of combination therapies requires a complex trial design, which likewise increases the price.
The Safety and Efficacy
While the promise of combination therapies is evident, their safety remains questionable. The large amount of research devoted to these strategies has uncovered some worrying findings. Toxicity is a considerable problem, particularly in certain combinations of checkpoint inhibitors. The dual pharmacological potency of combination therapies can in fact cause adverse side effects for the function and formation of the immune system. In 2018, a meta-analysis study conducted by the World Health Organization found that combining the immune checkpoint inhibitors anti PD-1 and PD-L1 with anti-CTLA-4, resulted in high numbers of toxic reactions that were fatal. Therefore, the accumulation of too much therapeutic substance in the bloodstream or undergoing several invasive treatments can sometimes be counteractive.
Taking the Lead: Predictive Biomarkers for Improved Patient Response
To accelerate and advance the efficacy of immuno-oncology therapies, the industry is turning its attention to the assurance of predictive biomarkers. The need for improved biomarkers is especially important in combination immunotherapy, given its higher cost and questionable efficacy. Predictive biomarkers identify whether a patient will be likely to experience either a favourable or unfavourable response to treatment. They work by identifying the presence or upregulation of a certain protein found on the tumour cells, which will either correlate a successful or unsuccessful immune response. This has the potential to unlock a much safer approach to combination therapies and the powerful pharmacological effects that they harness.
The identification and development of significant predictive biomarkers are also paving the way for more effective means of precision immuno-therapy treatment. Biomarkers enable specifically tailored treatments for individual patients. This offers a vital solution to preventing the dangerous levels of toxicity associated with some combination therapies. “By taking a more selective approach to combined administration you reduce the risk of immunotoxicity” explains Dinesh Chandra, Associate Principal Scientist, Immuno-oncology at AstraZeneca. As the intricate complexities of the immune system and its response to cancer varies from patient to patient, predictive biomarkers deliver actionable and indispensable information for the improved efficacy and safety of combination immuno-oncology. We, at Oxford Global, believe that by streamlining the amalgamation of these two key approaches, patient response rates will significantly improve, and the field of immuno-oncology will go from strength to strength.