Over the past decade immunotherapy has become a game changer in oncology; from ipilimumab improving survival and delay disease progression in advanced melanoma patients to the recent approval of the PARP inhibitor olaparib for BRCA breast cancer. Despite this success, it is only effective and/or available to a small percentage of patients. There are still many hurdles to overcome in order to make this revolutionary treatment modality available to a greater number of patients.
Efficacy is often unpredictable
So far we have observed dramatic effects in some patients treated with cancer immunotherapies. However, many of these immunotherapies have only exhibited efficacy in a select group of cancers and often in a minority of patients with those cancers.
Earlier in the year we explored the biology behind variations in immunotherapy; evaluated whether efficacy can be enhanced by reprogramming tumor blood vessels and highlighted research from AACR demonstrating the important role that immune cells in the microenvironment play in how patients respond to immunotherapy.
The heterogeneity of tumors impedes efficacy
Tumor tissue exhibits a high degree of intratumoral heterogeneity, making it difficult for the immune system to launch an effective attack. To explore this issue we spoke with Greg Hannon, who has likened tumors to an ecosystem and who recently won £20 million from Cancer Research UK to embark on a ground-breaking project to create virtual reality maps of tumors.
From this project the team hope to visualize the behaviour, location and characteristics of tumour cells simultaneously, to help us understand more about tumours and begin to answer questions that have eluded cancer scientists for years. Read the full interview here.
Resistance development to treatment
The challenge of resistance is closely related to tumor heterogeneity. Cancer signaling networks are remarkably flexible and adaptive, so resistance is likely to develop to any single-targeted cancer treatment. With this in mind, repeated biopsies at progression are required to determine resistant mechanisms and their potential targeted inhibition. However, biopsies are not always feasible in the clinic. Liquid biopsies are a more practical option and are leading the way in resistance-research settings [1, 2].
Recently a major advancement was made in this research area when a team of scientists took a major step towards one of the hottest goals in cancer research; a blood test that can detect tumors early. The test termed CancerSEEK, screens for eight common cancer types and helps identify the location of the tumor. The median overall sensitivity of the test – the ability to find cancer – was 70%. You can find out more details of this exciting story here.
It is difficult to identify clinically-significant biomarkers
A major roadblock in the effort to develop more efficacious immunotherapies is the lack of many known targetable tumor-specific antigens. Tumor-specific antigens also known as neoantigens, are solely expressed by tumor cells, this level of high specificity therefore should enhance both efficacy and safety .
In our online symposium, Roy S. Herbst, Yale University (CT, USA) highlighted this challenge in his talk titled Personalizing immunotherapy – the development of new biomarkers for predicting response. You can watch the full talk, along with several others addressing key areas in immuno-oncology here.
More predictive biomarkers are needed
Over the last decade, there has been a sharp increase in the number of both prognostic and predictive biomarkers in the research setting, however, only a few of these biomarkers have moved into widespread clinical use. To identify a new biomarker that will have either a predictive or prognostic value is a time consuming and complicated process .
These obstacles are highlighted in this free to access (via Oncology Central) review article from Biomarkers in Medicine titled Promises and challenges of predictive tissue biomarkers, which examines issues concerning tissue-biomarker development and the hurdles faced in reaching the goal of truly personalized medicine.
Distinct clinical designs are required
Cancer immunotherapies can often exhibit delayed antitumor activities meaning that traditional endpoints utilized in clinical trials could be inadequate in determining their efficacy. Therefore, adaptive clinical trial designs are needed.
There is a further issue when developing immunotherapy clinical trials for rare cancers, as when positive results are observed in early clinical trials, they must usually be confirmed in Phase III, randomized clinical trials to generate the data that must be submitted for FDA review and approval. To explore how this issue is being tackled, we spoke with investigators leading the way in the DART trial, a dual-immunotherapy basket trial designed for rare tumors. Find out more here.
Immuno-oncology drugs are expensive
Despite immunotherapy drugs becoming a game changer in oncology, the agents are very expensive and the effects of these costs on the health care system need to be considered carefully. This issue was highlighted in an interview we recently conducted appraising immunotherapy for high-risk neuroblastoma patients.
Juliet Gray explained: “The main immediate obstacle is the cost. Dinutuximab beta, like many new cancer drugs, is very expensive, and will need approval by the National Institute for Health and Care Excellence (NICE). It will need to be shown that the antibody not only offers clinical benefit to children, but also that it offers value for money to the NHS. Without this approval, it will not be possible to continue to provide the antibody to children in the UK with neuroblastoma.”
C. Lee Ventola Cancer immunotherapy, Part 3: Challenges and future trends Pharm. Ther. 42(8) 514–521 (2017).
[Zugazagoitia J, Guedes C, Ponce S, Ferrer I, Molina-Pinelo S, Paz-Ares L Current challenges in cancer treatment Clin. Ther. 38(7) 1551–1566 (2016).
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