Immunotherapy Response Prediction in Urothelial Cancer
While immunotherapy holds great promise for cancer treatment, challenges persist around limited response rate and severe immune-related adverse events.
We caught up with Dr. Georg Lautscham, CEO of Protagen, following the announcement of a new collaboration with the National Center for Tumor Diseases (NCT) Heidelberg.
Together, Protagen and NCT are working to improve the prediction of immunotherapy response in people with urothelial cancer.
Immunotherapy is the most promising approach to cancer treatment since the use of targeted therapies. A broad range of immunotherapeutic strategies, including immune checkpoint inhibitors, are already on the market, but numerous others are under active clinical development.
Can you give us an overview of checkpoint inhibitor therapy and drug-related toxicities that some people experience?
While these therapies are proving to be highly effective in some groups, it is now clear that many patients do not respond to treatment or suffer from inflammatory side effects known as immune-related adverse events (irAEs). IrAEs can range from non-life-threatening conditions such as skin rash, through to more severe, life-threatening ones involving the endocrine glands, joints, liver, lungs and other organs, resulting in the potential termination of treatment. In some cases, fatal irAEs have been reported. However, as few standardized diagnostic criteria for irAEs currently exist, concerns have been raised that their incidence is underestimated.
Such irAEs are most prominent with checkpoint inhibitor therapies, owing to their mechanism of action and their widespread use. Immune checkpoints act as negative immune regulators of autoreactive T cells – in essence, acting as ‘brakes’ – that prevent autoimmunity. However, once these checkpoints are inhibited and these brakes are removed, the activated T cells can cause an overstimulation of the immune system, resulting not only in beneficial anti-cancer effects but also in an autoimmune response that can trigger irAEs.
Not only have irAEs been known to put a stop to the clinical development of some drugs, they have also slowed the progress of new therapies in earlier stage cancer patients. Once severe irAEs are encountered, patients often decide (or are required) to discontinue their clinical trial participation or treatment. In some cases, regulatory bodies such as the US Food and Drug Administration have intervened to halt trials, even when promising results were observed.
Can you tell us about Protagen’s Cancer Immunotherapy Array? What is it and how does it work?Cancer immunotherapies, such as checkpoint inhibitors, are aiming to reactivate a patient’s immune system rather than targeting the tumor directly. Any biomarkers that address the main challenges in this field – response and irAE prediction – need to reflect this approach. Thus, detailed analysis of patients’ immune systems holds the key to understanding the biology of irAEs and predicting therapeutic response. Protagen firmly believes that tools based on autoantibodies will have an important role to play in analyzing a patient’s immune status or competence and establishing a risk/response profile that can support clinical development programs.
Protagen is uniquely positioned as an autoimmune and immuno-oncology specialist to develop precision diagnostic tools, and our Cancer Immunotherapy Array is designed to detect autoantibodies to enable the prediction of irAEs in patients undergoing cancer immunotherapy. We have also identified autoantibodies that can predict treatment response and overall survival for cancer patients undergoing immunotherapy – all using a single drop of patient blood.
The Cancer Immunotherapy Array is supported by more than 25,000 patient samples, including over 10,000 autoimmune disease samples as well as healthy controls, and has been tested by international experts. We have screened more than 4,000 samples across multiple cancer indications from patients receiving cancer immunotherapies, including checkpoint inhibitor therapies such as pembrolizumab, nivolumab, avelumab and ipilimumab, as well as therapeutic vaccines and various combination therapies.
Consisting of 850 antigens, the array has been developed together with Protagen's collaboration partners. With the option to tailor to specific indications, pathways or modes of actions, for example, it provides flexibility and single data point quality that is almost comparable to single marker assays. By coating beads with individual proteins, we can compile a bead set of up to 500 different bead colours. Batch sizes allow us to analyze up to 2,000 samples in one batch and our whole process is, as far as possible, automated. In addition, QC measures are in place to limit batch-to-batch variability and account for it, should that be required.
Why did you choose this particular group (people with urothelial carcinoma) for the current study?Protagen’s Cancer Immunotherapy Array was compiled to enable the analysis of a broad range of cancer indications. While we have already demonstrated its potential in malignant melanoma and prostate cancer patients, our next step is to explore other indications where cancer immunotherapies have been successful, but also face significant response and toxicity challenges.
Urothelial cancer is the most common form of bladder cancer, with around 81,000 new diagnoses expected during 2018 in the US alone, according to the American Cancer Society. In urothelial carcinoma especially, checkpoint inhibitor therapies can be successful in a subset of patients, however other subsets suffer from irAEs.
Protagen and our collaborators at the NCT Heidelberg, led by Prof. Grüllich, are working to understand better which patients with urothelial carcinoma are likely to respond to treatment and/or suffer from irAEs. The Cancer Immunotherapy Array will enable us to establish an immune-profile for each patient so we can assess their immuno-competence and help the team at the NCT Heidelberg treat their cancer more effectively. Our most recent phase of collaboration focusing on patients with urothelial carcinoma will study an extra, commercially available check-point inhibitor, in addition to the four we have already studied in different settings. This will involve implementing our cancer immunotherapy array to provide autoantibody data on 850 antigens.
What information is currently used to predict which patients are likely to a) respond well to checkpoint inhibitor therapy and b) which patients are likely to experience immune-related adverse events?To date, predicting treatment response for patients undergoing checkpoint inhibitor therapy has been largely limited to tumor-cell PD-L1 expression and/or tumor mutational burden assessment. Despite some promising data, these approaches have proven insufficient in the majority of indications, however, and are constrained in their practical application because tumor excision and/or biopsy is required. Historically, the field of irAE prediction has been largely neglected, but its importance is gaining recognition as the development of cancer immuno-herapies increasingly focuses on earlier stage cancer patients and irAEs become a growing concern for regulatory bodies.
For this reason, Protagen’s Cancer Immunotherapy Array has been designed to predict both the onset of irAEs and overall survival by screening for autoantibodies using a single drop of patient blood, which also enables repeated testing not just before the onset of therapy but also monitoring of patients during treatment.
How do you plan to assess the suitability of this array for predicting immunotherapy response?Protagen is privileged to be able to assess the suitability of our Cancer Immunotherapy Array technology for predicting immunotherapy response across different cancer indications as part of an international program of collaborative studies with experts from the NCI, NCT, Gustave Roussy, UCSF, and the NEC Laboratories Europe, amongst others.
Due to these collaborations involving significant patient cohorts across various indications treated with different immunotherapies, we can provide a broad overview of patient profiles to understand what differentiates a good from a bad responder and/or a patient likely to experience an irAE from one that will not suffer from an irAE.
What would an ‘immune profile’ look like, and what information could be extracted from it?Protagen is developing autoantibody-based biomarker panels, so called signatures, which will be indication specific and also offer mode-of-action specific biomarkers. Thus, the analysis of a set of autoantibodies will support clinical decision-making by providing insight into a patient’s immuno-competence. This information will inform healthcare professionals about how likely it is that a patient will respond favourably to a specific treatment or will suffer from an irAE while receiving such treatment.
Ultimately, we are addressing two main challenges with autoantibodies in immuno-oncology: response prediction and irAE prediction. We are exploring these challenges across different indications, such as melanoma and urothelial carcinoma to name but two, and with different immunotherapies, with a strong focus on checkpoint inhibitors. For each of these areas of interest, only a small set of biomarkers or autoantibodies are likely to be relevant and for some aspects these markers may be overlapping.
Dr. Georg Lautscham was speaking with Dr. Michele Wilson, Science Writer for Technology Networks.