June 15, 2018 (Vol. 38, No. 12)

Protagen Believes Immuno-Oncology Must Predict and Minimize Immune-Related Adverse Events

Immunotherapy represents the most promising approach to cancer treatment since the advent of targeted therapies. The goal of any immunotherapeutic drug is to boost the body’s immune response to fight cancer. Examples of this type of treatment include immune checkpoint inhibition (ICI), which releases the “brakes” tumors apply on the immune system; chimeric antigen receptor (CAR) T-cell therapy, which directs T cells to tumor antigens; cytokine immunotherapy, which activates signaling pathways that heighten the immune response; and therapeutic cancer vaccines, which help the immune system recognize and destroy cancer cells.

Many novel immunotherapeutic drugs and combination therapies are in development and responsible for an explosion of clinical trial numbers—far beyond 1000. Today, multiple ICI therapies have received marketing authorization, with an entire generation of novel therapeutics due to reach the market over the next few years. A recent report has estimated that the value of the global market for cancer immunotherapy will rise to $75.8 billion by 2022.1

Although immunotherapies are highly effective in some patients, many patients do not respond to treatment or suffer from inflammatory side effects known as immune-related adverse events (irAEs). These toxicities frequently lead to the discontinuation of treatment and sometimes cause severe damage to the patient. The future development of effective and safe therapies will, therefore, rely on our ability to predict and minimize these irAEs.

Upsetting the Immune Balance

The incidence of irAEs is known to compromise clinical drug development, as well as jeopardize the use of cancer immunotherapies within the marketplace. In clinical trials, patients may decide—or be required—to discontinue their participation, and (as observed recently) regulatory bodies may intervene and halt trials due to such irAEs, even when anticancer effects are observed.2 Generally, patients may miss experiencing immunotherapy’s benefits while still risking severe toxicities—and the loss of valuable time that could have been devoted to an alternative and potentially better therapy.

Today, irAEs are largely associated with ICI therapies and arise by virtue of ICI mechanisms of action. The physiological role of immune checkpoints, such as CTLA-4 and PD1/PD-L1, is to act as negative immune regulators (brakes) of autoreactive T cells, resulting in immune tolerance and the prevention of autoimmunity. However, once checkpoints are blocked, and these brakes released, the resulting activated T cells can cause an overstimulation of the immune system, leading to a widespread inflammatory autoimmune response. It is also worth mentioning that patients with a history of serious autoimmune disease are typically excluded from immuno-oncology trials, based on these patients’ increased risk of toxicities.3

irAEs can range in severity from non-life-threatening conditions, such as skin rash, to more serious complications involving the joints, endocrine glands, lungs, liver, and other organs. Because there are currently few standardized diagnostic criteria for irAEs, there is a concern that their incidences are underreported, making it difficult to assess the impact they may have on patients.

Although some of these irAEs can be resolved with additional medication, some patients may experience long-term irreversible effects that require continuing management. Indeed, in some cases, the immunotherapy necessitates the actual removal of an organ. For example, if ICI treatment with CTLA-4 induces severe colitis, a colectomy made become necessary.4 Even fatal irAEs have been reported, including high-grade liver toxicities.5

Clearly, it would be of great benefit to patients if their risk profiles could be assessed before—and monitored during—treatment, to help clinicians make informed decisions about the appearance and severity of irAEs, so that alternative treatment choices could be selected and irAEs could be avoided or managed.

What’s on the Horizon?

Combinations of immunotherapies are currently seen as the viable option for improving therapeutic efficacy, and the first reported results are very promising. The downside, though, is that such regimens often come at the price of increased toxicity, causing more severe irAEs. Helissey et al. found that when ipilimumab and nivolumab checkpoint inhibitors were co-administered, the rate at which grade 3 or 4 toxicities were observed was 55%.6

Given these challenges, the Society for Immunotherapy of Cancer has recently emphasized the need for research to investigate baseline biomarkers as predictors of clinical response and adverse events.7 Yet, the wide spectrum of irAEs and the complexity of the immune system make the discovery and development of biomarkers for irAEs very challenging. Significant steps, however, have been made through an improved understanding of the key pathways involved in this process.

Figure 1. Several autoantibodies are differentially expressed in patients who develop irAEs (A) compared to those who do not (B), demonstrating the role autoantibodies can play in confirming and predicting the incidence of irAEs.

True Patient Immuno-Profiling

Due to their inherent role in the immune response, autoantibodies constitute one class of biomarker that is especially promising when it comes to the prediction of irAEs and the generation of risk profiles for patients. Simply put, autoantibodies are antibodies produced by B cells that are geared against the body’s proteins and tissues.

Autoantibodies can be found in two clinically and immunologically opposing diseases: autoimmune disorders and cancer. Often referred to as antitumor antibodies, they are implicated heavily in cancer immunity and are deployed against cancerous cells for immune recognition and destruction via different mechanisms. Autoantibody effects can be mediated by natural killer cells or by the complement-mediated destruction of tumor cells.

Since B-cell responses and their autoantibody products may be directed against the same antigens as tumor-specific T cells, autoantibodies represent a unique opportunity to serve as circulating biomarkers of the baseline immunocompetence of cancer patients. Indeed, in the case of the tumor antigen NY-ESO-1, both a T-cell response and anti-NY-ESO-1 autoantibodies can be found in cancer patients.8 Further evidence was provided in a large proteomic study that compared a cohort that developed severe irAEs with one that did not, and that also revealed 129 immunoglobulin G autoantibodies that were significantly different in the pretreatment sera.9

In a recent study conducted in collaboration with the U.S. National Cancer Institute, Protagen (Dortmund, Germany) assessed autoantibody profiles as candidate biomarkers for ICI-based immunotherapies in serum samples of metastatic castration-resistant prostate cancer (mCRPC) patients. The study showed that several autoantibodies are differentially expressed in mCRPC patients who developed irAEs compared to those who did not (Figures 1A & 1B). Elevated autoantibody levels were found in pretreatment samples, suggesting that patients who later develop irAEs may have a certain level of subclinical or unrecognized autoimmunity, which is unleashed by checkpoint inhibitors. It is also worth noting that autoantibodies that predict the occurrence of irAEs differ biologically from autoantibodies that predict the absence of irAEs (Figure 2).

Figure 2. Autoantibodies expressed by subjects who experience an irAE versus those who do not were implicated in different molecular pathways. In subjects who did not develop irAEs, the autoantibodies targeted proteins that played a role in immune response pathways. For those who did have irAEs, autoantibodies were expressed that target proteins that are involved in a number of cancer-development pathways (cell cycle and cell death pathways, for example).


Currently, cancer immunotherapy works only in a subset of patients—some patients develop resistance to therapy, whereas others experience cures. Cancer immunotherapy can also cause severe, life-threatening side effects (irAEs), particularly in the case of checkpoint inhibitors. From recent advancements and ongoing trends, it is safe to conclude that the profiling of an individual patient’s immune competence will become a standard requirement prior to and during treatment.

As autoantibodies are established biomarkers for predicting the onset of several autoimmune and inflammatory diseases, they appear to constitute the logical biomarker class for identifying patients at risk of developing irAEs. The ability of autoantibodies to act as strong biomarkers for immunotherapy response and the onset of irAEs is now being recognized by a growing number of leading cancer centers, with the Society for Immunotherapy of Cancer’s biomarker task force stating that autoantibody measurement can be performed during therapy to monitor treatment response using easily accessible “liquid biopsy” samples.

Autoantibody data can help tease out key relationships between disease onset and progression, between a treatment’s mechanism of action and its outcome, and between therapeutic options and the molecular phenotypes underlying disease. A better understanding of these relationships can help developers and clinicians predict which patients will respond to a given therapy, design clinical trials, and even anticipate adverse inflammatory and autoimmune reactions before clinical symptoms even occur.

Peter K. Schulz-Knappe, M.D., is chief scientific officer and Georg Lautscham, Ph.D. ([email protected]), is chief business officer at Protagen

Previous articleThe Present and Future of Mini Brains
Next articleKinetic Imaging: Using Zebrafish to Study Toxicology