Genetic Engineering & Biotechnology News

JUN15 2018

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Page 30 of 37 | Genetic Engineering & Biotechnology News | JUNE 15, 2018 | 29 resolved with additional medication, some patients may experience long-term irrevers- ible effects that require continuing manage- ment. Indeed, in some cases, the immuno- therapy necessitates the actual removal of an organ. For example, if ICI treatment with CTLA-4 induces severe colitis, a col- ectomy made become necessary. 4 Even fatal irAEs have been reported, including high- grade liver toxicities. 5 Clearly, it would be of great benefit to pa- tients 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 im- proving therapeutic efficacy, and the first reported results are very promising. The downside, though, is that such regimens of- ten 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 em- phasized the need for research to investigate baseline biomarkers as predictors of clini- cal 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 un- derstanding of the key pathways involved in this process. 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 im- munity and are deployed against cancerous cells for immune recognition and destruc- tion via different mechanisms. Autoan- tibody effects can be mediated by natural killer cells or by the complement-mediated destruction of tumor cells. Since B-cell responses and their autoan- tibody products may be directed against the same antigens as tumor-specific T cells, auto- antibodies represent a unique opportunity to serve as circulating biomarkers of the baseline immunocompetence of cancer patients. In- deed, 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 immunoglob- ulin G autoantibodies that were significantly different in the pretreatment sera. 9 In a recent study conducted in collabo- ration with the U.S. National Cancer In- stitute, 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 autoantibod- ies 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 unrecog- nized 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). Conclusion Currently, cancer immunotherapy works only in a subset of patients—some patients develop resistance to therapy, whereas oth- ers experience cures. Cancer immunotherapy can also cause severe, life-threatening side ef- fects (irAEs), particularly in the case of check- point 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 bio- markers for predicting the onset of several autoimmune and inflammatory diseases, they appear to constitute the logical biomarker class for identifying patients at risk of devel- oping 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 Immu- notherapy 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 mecha- nism of action and its outcome, and between therapeutic options and the molecular phe- notypes underlying disease. A better un- derstanding of these relationships can help developers and clinicians predict which pa- tients will respond to a given therapy, design clinical trials, and even anticipate adverse inflammatory and autoimmune reactions be- fore clinical symptoms even occur. References are available online. The Premier Peer-Reviewed Journal on Gene Therapy Providing end-to-end coverage of the research, methods, and clinical developments driving today's explosion of gene therapy advances developments driving today's explosion of gene therapy advances Editor-in-Chief Terence R. Flotte, MD Deputy Editors, Europe Nathalie Cartier, MD Thierry VandenDriessche, PhD Deputy Editors, US Barry J. Byrne, MD, PhD Mark A. Kay, MD, PhD Human Gene Therapy Editor Guangping Gao, PhD Methods Editor Hildegard Büning, PhD Clinical Development Editor James M. Wilson, MD, PhD Sign up for TOC alerts Translational Medicine Peter K. Schulz-Knappe, M.D., is chief scientific officer and Georg Lautscham, Ph.D. ( is chief business officer at Protagen. Website: 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).

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