Therapeutics


potential combinations with cancer vaccines and different chemotherapeutic agents, this task seems particularly daunting. Further, although effica- cious, CAR-T cells along with other immune mod- ulatory therapies can be associated with significant immune toxicity. Managing the balance between efficacy and toxicity remains a challenge and as patient survival increases following successful treatment, there will also be a need to understand more about how IO therapies affect the immune system long-term.


JS: Many of the challenges in IO go back to the rapid development the field experienced in the last few years. The high number of compounds enter- ing clinical trials, without any reliable biomarker for patient stratification, leads to results that are difficult to interpret. Many of those compounds entered clinical trials lacking complete pre-clinical data packages. This exaggerates the problem as many observations were completely unexpected, especially regarding side-effects. The delicately-tuned immune system in a patient


suffering from cancer is difficult to control and the toxicities are completely different from those of targeted therapies or cytostatics. In contrast to the latter, side-effects in IO seem only partly dose- dependent. The design of beneficial combination therapies for defined indications or even individual patients is challenging. The lack of predictive biomarkers and the fragmented understanding of the biology behind it lead to disappointing results in clinical trials.


How do you anticipate IO drug discovery and development changing in the next five years? LB: Looking towards the future, cancer therapies will become more specific and targeted to minimise off-target effects. Macrophage-targeted com- pounds, such as CSF1 modulators are likely to result in specific depletion of MDSCs and other myeloid populations while leaving the lymphocytic compartment intact, whereas Treg-targeted biolog- ics, such as anti-TIGIT or anti-GITR antibodies, may specifically deplete this population through antibody-dependent cellular cytotoxicity. This will ultimately allow a more robust anti-tumour immune response. Our increasing ability to manip- ulate genetic information and introduce or delete specific genes using CRISPR/Cas9 technology gives us a unique opportunity, perhaps in combination with immunomodulators, to induce neoantigen- specific CTL responses while preventing or revers- ing exhaustion of the expanded T-cells.


Drug Discovery World Spring 2018


High-throughput gene sequencing, in combina-


tion with proteomic approaches, will allow for more specific analysis of tumour biopsies and determine which combination of IO modulators are most appropriate for the patient at that time. As tumour escape mutants evolve and the therapy loses effectiveness, this process could be repeated to identify novel neoantigen targets. Finally, through the use of high content analysis, the biomarker field will catch up, enabling better patient stratification and targeting of what will become a suite of immunotherapy combinations to the specific needs of the patient. This is an exciting time to be involved in IO drug discovery and I believe that this field offers real potential to enhance long-term survival rates, particularly in hard-to-treat cancers.


JS: IO drug discovery will broaden by manipulat- ing not only T-cells in well-described ways, but by targeting myeloid populations to trigger tumour shrinkage. New advents like the microbiome and the combination of treating different parts of the TME are evolving tremendously and are rapidly moving toward innovative therapeutic strategies that could translate into tangible benefit for cancer patients. The emerging field of cell-based therapies will have a remarkable impact on the FDA approval policies in oncology. In the past, approvals were typically restricted to compounds, but the field will be expanded to include medical devices which enable the production of person- alised cell-based therapies. This will have an impact on drug development strategies in the pre- clinical space as well as in clinical trials. DDW


Dr Julia Schüler studied veterinary medicine at the Freie Unversität Berlin, Germany and at the Tierspital Zürich, Switzerland, where she received her DVM. She then joined the lab of Professor Dr Heiner Fiebig, founder of Oncotest GmbH, where she worked on orthotopic implantation of solid cancer PDX in immunocompromised mice. After receiving her PhD from the University of Berlin, Dr Schüler worked in the field of innate immunology at the Max-Planck Institute for Immunobiology, Freiburg.


Dr Louise Brackenbury received her PhD in viral immunology from UCL, prior to two postdoctoral fellowships at Imperial College and Bristol University. She joined KWS BioTest in 2012 before being acquired by Charles River in early 2018.


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References 1 Galon, J, Costes, A, Sanchez- Cabo, F et al (2006). Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science, 313: 1960-1964. 2 Hodi, FS et al (2010). Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363, 711-723. 3Wolchock, JD et al (2013). Nivolumab plus Ipilimumab in Advanced Melanoma. N Engl J Med 369, 122-133. 4 Sharma, et al (2017). Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy. Cell. 168, 707-723. 5 Leone et al (2013). MHC Class I Antigen Processing and Presenting Machinery: Organization, Function, and Defects in Tumor Cells. J Nat Can Inst. 105; 16, 1172-1187. 6 Rabinovich et al (2007). Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol. 25, 267-296. 7 Postow et al (2012). Immunological correlates of the abscopal effect in a patient with melanoma. N Engl J Med 366, 925-931. 8Yoshimoto et al (2015). Anti- tumor immune responses induced by radiotherapy: A Review. Fukushima J Med Sci. 61(1): 13-22. 9 Garg et al (2010). Immunogenic cell death, DAMPs and anticancer therapeutics: an emerging amalgamation. Biochem. Biophys. Acta. 1805;1. 53-71.


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