Therapeutics
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11 Spiess, C et al (2015). Alternative molecular formats and therapeutic applications for bispecific antibodies. Molecular Immunology 2(A): 95-106. 12Topp, MS et al (2011). Targeted Therapy With the T- Cell-Engaging Antibody Blinatumomab of Chemotherapy-Refractory Minimal Residual Disease in B- Lineage Acute Lymphoblastic Leukemia Patients Results in High Response Rate and Prolonged Leukemia-Free Survival. Journal of Clinical Oncology 28 (18): 2493-2498. 13 Zhang, X et al (2017). The development of bispecific antibodies and their applications in tumor immune escape. Experimental Hematology & Oncology 6:12. 14 Schwab, CL et al (2014). Past, present and future targets for immunotherapy in ovarian cancer. Immunotherapy 6(12): 1279-1293. 15 Zavala, VA, Kalergis, AM (2015). New clinical advances in immunotherapy for the treatment of solid tumours. Immunology 145(2): 182-201. 16 Assal, A et al (2015). Emerging targets in cancer immunotherapy: beyond CTLA-4 and PD-1. Immunotherapy 7(11): 1169- 1186.
Thirdly, having a study pathologist that is expe- rienced in evaluating slides from tissue cross-reac- tivity studies is another key consideration, to ensure that the data output is accurate and reliable. A peer review of pathology data, often from a sub- set of study slides, adds to the integrity of study data and reduces any bias.
A look to the future
There is still huge scope within the area of I-O, and scientists are experimenting with novel antibody structures and ways to enhance immune cell recruitment and target cancer cells11. Bispecific antibodies are of particular interest to scientists, as these structures have the ability to bind to two dif- ferent surface receptors with a high level of speci- ficity, allowing a direct connection between a tumour cell and a T-cell13. Bispecific T-Cell engager (BiTE) technology has produced several FDA-approved therapies such as blinatumomab, for the treatment of chemotherapy-resistant acute lymphocytic leukaemia, with a whole host in clini- cal development10. BiTEs are small molecules con- sisting of the variable regions only, which are con- nected by a flexible linker peptide10. They present as a potent molecule which can be used in low con- centrations but also have a short serum half-life which is due to their structure. Preclinical safety assessments for these antibody structures will also require an on-off target binding assessment via tis- sue cross-reactivity studies, along with other phar- macological assessments. The varying formats, structures and pharmacokinetic profiles of these molecules will allow clinicians to have a greater choice when it comes to therapies and treatment regimes, allowing a more personalised approach in the future.
In addition to novel constructs, scientists have turned to combination therapies to help improve treatment
response rates. CTLA-4 and PD-1
inhibitors are currently used as individual therapies in the treatment of advanced melanoma and lung cancer, and when administered in combination a greater efficacy can be achieved in a broader pop- ulation of patients3,8,16. A new challenge is pre- sented in the safety considerations of these novel immunotherapies as scientists explore combination therapies to improve efficacy. This adds to the complexity of safety assessment assay designs which must take into consideration the non-stan- dard response kinetics and potential autoimmune side effects when combining two or more agents that actively stimulate the immune system. Furthermore, the sequence in which these agents are administered can have differing effects and out-
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comes. This presents an opportunity to develop predictive and prognostic biomarkers that can aid in patient selection and direct therapy to the patients who will benefit the most, along with the prediction of immunotherapy toxicity6,9. As yet validated biomarkers with predictive and prognos- tic value do not exist and is another area of active research9. Until these biomarkers are developed, it is important to understand the safety profile and off-target binding toxicities of these agents, partic- ularly when used in combination therapies.
Conclusion
The landscape of cancer treatment has changed dramatically over the last two decades. As our understanding of new immunotherapies progress- es, and the way we target the treatment of cancer adapts, so too must the way we assess the safety profile of these agents. There are still many chal- lenges to overcome as we explore the possibilities of novel antibody constructs, along with mono- and combination immunotherapy. As we increase our understanding of this novel therapy for cancer, there also becomes a requirement for predictive and prognostic biomarkers that can aid in patient selection and direct therapy to the patients who will benefit the most6. Until these biomarkers are developed, and a personalised treatment regime can be implemented, it is important to understand the safety profile and off-target binding toxicities of these therapies, particularly when used in com- bination. Compared to a clinical trial, the invest- ment required in a preclinical tissue cross-reactivity study is modest, and provides valuable information that enables scientists to make evidence-based deci- sions on whether to progress a candidate into clin- ical trials and how clinical investigations should be directed. It may still be too early in the develop- ment of immunotherapies to know the best prac- tice for complete risk assessment in preclinical studies. However, evaluation of antibody tissue cross-reactivity in a panel of 33 or 38 organs is likely to remain a critical element of preclinical safety assessment for this new age of immunother- apies, playing a vital role in accelerating new can- didates into human clinical trials.
DDW
Edward Cribb is Client Services Manager at Propath UK, one of Europe’s leading specialists in GLP- and GCP-compliant molecular pathology and histopathology services. With more than 10 years’ experience in molecular pathology and histopathology, Ed works closely with biopharma- ceutical companies to help develop research strate- gies to achieve their study objectives.
Drug Discovery World Summer 2017
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