![]() Factors that are likely to affect the PD-1/PD-L1 axis and thus must be represented in animal models, include aggressive and metastatic cancer behavior, tumor heterogeneity, mutational landscape, genetic and epigenetic cross-talk, cancer molecular subtypes, immune cell responsiveness, and innate and acquired mechanisms of drug resistance. Relevant preclinical animal models are essential to developing these strategies and testing multiple combination approaches. Strategies to improve PD-1/PD-L1 blockade therapies in bladder cancer and other cancers include: (i) identifying host factors including genetics, immune state, and molecular subtype that drive a relevant response, (ii) assessing biomarkers and combinations of biomarkers to predict response and to personalize therapy, (iii) developing better tools to monitor immune effects, and (iv) selecting combination drug approaches/regimens to address multiple “defects” in the immune response in addition to PD-1/PD-L1 blockade. Therefore, new immunotherapeutic strategies to improve the efficacy of current PD-1/PD-L1 blockade therapies are urgently needed. Although this worthy milestone conveys the excitement and promise of this novel form of cancer treatment, PD-1/PD-L1 blockade therapy in cancer is currently not satisfactory due to the limited response rates (20%–40% refs. Given the promising and durable clinical responses, the FDA approved three PD-1 antibodies, nivolumab, pembrolizumab, and cemiplimab, and three PD-L1 antibodies, atezolizumab, avelumab, and durvalumab, for multiple types of cancer in humans ( 4, 5). In particular, programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway blockade using anti-PD-1 or anti-PD-L1 antibodies has elicited durable clinical responses in patients with cancer, presumably by normalizing imbalances in antitumor immunity ( 3). Immune checkpoint blockade therapy, one of the most promising forms of cancer immunotherapy, has been successful in multiple cancer types, including invasive urinary bladder cancer, the focus of this study ( 1, 2). Our new therapeutic antibody and caninized PD-L1 mouse model will be essential translational research tools in raising the success rate of immunotherapy in both dogs and humans. Together, these in vitro and in vivo data, which include an initial safety profile in laboratory dogs, support development of this cPD-L1 antibody as an immune checkpoint inhibitor for studies in dogs with naturally occurring cancer for translational research. We also evaluated the therapeutic efficacy of cPD-L1 antibodies in our unique caninized PD-L1 mice. Here, we developed a new cPD-L1 antibody as an immuno-oncology drug and characterized its functional and biological properties in multiple assays. The challenge has been, however, that immunotherapeutic antibodies targeting canine immune checkpoint molecules such as canine PD-L1 (cPD-L1) have not been commercially available. Therefore, the canine studies of immuno-oncology drugs can generate knowledge that informs and prioritizes new immuno-oncology therapy in humans. Companion dogs naturally develop several types of cancer that in many respects resemble clinical cancer in human patients. To improve the success of immune checkpoint blockade therapy, relevant preclinical animal models are essential for the development and testing of multiple combination approaches and strategies. Despite the recent success of immune checkpoint blockade therapy, however, the response rates in patients with cancer are limited (∼20%–40%). Immune checkpoint blockade therapy, one of the most promising cancer immunotherapies, has shown remarkable clinical impact in multiple cancer types.
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