Project Summary / Abstract
Invasive urinary bladder cancer (invasive urothelial carcinoma, InvUC) is lethal in 50% of patients. Immune
checkpoint inhibitors (ICIs) can cause dramatic remission of advanced InvUC, but only ~20% of patients have
this level of benefit. Pre-clinical animal models are critical for research to improve ICI outcomes, but
experimental models lack many of the hallmark features of human cancer and are poor predictors of outcomes
in humans. To address the gap in relevant animal cancer models for immunotherapy research, we will study
dogs with naturally-occurring InvUC as canine InvUC closely mimics the human condition in pathology,
molecular features including luminal and basal subtypes, clinical presentation, local invasion, and frequent
metastasis. The proposed work will strengthen the canine InvUC model by defining immune cell
responsiveness and ICI outcomes, with comparison to human studies. Our long range goal is to improve the
outlook for people with InvUC. The objective of this proposal is to address the gap by determining the suitability
of canine InvUC to serve as a model to improve ICI therapy in humans. The central hypothesis is marked
similarities will exist between dogs and humans in the immune cell responses in InvUC, and ICI therapy effects
including immune adverse events, antitumor activity, immunological responses, and predictors of treatment
success and failure. Some differences between dogs and humans are expected, with these also being
informative. The hypothesis is formulated and based on strong evidence in the literature and preliminary data.
The rationale is that demonstrating the shared immune cell responses and ICI effects between dogs and
humans with InvUC will allow the canine model to be fully employed to improve ICI therapy for humans. The
objective will be accomplished through two specific aims: (1) determine similarities and differences between
dogs and humans in the immune cell responsiveness to InvUC, and (2) determine the safety and antitumor
activity of a canine PD-L1 antibody and predictors of success and failure in dogs with InvUC with comparison
to findings in humans. The approach will be to: (1) perform dog-human comparison of InvUC through analyses
of RNA-seq, scRNA-seq, WGS, and CITE-seq data, and (2) conduct a clinical trial of an ICI, our canine PD-L1
antibody, in dogs with InvUC to assess antitumor activity, pharmacokinetics, adverse event profile, and
correlative sequencing and clinical data to predict outcomes, and to compare results to those from human PD-
L1 antibody trials. The expected results will define shared immune cell responses and ICI effects in dogs and
humans, expand the understanding of predictors of ICI therapy, and justify use of the canine model to improve
ICI and other immunotherapies in humans. Samples from dogs in the ICI trial will also be made available for
other immune, microRNA, and microbiome research by our collaborators and beyond. We look forward to
contributing to the Canine Cancer Immunotherapy Network and depositing our study data in the NCI's
Integrated Canine Data Commons, to complement two InvUC data sets that we have previously deposited.
