A Japanese study has shown that targeting the chemokine receptor CCR4 using treatment with the monoclonal antibody (MAb) mogamulizumab (Poteligeo, Kyowa, Amgen) depleted immune regulatory T cells (Tregs) and significantly improved survival in a canine model of advanced prostate cancer.
"This is the first study to show that an anti-CCR4 MAb depletes Tregs and improves survival in dogs with advanced prostate cancer," said corresponding author Shingo Maeda, an associate professor in the Department of Veterinary Clinical Pathobiology at The University of Tokyo.
These study findings not only suggest that mogamulizumab may be a safe and effective treatment for advanced prostate cancer in dogs, but also that dogs may represent better preclinical models for studying prostate cancer than mice, the authors reported in the Feb. 7, 2022, issue of Journal for ImmunoTherapy of Cancer.
Prostate cancer is the most common male malignancy worldwide, with most prostate cancer-related deaths being due to advanced metastatic disease.
Androgen deprivation alone or in combination with chemotherapy is initially effective in 80-90% of advanced prostate cancers, but the disease eventually relapses, progresses and becomes irresponsive to treatments, with a typically poor prognosis.
Tregs, which play a key immune system role by ensuring that lymphocytes recognize and attack only foreign cells, are thought to inhibit the immune system's ability to recognize and attack prostate cancer and other cancer cell types.
Tregs are often associated with cancers that avoid immune detection via Treg tumor infiltration, which may deceive other T cells into not recognizing the cancer as foreign.
Expression of the gene controlling production of the transcription factor, Forkhead box protein 3 (FOXP3), controls the rate of Treg expression. Thus, regulation of this pathway might be used as an immunotherapy for advanced prostate cancer.
However, the precise role of Tregs and therapeutic potential of their depletion in prostate cancer remain unknown, while much of what is known is from preclinical studies in mice, which may poorly reflect outcomes in humans.
Mice and men
Although rodent models are indispensable in cancer research, "the controlled environment under which highly inbred rodents are kept offers completely different settings from the diverse conditions prevalent in human cancers," said Maeda.
Moreover, preclinical studies using murine models have often failed to predict the results of human clinical trials, with the average rate of successful translation from rodent models to clinical cancer trials being less than 10%, hence the need for better models, such as dogs.
Versus man's best friend
"Dogs are the only other animals with a significant incidence of prostate cancer, with the cancer having very similar clinical features [to humans], including late-age onset and the pattern of cancer growth," said Maeda.
These similarities suggest that dogs might be particularly suitable models for studying prostate cancer in humans, especially as the canine prostate gland shares morphological and functional similarities with the human prostate.
"Therefore, naturally occurring prostate cancer in dogs could serve as a bridge between laboratory animal models and human patients," Maeda told BioWorld Science.
In their new study, the University of Tokyo researchers studied the molecular mechanisms underlying Treg tumor infiltration and the effect of anti-Treg MAb treatment with mogamulizumab in 23 dogs with naturally occurring prostate cancer.
They first used immunohistochemistry to evaluate and compare tumor-infiltrating Tregs in dogs and humans.
Then, RNA sequencing and protein analyses showed a possible link between an increase of tumor-infiltrating Tregs and the production of the chemokine CCL17, which attracts Tregs by binding to CCR4.
Finally, the researchers analyzed a series of human prostate cancer data sets, in order to compare gene expression in dogs and humans.
Using this information, the researchers conducted a preclinical trial of mogamulizumab in dogs, "which has been approved for relapsed or refractory CCR4-positive peripheral T-cell lymphoma and cutaneous T-cell lymphoma in humans," noted Maeda.
Compared with pretreatment baseline, treated dogs showed significantly decreased circulation of Tregs. In addition, mogalumizumab treatment improved survival with a low incidence of adverse events in dogs with prostate cancer.
"A 60% reduction was observed in circulating Treg levels, together with an approximately 3-fold increase in survival in the mogamulizumab group versus controls," said Maeda. "Given that survival in dogs with prostate cancer was more than 3 times longer than that seen with conventional treatments, we believe this will be an innovative treatment, pending clinical trials of mogamulizumab in humans with prostate cancer."
Together, these findings show that anti-Treg treatment with mogamulizumab may be a safe and effective therapeutic approach for advanced prostate cancer in dogs and possibly in men.In future, he said, "in this study, we were able to show that some human prostate cancer patients have a gene expression pattern similar to that of canine prostate cancer and we are now planning to search for molecular mechanisms, other than CCR4, that are common between humans and dogs."