Abstract
Simple SummaryNovel treatments in immunotherapy for gynecologic oncology have not successfully developed from preclinical research to clinical trials. Preclinical models used to investigate immunotherapy agents are summarized in order to enhance understanding of the inherent limitations and areas of improvement necessary to optimize this research. It is necessary to develop and utilize appropriate preclinical models whose outcomes can be translated to clinical practice in order to identify novel treatments to improve outcomes in patients with gynecologic malignancies.Gynecologic malignancies are increasing in incidence, with a plateau in clinical outcomes necessitating novel treatment options. Immunotherapy and modulation of the tumor microenvironment are rapidly developing fields of interest in gynecologic oncology translational research; examples include the PD-1 (programmed cell death 1) and CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) axes and the Wnt pathway. However, clinical successes with these agents have been modest and lag behind immunotherapy successes in other malignancies. A thorough contextualization of preclinical models utilized in gynecologic oncology immunotherapy research is necessary in order to effectively and efficiently develop translational medicine. These include murine models, in vitro assays, and three-dimensional human-tissue-based systems. Here, we provide a comprehensive review of preclinical models for immunotherapy in gynecologic malignancies, including benefits and limitations of each, in order to inform study design and translational research models. Improved model design and implementation will optimize preclinical research efficiency and increase the translational value to positive findings, facilitating novel treatments that improve patient outcomes.
Highlights
An Unmet Need for Novel Treatments in Gynecologic Oncology: The Potential of Immunotherapy
Anti-VEGF agents provide an example of TME-directed therapy, and studies are ongoing regarding optimal use, as it relates to its potential in causing hypoxia, which could sensitize cells to ICB
Humanized mice represent an in vivo model with significant potential in gynecologic oncology immunotherapy research
Summary
An Unmet Need for Novel Treatments in Gynecologic Oncology: The Potential of Immunotherapy. Uterine cancers are the third most common malignancy for women in the United States and are increasing in incidence and prevalence These cancers, when recurrent or advanced-stage, exhibit limited responses to existing treatments. OC is the most deadly gynecologic malignancy, with 13,940 deaths estimated for 2020 and a five-year overall survival rate of approximately 39% [1] These statistics indicate an unmet need for landscape-changing therapies for gynecologic malignancies. Preclinical immunotherapy research in gynecologic oncology has far shown limited translational value to the clinical setting. This may be in part due to the inherent limitations of currently used models in accurately representing the human immune system and TME. We will interpret the unique aspects of each methodology with a focus on translational applicability to the clinical setting, including limitations of each model that may preclude meaningful outcomes for immunotherapy agents in human trials
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