Recently, there is an increasing interest in antigens arising from spontaneous mutations in cancer cells, known as tumor-specific antigens (TSAs) or neoantigens, for their potential ability to predict susceptibility to immunotherapy products. The general mechanism includes activation of immune cells after exposure to specific target antigens known as tumor-associated antigens (TAAs) that are overexpressed in tumors. In recent years, a spotlight has been placed on the role of the gut microbiome on an individual host’s response to immunotherapy, with ongoing research underscoring this previously unknown wild card. The many variables to consider include and are not limited to variability of the host immune system between individual patients and patient populations, co-morbid conditions, and varying immunological milieu within tumor microenvironments (TMEs) that will result in variation of responses and require further investigation. To get to that point, there are major challenges and unanswered questions that will need to be addressed in well-designed human trials. Furthermore, as a majority of cases of recurrent disease will manifest with distant metastatic disease, consideration of upfront immunotherapy offers an additional theoretical benefit by adding an immune-surveillance component that would further reduce recurrence risk in the long term and also potentially lowering risk of short- and long-term adverse side effects compared to cytotoxic chemotherapies in certain patient populations. Thus far, evidence supporting the use of immune checkpoint inhibitors (ICIs) is most abundant in cases of metastatic treatment-refractory cases of gastric cancer and hepatocellular carcinoma Įven further, as investigations in this field to date have focused on patients with metastatic drug-refractory forms of CRC, findings thus far demonstrating exceptional response rates in some subsets of tumors and patients point to a fertile opportunity to also reexamine regimens currently being used for the neoadjuvant setting for resectable and locally advanced forms of rectal carcinomas, as these patients reside within a window of opportunity to succeed in curative intent treatment due to a relatively limited extent of measurable disease. However, the extent of that success has not immediately transferred as well to many other forms of systemic malignancies, including cancers of the gastrointestinal tract, and CRC quite specifically. The reality of biologic discovery and implementation of immunotherapy has been a longer process than anticipated but has certainly entered more mainstream acceptance over the past decade with randomized controlled trials (RCTs) demonstrating success in the form of longer survival for patients with metastatic melanoma and non-small cell lung cancer, most prominently. Implementation of immunotherapy has long been a desired goal in the field of cancer research due to its promise for tailoring treatments to individual patients while also promising potential for inducing a longer-term form of immune surveillance that theoretically could decrease risks of future recurrence of disease. Many novel therapeutic measures have been considered and investigated in recent years to bridge this gap. The aim of this article is to identify current challenges and barriers to improvement and to specify opportunities for applying knowledge in the immunotherapy sphere to rational design of clinical trials intended to improve survival and related outcomes in patients treated in the neoadjuvant setting. Finally, we summarize current understanding on a recently identified integral factor in local immune regulation, the colonic microbiome. We provide particular focus on various combination approaches under investigation for reversing cancer-induced immunosuppression, especially in mismatch repair-proficient/microsatellite-stable colorectal tumors. In this article, we provide a comprehensive review of the current landscape of immunotherapeutic strategies in colorectal cancer and provide insight into how these strategies may evolve in the next decade and be adapted to more localized forms of cancers of the colon and rectum. Strategies including adoptive cellular therapies, tumor vaccines, and antibodies have also demonstrated the ability to enhance antitumor immunity. The category of immune checkpoint inhibitors has especially emerged as a class of therapy predicated on a more comprehensive understanding of immune cell-cancer cell regulation and evolution of the tumor microenvironment over time. Immunotherapy in the metastatic setting has drastically altered the landscape of treatment for various types of malignancy, including colorectal cancer.
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