Immunotherapy in Gastroenteropancreatic Neuroendocrine Neoplasia

Abstract

The worldwide prevalence and incidence of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) and of NENs, in general, have been increasing recently. While valuing the considerable progress made in the treatment strategies for GEP-NEN in recent years, patients with advanced, metastasized disease still have a poor prognosis, which calls for urgent novel therapies. The immune system plays a dual role: both host-protecting and “tumor-promoting.” Hence, immunotherapy is potentially a powerful weapon to help NEN patients. However, although recent successes with checkpoint inhibitors have shown that enhancing antitumor immunity can be effective, the dynamic nature of the immunosuppressive tumor microenvironment presents significant hurdles to the broader application of these therapies. Studies led to their approval in NEN of the lung and Merkel cell carcinoma, whereas results in other settings have not been so encouraging. Oncolytic viruses can selectively infect and destroy cancer cells, acting as an in situ cancer vaccine. Moreover, they can remodel the tumor microenvironment toward a T cell-inflamed phenotype. Oncolytic virotherapy has been proposed as an ablative and immunostimulatory treatment strategy for solid tumors that are resistant to checkpoint inhibitors alone. Future efforts should focus on finding the best way to include immunotherapy in the GEP-NEN treatment scenario. In this context, this study aims at providing a comprehensive generalized review of the immune checkpoint blockade and the oncolytic virotherapy use in GEP-NENs that might improve GEP-NEN treatment strategies.

In Vitro Sensitivity of Neuroendocrine Neoplasms to an Armed Oncolytic Measles Vaccine Virus

“…Neuroendocrine neoplasms display a very heterogeneous group of different tumors, which urgently require new and effective treatment options due to a rising incidence as well as poor prognosis in advanced stages. While several oncolytic viruses have been tested for their efficiency in neuroendocrine neoplasms [20,21], to the best of our knowledge, MeV vectors have not been evaluated as a potential oncolytic virotherapeutic agent for NENs yet. Therefore, this paper aims to analyze MeV-SCD´s oncolytic potential in a panel of five well-characterized human NEN cell lines derived from different anatomic origins.…”

“…As mentioned above, different viruses have been tested for the treatment of NENs [20,21]. The three most current investigated viruses are T-VEC [28] and GLV-1h68 [29] in our laboratory, as well as the oncolytic adenovirus "AdVince" [26].…”

“…Although a large variety of oncolytic viruses have been tested preclinically for their potential oncolytic effect on NENs [20,21], only two of them have been investigated in clinical trials. One of them is the Seneca Valley virus (SVV001), which was evaluated in both children and adults for various cancers with neuroendocrine features.…”

PD-L1 expression, tumor-infiltrating lymphocytes, and mismatch repair proteins status in digestive neuroendocrine neoplasms: exploring their potential role as theragnostic and prognostic biomarkers

“…The CPS score includes the evaluation of PD-L1 expression in both neoplastic and inflammatory cells and is generally used in cancers arising in the head and neck region or in urothelial mucosa [36][37][38]. A comparison between TPS and CPS scores has never previously been reported in digestive NENs and the use of ICI has only been used in advanced with limited response and poor connection with PD-L1 expression in immunohistochemistry [31,[39][40][41][42][43][44]. In our series, we have found more tumors with CPS > 1 than with TPS > 1% and it is conceivable that CPS may be proposed as the standard score for determining PD-L1 positivity in NENs for treatment with ICIs, although specific clinical trials are needed to determine which of the two scoring systems is truly more effective.…”

Gastroenteropancreatic neuroendocrine neoplasms: current development, challenges, and clinical perspectives

“…Immunotherapy has emerged as a novel therapeutic option, and ongoing clinical trials are currently evaluating its efficacy in GEP-NENs. Genetic profiling also plays a crucial role in predicting immunotherapy response [ 134 ].…”