Innovative Treatment Strategies in High-Grade Neuroendocrine Cancer: Clinical Trial Insights

A new clinical trial is underway at the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, targeting patients with high-grade neuroendocrine tumors—a group of aggressive and often treatment-resistant cancers. This initiative represents a novel effort to address a disease that has historically seen limited therapeutic innovation due to its rarity and complexity, leaving most patients with few options beyond standard chemotherapy.

High-grade neuroendocrine tumors can arise from neuroendocrine cells distributed throughout the body, affecting multiple organ systems including the lungs, gastrointestinal tract, prostate, and gynecological organs. Approximately one-sixth of all neuroendocrine tumors are classified as high grade. While most cases occur in individuals over 60, these malignancies can also affect younger adults, frequently progressing rapidly and leading to poor survival outcomes. Many patients succumb to the disease within one to two years of diagnosis, underscoring the urgent need for more effective treatments.

The new trial at Sylvester takes an integrated approach, combining two classes of immunotherapy: checkpoint inhibitors and an oncolytic virus. Patients enrolled in the phase 1 study will receive nivolumab and ipilimumab, two well-established checkpoint inhibitors designed to release the brakes on the immune system and facilitate a more robust attack on cancer cells. In parallel, patients will also be treated with Seneca Valley Virus-001 (SVV-001), a genetically selective oncolytic virus that preferentially infects and destroys tumor cells without harming normal tissues. The virus not only directly lyses cancer cells but also exposes tumor antigens to the immune system, potentially enhancing the efficacy of checkpoint inhibitors by converting immunologically “cold” tumors into “hot” ones that are more responsive to immune-mediated attack.

This therapeutic strategy is informed by earlier preclinical research showing that the combination of SVV-001 with checkpoint inhibitors led to tumor shrinkage and durable responses in cancer models. In these experiments, SVV-001 amplified immune recognition by initiating a cascade of tumor cell destruction and immune activation, while the checkpoint inhibitors intensified this response by preventing the immune system from prematurely shutting down its attack.

A distinctive aspect of the trial is its incorporation of biomarker testing for TEM8, a protein found on tumor cell surfaces that binds the oncolytic virus, thereby facilitating viral entry and replication within the cancer cells. Identifying the presence of TEM8 could help refine patient selection and support the role of SVV-001 as a targeted immunotherapy.

Approximately 36 patients whose disease has progressed despite standard treatments are expected to enroll in the trial. The primary objectives are to determine the safety and optimal dosing of this novel combination, while also collecting preliminary data to compare its effectiveness against historical outcomes with conventional therapies.

This effort reflects a broader commitment at Sylvester Comprehensive Cancer Center to advance care for patients with neuroendocrine tumors. Over the past two years, more than 550 new patients from across the United States and multiple countries have sought evaluation and participation in neuroendocrine tumor clinical trials at the center. The current study is the first investigator-initiated trial at Sylvester specifically designed for patients with high-grade neuroendocrine cancers.

This trial also highlights the essential role of patient advocacy organizations, which have been instrumental in connecting patients with clinical research opportunities and providing critical psychosocial support. Advocacy groups continue to help ensure that patients facing these rare and formidable cancers do not navigate their diagnoses alone, fostering both awareness and participation in research that could reshape future standards of care.

With this new study, Sylvester’s researchers aim to establish a more hopeful trajectory for patients with high-grade neuroendocrine tumors, expanding the range of therapeutic possibilities through innovative combinations of immunotherapy and oncolytic virotherapy.