Exploring Changing Treatment Paradigms in Medullary Thyroid Carcinoma, the Immune Milieu of the Tumour Microenvironment and a Novel Targeted Therapy for Advanced Disease

Abstract

The immune milieu of the tumour microenvironment (TME) in Medullary Thyroid Cancer (MTC) and the potential role of immune therapies have not been extensively explored. This study aimed to define the current treatment landscape and changing management paradigms in MTC, describe the nature of the immune microenvironment of these tumours, and ultimately explore a novel targeted therapy for advanced disease. Tumour-infiltrating lymphocytes (TILs) in the TME of MTC patients were assessed and correlated with clinicopathological prognostic variables and survival outcomes. All patients with MTC had low TILs (≤10%), and there was no significant association between TILs and local recurrence or disease-specific survival on multivariable analysis. These findings highlight that MTC is an immune-quiescent tumour. A novel targeted therapy for advanced MTC was also investigated. The EDV™ (EnGeneIC Dream Vector) is a bacterially-derived construct loaded with cytotoxic drugs and conjugated with a bispecific antibody directed against specific overexpressed surface receptors on tumour cells. The EDV™ effectively killed human MTC cells in vitro and in a nude-mouse xenograft and syngeneic neuroendocrine tumour model. In addition to targeted delivery of the cytotoxin PNU-159682 mediated by antibody binding, EDV treatment triggered an innate and adaptive immune response against tumour cells, with upregulation of M1 macrophages, cytotoxic natural killer (NK) cells, and invariant natural killer T cells, followed by CD8 effector T cells. The shift to an immune-activated phenotype in the TME correlated with changes in the cytokine and chemokine profile, with upregulation of the key drivers of macrophage, NK cell and T cell activation and chemotaxis in the serum and TME. These results provide preclinical data demonstrating the efficacy of a novel targeted therapy for advanced MTC and form the evidence base to support a human clinical trial to confirm the translational relevance of the results