Durable remissions associated with anti-CTLA-4 and anti-PD1 checkpoint inhibitors in a single center

Abstract

Background: Tumor vaccines are a specific modality of cancer immunotherapy. They are based on the administration to a cancer patient of tumor antigens (TAs) or dendritic cells (DCs) previously pulsed with known TAs. In spite of significant development and testing, DC-based tumor vaccines have largely delivered unsatisfactory clinical results. Extracellular vesicles (EVs) released by cancer cells can potentially deliver TAs to DCs, so as to promote the initiation of anti-Tumor immune responses. However, clinical translation of this procedure requires the isolation and ex vivo manipulation of both tumor-derived EVs and patient-derived DCs, which impose significant hurdles. Methods: We here describe an engineered receptor, called extracellular vesicle-internalizing receptor (EVIR), which enables the selective uptake and processing of endogenous, cancer cell-derived EVs from the patient's body, thereby circumventing the need of exposing DCs to tumor-derived material ex vivo. EVIRs encompass a truncated lowaffinity nerve growth factor receptor fused to an extracellular antibody domain specific to a cancer protein. We developed EVIRs that selectively internalize EVs derived from various cancer cell types, including breast cancer cells that overexpress HER2 and melanoma cells that overexpress diasialoganglioside (GD2). Results: Lentiviral vector-mediated transduction of the EVIR into primaryDCs efficiently and specifically promotedmacropinocytosis-mediated uptake of cancer cell-derived EVs and greatly enhanced the presentation of EV-Associated TAs to naïve CD8+ T cells. EVIRengineeredDCs effectively inhibited the growth ofHER2+ tumors and promoted the expansion of tumor-specific cytotoxic T cells. By employing CRISPR technology for disrupting the expression of either H-2Kb or B2MMHCI components in cancer cells, we found that the EVIR promotes T-cell activation largely through cross-dressing, a process that involves the acquisition byDCs ofMHCI/antigen complexes shed by other cells. Conclusions: EVIR-engineered DCs may be employed to foster the acquisition and presentation of a broad repertoire of cancer-specific TAs by antigen-presenting cells, enabling personalized DC-vaccination protocols for cancer immunotherapy.