50P - Extracellular vesicle-internalizing receptors (EVIRs) for dendritic cell-based tumor vaccines (50P)

Date 08 December 2017
Event ESMO Immuno-Oncology Congress 2017
Session Lunch & Poster Display session
Topics Central Nervous System Malignancies
Translational Research
Presenter Mario Leonardo Squadrito
Citation Annals of Oncology (2017) 28 (suppl_11): xi6-xi29. 10.1093/annonc/mdx711
Authors M.L. Squadrito, C. Cianciaruso, S.K. Hansen, M. De Palma
  • Swiss Institute For Experimental Cancer Research (isrec), École polytechnique fédérale de Lausanne (EPFL), 1015 - Lausanne/CH

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 low-affinity 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 primary DCs efficiently and specifically promoted macropinocytosis-mediated uptake of cancer cell-derived EVs and greatly enhanced the presentation of EV-associated TAs to naïve CD8+ T cells. EVIR-engineered DCs effectively inhibited the growth of HER2+ tumors and promoted the expansion of tumor-specific cytotoxic T cells. By employing CRISPR technology for disrupting the expression of either H-2Kb or B2M MHCI components in cancer cells, we found that the EVIR promotes T-cell activation largely through cross-dressing, a process that involves the acquisition by DCs of MHCI/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.

Clinical trial identification

Legal entity responsible for the study

EPFL

Funding

European Research Council (ERC) Consolidator Grant 2017

Disclosure

All authors have declared no conflicts of interest.