Dendritic cell-derived exosomes as maintenance immunotherapy after first line chemotherapy in NSCLC

Abstract

Dendritic cell-derived exosomes (Dex) are small extracellular vesicles secreted by viable dendritic cells. In the two phase-I trials that we conducted using the first generation of Dex (IFN-γ-free) in end-stage cancer, we reported that Dex exerted natural killer (NK) cell effector functions in patients. A second generation of Dex (IFN-γ-Dex) was manufactured with the aim of boosting NK and T cell immune responses. We carried out a phase II clinical trial testing the clinical benefit of IFN-γ-Dex loaded with MHC class I- and class II-restricted cancer antigens as maintenance immunotherapy after induction chemotherapy in patients bearing inoperable non-small cell lung cancer (NSCLC) without tumor progression. The primary endpoint was to observe at least 50% of patients with progression-free survival (PFS) at 4 mo after chemotherapy cessation. Twenty-two patients received IFN-γ-Dex. One patient exhibited a grade three hepatotoxicity. The median time to progression was 2.2 mo and median overall survival (OS) was 15 mo. Seven patients (32%) experienced stabilization of >4 mo. The primary endpoint was not reached. An increase in NKp30-dependent NK cell functions were evidenced in a fraction of these NSCLC patients presenting with defective NKp30 expression. Importantly, MHC class II expression levels of the final IFN-γ-Dex product correlated with expression levels of the NKp30 ligand BAG6 on Dex, and with NKp30-dependent NK functions, the latter being associated with longer progression-free survival. This phase II trial confirmed the capacity of Dex to boost the NK cell arm of antitumor immunity in patients with advanced NSCLC.

Extracellular vesicles as a platform for membrane‐associated therapeutic protein delivery

“…Similar to DCs, DC-derived exosomes bearing MHC-I complexed with tumour-derived peptides were found to activate T and/or B cells to induce anti-tumour immune responses [17,77,101,102]. To test the potential for exosomes to be used as cell-free vaccines against cancers, DC-derived exosomes have undergone phase I trial and are currently in phase II trial [12,103–105]. In addition to MHC-bound antigens expressed on the exosomal surface, mature DC-derived exosomes also show surface expression of ICAM-1, which is important for the induction of immune responses, such as T-cell activation [106], and the NKG2D ligand, which is a TNF superfamily ligand that binds directly to NK cells to induce their activation/proliferation and cause an anti-tumour immune response [107,108].…”

Precipitation with polyethylene glycol followed by washing and pelleting by ultracentrifugation enriches extracellular vesicles from tissue culture supernatants in small and large scales

“…For instance, B-cell derived EVs expressing Major Histocompatibility Complex (MHC)-class II molecules are able to induce specific T-cell responses (Raposo et al 1996). Also, EVs derived from other immune cell-types have been demonstrated to promote pro-inflammatory responses [8]; for example, EVs from mature dendritic cells (DCs) that had been pulsed with tumour-specific antigens can induce antitumour responses in mouse and man [9–12]. …”

Scalable, cGMP‐compatible purification of extracellular vesicles carrying bioactive human heterodimeric IL‐15/lactadherin complexes

“…Immunomodulation using natural or engineered EV, especially for the treatment of cancer, is being explored by multiple groups [5]. Notably, several clinical trials have tested primary human dendritic cell-derived EV as a cell-free cancer vaccine platform [6,7]. One of the immunostimulatory effects associated with dendritic cell EV was direct activation of NK cells through NKG2D and interleukin-15 (IL-15) pathways [8].…”