Abstract
BackgroundThere is a continued need to develop more effective cancer immunotherapy strategies. Exosomes, cell-derived lipid vesicles that express high levels of a narrow spectrum of cell proteins represent a novel platform for delivering high levels of antigen in conjunction with costimulatory molecules. We performed this study to test the safety, feasibility and efficacy of autologous dendritic cell (DC)-derived exosomes (DEX) loaded with the MAGE tumor antigens in patients with non-small cell lung cancer (NSCLC).MethodsThis Phase I study enrolled HLA A2+ patients with pre-treated Stage IIIb (N = 4) and IV (N = 9) NSCLC with tumor expression of MAGE-A3 or A4. Patients underwent leukapheresis to generate DC from which DEX were produced and loaded with MAGE-A3, -A4, -A10, and MAGE-3DPO4 peptides. Patients received 4 doses of DEX at weekly intervals.ResultsThirteen patients were enrolled and 9 completed therapy. Three formulations of DEX were evaluated; all were well tolerated with only grade 1–2 adverse events related to the use of DEX (injection site reactions (N = 8), flu like illness (N = 1), and peripheral arm pain (N = 1)). The time from the first dose of DEX until disease progression was 30 to 429+ days. Three patients had disease progression before the first DEX dose. Survival of patients after the first DEX dose was 52–665+ days. DTH reactivity against MAGE peptides was detected in 3/9 patients. Immune responses were detected in patients as follows: MAGE-specific T cell responses in 1/3, increased NK lytic activity in 2/4.ConclusionProduction of the DEX vaccine was feasible and DEX therapy was well tolerated in patients with advanced NSCLC. Some patients experienced long term stability of disease and activation of immune effectors
Highlights
Vaccine immunotherapy as an approach to cancer treatment has evolved over the last 10 years as the basic biology of the immune response has been elucidated
Tumorassociated antigens that are capable of eliciting cytotoxic T cell responses have been identified
Among the most frequently expressed across many malignancies are the MAGE antigens, originally described in melanoma, but expressed by other tumors including non-small cell lung cancer (NSCLC) [1,2,3]
Summary
Vaccine immunotherapy as an approach to cancer treatment has evolved over the last 10 years as the basic biology of the immune response has been elucidated. Immune responses to MAGE 3 have been correlated with clinical outcome in melanoma patients [4]. This has lead to many tumor antigen-specific strategies for the treatment of cancer, including the use of an immunodominant peptide alone, protein or peptidepulsed dendritic cells, and antigen/co-stimulatory fusion proteins expressed from viral vectors. A novel platform for delivering high levels of antigen in conjunction with costimulatory molecules has been described, called exosomes, cell-derived lipid vesicles that express high levels of a narrow spectrum of cell proteins. Cell-derived lipid vesicles that express high levels of a narrow spectrum of cell proteins represent a novel platform for delivering high levels of antigen in conjunction with costimulatory molecules. We performed this study to test the safety, feasibility and efficacy of autologous dendritic cell (DC)-derived exosomes (DEX) loaded with the MAGE tumor antigens in patients with non-small cell lung cancer (NSCLC)
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