A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer
Michael A. Morse,Jennifer Garst,Takuya Osada,Shubi Khan,Amy Hobeika,Timothy M. Clay,Nancy Valente,Revati Shreeniwas,Mary Sutton,Alain Delcayre,Di-Hwei Hsu,Jean-Bernard Le Pecq,H. Kim Lyerly +12 more
TLDR
Production of the DEX vaccine was feasible and DEX therapy was well tolerated in patients with advanced NSCLC, and some patients experienced long term stability of disease and activation of immune effectors.Abstract:
There 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). This 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. Thirteen 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. Production 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 effectorsread more
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Microenvironmental regulation of tumor progression and metastasis.
TL;DR: The paradoxical roles of the tumor microenvironment during specific stages of cancer progression and metastasis are discussed, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.
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Membrane vesicles as conveyors of immune responses
TL;DR: The role of membrane vesicles, in particular exosomes, in the communication between immune cells, and between tumour and immune cells is focused on.
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Exosomes: extracellular organelles important in intercellular communication.
TL;DR: This review focuses on various strategies for purifying exosomes and discusses their biophysical and biochemical properties, and an update on proteomic analysis of exosome from various cell types and body fluids is provided and host-cell specific proteomic signatures are discussed.
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Standardization of sample collection, isolation and analysis methods in extracellular vesicle research
Kenneth W. Witwer,Edit I. Buzás,Lynne T. Bemis,Adriana Bora,Cecilia Lässer,Jan Lötvall,Esther Nolte-‘t Hoen,Melissa G. Piper,Sarada Sivaraman,Johan Skog,Clotilde Théry,Marca H. M. Wauben,Fred H. Hochberg +12 more
TL;DR: The need for standardization of specimen handling, appropriate normative controls, and isolation and analysis techniques to facilitate comparison of results is emphasized, and it is recognized that continual development and evaluation of techniques will be necessary as new knowledge is amassed.
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Exosomes: Current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials
TL;DR: Strategies for exosome isolation, the understanding to date of exosomes composition, functions, and pathways, and their potential for diagnostic and therapeutic applications are summarized.
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