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Abstract

Background: DC derived-exosomes are nanomeric vesicles harboring functional MHC/peptide complexes capable of promoting T cell immune responses and tumor rejection. Here we report the feasability and safety of the first Phase I clinical trial using autologous exosomes pulsed with MAGE 3 peptides for the immunization of stage III/IV melanoma patients. Secondary endpoints were the monitoring of T cell responses and the clinical outcome.

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].…”

“…Therefore, gaining a better understanding of the heterogeneity and molecular composition of EVs could allow us to determine more suitable subpopulations for certain EV-based therapeutics (i.e., by identifying subpopulations that can exert particular effects without unwanted side-effects). The vesicle doses have varied across the existing studies, ranging from 1 to 500 μg per in vivo injection [12,104,105,149–151], further emphasizing that the heterogeneity of EVs needs to be characterized to avoid the induction of adverse effects in patients. Although some methods have been developed to detect EV heterogeneity, their detection sensitivities and specificities must be improved to enable researchers to precisely characterize each subpopulation and the compositions of individual vesicles.…”

“…Given the problems associated with many of the current nanoparticle delivery systems, they hold great appeal as “nature’s delivery system” for the distribution of native biological molecules and as drug-delivery vehicles [8–11]. EVs have also been applied for the development of cancer vaccines [12–17] and cell-free therapeutics [16–19]. …”

The exosomes in tumor immunity

“…Vaccination of patients with DEXs from metastatic melanoma and advanced non-small cell lung cancer resulted in activation of immune responses and prolonged stability of diseases, as demonstrated in phase I clinical trials. 77,78 However, how to break down the obstacles of host immunosuppression and rescue insufficient T cell responses when using DEXs as tumor vaccines calls for further studies.…”

Los exosomas de las células presentadoras de antígeno y su papel en la regulación de las respuestas inmunológicas

“…59,60 Actualmente algunos estudios han demostrado la factibilidad de la producción a gran escala de exosomas derivados de DC, confirmando, además, su perfil de seguridad adecuado durante su administración a pacientes. 61 En un ensayo clínico que incluyó pacientes con un estadio avanzado de melanoma, se demostró que tras la administración de una primera generación de exosomas de DC, dichos individuos mostraron un incremento relevante en las respuestas de células NK, no así las que involucran células T específicas. 61 La inmunogenicidad limitada de las mencionadas nanovesículas llevó al desarrollo de una segunda generación de exosomas derivados de DC, en este caso obtenidos a partir de células tratadas con INF-γ, que expresan niveles mayores de CD40, CD80, CD86 e ICAM1 respecto a los exosomas de DC inmaduras, características que, como se ha mencionado, favorecen la inmunogenicidad de estas estructuras.…”