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Targeting the mTOR pathway uncouples the efficacy and toxicity of PD-1 blockade in renal transplantation

Immune checkpoint inhibitor (ICI) use remains a challenge in patients with solid organ allografts as most would undergo rejection. In a melanoma patient in whom programmed-death 1 (PD-1) blockade resulted in organ rejection and colitis, the addition of the mTOR inhibitor sirolimus resulted in ongoin...

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Detalles Bibliográficos
Autores principales: Esfahani, Khashayar, Al-Aubodah, Tho-Alfakar, Thebault, Pamela, Lapointe, Réjean, Hudson, Marie, Johnson, Nathalie A., Baran, Dana, Bhulaiga, Najwa, Takano, Tomoko, Cailhier, Jean-François, Piccirillo, Ciriaco A., Miller, Wilson H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797722/
https://www.ncbi.nlm.nih.gov/pubmed/31624262
http://dx.doi.org/10.1038/s41467-019-12628-1
Descripción
Sumario:Immune checkpoint inhibitor (ICI) use remains a challenge in patients with solid organ allografts as most would undergo rejection. In a melanoma patient in whom programmed-death 1 (PD-1) blockade resulted in organ rejection and colitis, the addition of the mTOR inhibitor sirolimus resulted in ongoing anti-tumor efficacy while promoting allograft tolerance. Strong granzyme B(+), interferon (IFN)-γ(+) CD8(+) cytotoxic T cell and circulating regulatory T (T(reg)) cell responses were noted during allograft rejection, along with significant eosinophilia and elevated serum IL-5 and eotaxin levels. Co-treatment with sirolimus abated cytotoxic T cell numbers and eosinophilia, while elevated T(reg) cell numbers in the peripheral blood were maintained. Interestingly, numbers of IFN-γ(+) CD4(+) T cells and serum IFN-γ levels increased with the addition of sirolimus treatment likely promoting ongoing anti-PD-1 efficacy. Thus, our results indicate that sirolimus has the potential to uncouple anti-PD-1 therapy toxicity and efficacy.