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Local delivery of cell surface-targeted immunocytokines programs systemic antitumor immunity.
Santollani, Luciano; Maiorino, Laura; Zhang, Yiming J; Palmeri, Joseph R; Stinson, Jordan A; Duhamel, Lauren R; Qureshi, Kashif; Suggs, Jack R; Porth, Owen T; Pinney, William; Msari, Riyam Al; Walsh, Agnes A; Wittrup, K Dane; Irvine, Darrell J.
Afiliação
  • Santollani L; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Maiorino L; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Zhang YJ; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Palmeri JR; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
  • Stinson JA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Duhamel LR; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Qureshi K; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Suggs JR; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Porth OT; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Pinney W; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Msari RA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Walsh AA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Wittrup KD; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Irvine DJ; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
Nat Immunol ; 25(10): 1820-1829, 2024 Oct.
Article em En | MEDLINE | ID: mdl-39112631
ABSTRACT
Systemically administered cytokines are potent immunotherapeutics but can cause severe dose-limiting toxicities. To overcome this challenge, cytokines have been engineered for intratumoral retention after local delivery. However, despite inducing regression of treated lesions, tumor-localized cytokines often elicit only modest responses at distal untreated tumors. In the present study, we report a localized cytokine therapy that safely elicits systemic antitumor immunity by targeting the ubiquitous leukocyte receptor CD45. CD45-targeted immunocytokines have lower internalization rates relative to wild-type counterparts, leading to sustained downstream cis and trans signaling between lymphocytes. A single intratumoral dose of αCD45-interleukin (IL)-12 followed by a single dose of αCD45-IL-15 eradicated treated tumors and untreated distal lesions in multiple syngeneic mouse tumor models without toxicity. Mechanistically, CD45-targeted cytokines reprogrammed tumor-specific CD8+ T cells in the tumor-draining lymph nodes to have an antiviral transcriptional signature. CD45 anchoring represents a broad platform for protein retention by host immune cells for use in immunotherapy.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Antígenos Comuns de Leucócito / Linfócitos T CD8-Positivos Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Antígenos Comuns de Leucócito / Linfócitos T CD8-Positivos Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article