Cysteine-binding adjuvant enhances survival and promotes immune function in a murine model of acute myeloid leukemia.

Autor:	Slezak AJ; Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL., Chang K; Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL., Beckman TN; Committee on Molecular Metabolism and Nutrition, University of Chicago, Chicago, IL., Refvik KC; Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL., Alpar AT; Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL., Lauterbach AL; Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL., Solanki A; Animal Resource Center, University of Chicago, Chicago, IL., Kwon JW; Department of Pathology, University of Chicago, Chicago, IL., Gomes S; Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL., Mansurov A; Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL., Hubbell JA; Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL.; Committee on Immunology, University of Chicago, Chicago, IL.; Committee on Cancer Biology, University of Chicago, Chicago, IL.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2024 Apr 09; Vol. 8 (7), pp. 1747-1759.
DOI:	10.1182/bloodadvances.2023012529
Abstrakt:	Abstract: Therapeutic vaccination has long been a promising avenue for cancer immunotherapy but is often limited by tumor heterogeneity. The genetic and molecular diversity between patients often results in variation in the antigens present on cancer cell surfaces. As a result, recent research has focused on personalized cancer vaccines. Although promising, this strategy suffers from time-consuming production, high cost, inaccessibility, and targeting of a limited number of tumor antigens. Instead, we explore an antigen-agnostic polymeric in situ cancer vaccination platform for treating blood malignancies, in our model here with acute myeloid leukemia (AML). Rather than immunizing against specific antigens or targeting adjuvant to specific cell-surface markers, this platform leverages a characteristic metabolic and enzymatic dysregulation in cancer cells that produces an excess of free cysteine thiols on their surfaces. These thiols increase in abundance after treatment with cytotoxic agents such as cytarabine, the current standard of care in AML. The resulting free thiols can undergo efficient disulfide exchange with pyridyl disulfide (PDS) moieties on our construct and allow for in situ covalent attachment to cancer cell surfaces and debris. PDS-functionalized monomers are incorporated into a statistical copolymer with pendant mannose groups and TLR7 agonists to target covalently linked antigen and adjuvant to antigen-presenting cells in the liver and spleen after IV administration. There, the compound initiates an anticancer immune response, including T-cell activation and antibody generation, ultimately prolonging survival in cancer-bearing mice. (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
Databáze:	MEDLINE
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