Combination strategies to promote sensitivity to cytarabine-induced replication stress in acute myeloid leukemia with and without DNMT3A mutations

Shabashvili, Daniil E.; Feng, Yang; Kaur, Prabhjot; Venugopal, Kartika; Guryanova, Olga A.

doi:10.1016/j.exphem.2022.03.008

Cited by 4 publications

(1 citation statement)

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“… 10 Newly developed drugs that target mutant proteins, such as gilteritinib and olutasidenib, are often dosed in combination with cytarabine and other chemotherapies 11 , 12 to promote sensitivity to cytarabine. 13 In other cancers, chemotherapy has been used in combination with immune-stimulating agents to encourage an immune response against tumor antigens released during cell death. 14 , 15 , 16 Several studies have explored adjuvants such as toll-like receptor (TLR) agonists, including poly(I:C) (TLR3), 17 LPS (TLR4), 18 R848 (TLR7/8), 19 CpG (TLR9), 20 and others, 21 for the treatment of leukemia.…”

Section: Introductionmentioning

confidence: 99%

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

Slezak,

Chang,

Beckman

et al. 2024

Blood Advances

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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. While 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 like 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 co-polymer with pendant mannose groups and TLR7 agonists to target covalently linked antigen and adjuvant to antigen-presenting cells in the liver and spleen after intravenous administration. There, the compound initiates an anti-cancer immune response, including T cell activation and antibody generation, ultimately prolonging survival in cancer-bearing mice.

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