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Accelerated elimination of human cancer cells by a CD40 agonist antibody combined with a PD-1 antagonist in CD4-depleted mice.

ABSTRACT: The elimination of residual microscopic cancer cells is important cancer treatment. The immunoediting theory describes the balance between the immune system and cancer cells. The current study investigated changes in the immune system during the elimination of cancer cells and evaluated the influence of cluster of differentiation (CD)4 or CD8 depletion. A human squamous cell cancer cell line (SNU1041) was injected in the lateral tongue of immunocompetent mice and the changes in the CD4, CD8, CD11b, CD19, CD40 and CD40 ligand (L) populations in the blood, lymph nodes and spleen were evaluated using flow cytometry, and changes in serum cytokine levels were evaluated using a magnetic bead panel. Cancer cell elimination was delayed by CD4 depletion but not by CD8 depletion. The CD8-depleted group indicated increased levels of CD40L, interferon-gamma, interleukin (IL)-10, IL-6, and tumor necrosis factor-?. It was concluded that CD4 served a crucial role in the elimination of human cancer cells. Furthermore, the efficacies of CD40 agonist and programmed cell death protein 1 (PD1) antagonist treatments were assessed in CD4-depleted mice. CD40 agonist treatment resulted in faster cancer cell elimination and increased cytokine excretion. In conclusion, CD4 or CD40L significantly influenced cancer elimination. CD40 agonist antibodies may be potent adjuvant agents that can be used in patients with reduced CD4 or CD40L expression.

SUBMITTER: Ahn SH

PROVIDER: S-EPMC6865608 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Accelerated elimination of human cancer cells by a CD40 agonist antibody combined with a PD-1 antagonist in CD4-depleted mice.

Ahn Soon-Hyun SH Choi Joo Yeon JY Kim Seong Dong SD Park Sung Joon SJ Kim Hyojin H

Oncology letters 20191014 6

The elimination of residual microscopic cancer cells is important cancer treatment. The immunoediting theory describes the balance between the immune system and cancer cells. The current study investigated changes in the immune system during the elimination of cancer cells and evaluated the influence of cluster of differentiation (CD)4 or CD8 depletion. A human squamous cell cancer cell line (SNU1041) was injected in the lateral tongue of immunocompetent mice and the changes in the CD4, CD8, CD1 ...[more]

PMID: 31788062

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Project description:BackgroundA novel [64Cu]Cu-NOTA-aCD40 immunoPET tracer was developed to image a CD40+ pancreatic tumor model in C57BL/6 mice and to study the biodistribution profile of the agonist CD40 (aCD40) monoclonal antibody (mAb) alone or combined with other mAbs.ProceduresCopper-64 ([64Cu]Cu) labeled NOTA-aCD40 and NOTA-IgG (10 μg; 7 MBq) were injected intravenously into C57BL/6 mice with subcutaneous mT4 tumors to assess specificity 48 h post injection (p.i.) through positron emission tomography/computed tomography (PET/CT) imaging and biodistribution studies (n = 5). [64Cu]Cu-NOTA-aCD40 was injected alone or simultaneously in combination with a therapeutic mass of cold aCD40 (100 μg), aPD-1 (200 μg) and aCTLA-4 (200 μg) mAbs. A group of mice with or without tumor received the second round of injections 1 or 3 weeks apart, respectively. PET/CT imaging and biodistribution studies were performed at 48 h p.i. The organ dose for [64Cu]Cu was estimated based on biodistribution studies with 2 μg [64Cu]Cu-NOTA-aCD40 (corresponds to 5 mg patient dose) in non-tumor bearing mice.Results[64Cu]Cu-NOTA-aCD40 accumulation was 2.3- and 7.8-fold higher than [64Cu]Cu-NOTA-IgG in tumors and spleen, respectively, indicating the specificity of aCD40 mAb in a mouse pancreatic tumor model. Tumor accumulation of [64Cu]Cu-NOTA-aCD40 was 21.2 ± 7.3%ID/g at 48 h after injection. Co-injection of [64Cu]Cu-NOTA-aCD40 with cold aCD40 mAb alone or with PD-1 and CTLA-4 mAbs reduced both spleen and tumor uptake, whereas liver uptake was increased. With the second round of injections, the liver was the only organ with substantial uptake. With a 2 μg administered dose of [64Cu]Cu-NOTA-aCD40 in a dosimetry study, the liver to spleen ratio was greater compared to the 10 μg dose (2.8 vs 0.37; respectively). The human equivalent for the highest dose organ (liver) was 198 ± 28.7 μSv/MBq.ConclusionsA CD40-immunoreactive [64Cu]Cu-NOTA-aCD40 probe was developed. The ratio of spleen to liver accumulation exceeded that of the IgG isotype and was greatest with a single small, injected mass. The safety of human patient imaging with [64Cu]Cu was established based on extrapolation of the organ specificity to human imaging.

Dataset Information

Accelerated elimination of human cancer cells by a CD40 agonist antibody combined with a PD-1 antagonist in CD4-depleted mice.

Publications

Accelerated elimination of human cancer cells by a CD40 agonist antibody combined with a PD-1 antagonist in CD4-depleted mice.

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