PD-1 blockade restores impaired function of ex vivo expanded CD8&lt;sup&gt;+&lt;/sup&gt; T cells and enhances apoptosis in mismatch repair deficient EpCAM&lt;sup&gt;+&lt;/sup&gt;PD-L1&lt;sup&gt;+&lt;/sup&gt; cancer cells

Kumar, Rajeev; Yu, Fang; Zhen, Yuan-Huan; Li, Bo; Wang, Jun; Yang, Yuan; Ge, Hui-Xin; Hu, Peng; Jin, Xin

doi:10.2147/ott.s130131

Cited by 21 publications

(19 citation statements)

References 51 publications

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“…2B) . The observed level of direct target killing by E8 in-vitro and ex-vivo ranged between~20-40% in independent biological replicate experiments, which is comparable to the levels observed with approved anti-cancer biologicals [27][28][29] . E8 demonstrated remarkable selectivity at the target cell level, killing TNBC9 but not MCF10A cells, which were used as negative targets in the in-vitro evolution process (Fig.…”

Section: Resultssupporting

confidence: 64%

Discovery of tumoricidal DNA oligonucleotides by effect-directedin-vitroevolution

Mamet

Amir

Lavi

et al. 2019

Preprint

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Our current model of drug discovery is challenged by the relative ineffectiveness of drugs against highly variable and rapidly evolving diseases and their relatively high incidence of adverse effects due to poor selectivity. Here we describe a robust and reproducible platform which could potentially address these limitations. The platform enables rapid, de-novo discovery of DNA aptamers evolved in-vitro to exert specific biological effects on target cells. Unlike conventional aptamers, which are selected by their ligand binding capacity, this platform is driven directly by therapeutic effect and selectivity towards target vs negative target cells. The process could, therefore, operate without any a-priori knowledge (e.g. mutations, biomarker expression, or known drug resistance) of the target. We report the discovery of DNA aptamers with direct and selective cytotoxicity towards several tumor cell lines as well as primary, patient-derived solid and hematological tumors, some with chemotherapy resistance. Aptamers discovered by this platform exhibited favorable biodistribution in animals, persistence in target tumors up to 48 hours after injection, and safety in human blood. These aptamers showed remarkable efficacy in-vivo as well as ex-vivo in freshly obtained, 3D cultured human tumors resistant to multiple chemotherapies. With further improvement, these findings could lead to a drug discovery model which is target-tailored, mechanism-flexible, and nearly on-demand.

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Section: Resultssupporting

confidence: 64%

Discovery of tumoricidal DNA oligonucleotides by effect-directedin-vitroevolution

Mamet

Amir

Lavi

et al. 2019

Preprint

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“…Nivolumab targets mainly PD-1 on T-lymphocytes to prevent its ligation with PD-L1 on tumor cells, and hereafter prevent tumor cells from escaping immune surveillance. In addition, previous in vitro studies had utilized human T-lymphocytes, co-cultured with tumor cells to evaluate the efficacy of checkpoint blockade in treating cancer [18,19], thereby we included T-lymphocytes in our in vitro model. This idea was also supported by myocardium T-lymphocytes infiltration in PD-1 -/and PD-L1 -/knockout mice [13,20].…”

Section: Discussionmentioning

confidence: 99%

Programmed Cell Death-1: Programmed Cell Death-Ligand 1 Interaction Protects Human Cardiomyocytes Against T-Cell Mediated Inflammation and Apoptosis Response In Vitro

Tay

Fang

Beh

et al. 2020

IJMS

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Aim: Immunological checkpoint therapy is considered a powerful method for cancer therapy and acts by re-activating autologous T cells to kill the cancer cell. Myocarditis cases have been reported in cancer patients after immunological therapy; for example, nivolumab treatment is a monoclonal antibody that blocks programmed cell death-1/programmed cell death ligand-1 ligand interaction. This project provided insight into the inflammatory response as a benchmark to investigate the potential cardiotoxic effect of T cell response to the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis in regulating cardiomyocyte injury in vitro. Methods and Results: We investigated cardiomyopathy resulted from the PD-1/PD-L1 axis blockade using the anti-PD-1 antibody in Rockefeller University embryonic stem cells-derived cardiomyocytes (RUES2-CMs) and a melanoma tumor-bearing murine model. We found that nivolumab alone did not induce inflammatory-related proteins, including PD-L1 expression, and did not induce apoptosis, which was contrary to doxorubicin, a cardiotoxic chemotherapy drug. However, nivolumab was able to exacerbate the immune response by increasing cytokine and inflammatory gene expression in RUES2-CMs when co-cultured with CD4+ T lymphocytes and induced apoptosis. This effect was not observed when RUES2-CMs were co-cultured with CD8+ T lymphocytes. The in vivo model showed that the heart function of tumor-bearing mice was decreased after treatment with anti-PD-1 antibody and demonstrated a dilated left ventricle histological examination. The dilated left ventricle was associated with an infiltration of CD4+ and CD8+ T lymphocytes into the myocardium. PD-L1 and inflammatory-associated gene expression were significantly increased in anti-PD-1-treated tumor-bearing mice. Cleaved caspase-3 and mouse plasma cardiac troponin I expressions were increased significantly. Conclusion: PD-L1 expression on cardiomyocytes suppressed T-cell function. Blockade of PD-1 by nivolumab enhanced cardiomyocyte inflammation and apoptosis through the enhancement of T-cell response towards cardiomyocytes.

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“…[6][7][8][9][10][11][12]. The observed level of direct target killing by E8 in vitro and ex vivo ranged between~20-40% in independent biological replicate experiments, which is comparable to the levels observed with approved anti-cancer biologicals [27][28][29] . E8 demonstrated remarkable selectivity at the target cell level, killing TNBC9 but not MCF10A cells, which were used as negative targets in the in vitro evolution process ( Fig.…”

Section: Resultsmentioning

confidence: 79%

Discovery of tumoricidal DNA oligonucleotides by response-directed in vitro evolution

et al. 2020

View full text Add to dashboard Cite

Drug discovery is challenged by ineffectiveness of drugs against variable and evolving diseases, and adverse effects due to poor selectivity. We describe a robust platform which potentially addresses these limitations. The platform enables rapid discovery of DNA oligonucleotides evolved in vitro for exerting specific and selective biological responses in target cells. The process operates without a priori target knowledge (mutations, biomarkers, etc). We report the discovery of oligonucleotides with direct, selective cytotoxicity towards cell lines, as well as patient-derived solid and hematological tumors. A specific oligonucleotide termed E8, induced selective apoptosis in triple-negative breast cancer (TNBC) cells. Polyethylene glycol-modified E8 exhibited favorable biodistribution in animals, persisting in tumors up to 48-hours after injection. E8 inhibited tumors by 50% within 10 days of treatment in patient-derived xenograft mice, and was effective in ex vivo organ cultures from chemotherapy-resistant TNBC patients. These findings highlight a drug discovery model which is target-tailored and on-demand.

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PD-1 blockade restores impaired function of ex vivo expanded CD8<sup>+</sup> T cells and enhances apoptosis in mismatch repair deficient EpCAM<sup>+</sup>PD-L1<sup>+</sup> cancer cells

Cited by 21 publications

References 51 publications

Discovery of tumoricidal DNA oligonucleotides by effect-directedin-vitroevolution

Discovery of tumoricidal DNA oligonucleotides by effect-directedin-vitroevolution

Programmed Cell Death-1: Programmed Cell Death-Ligand 1 Interaction Protects Human Cardiomyocytes Against T-Cell Mediated Inflammation and Apoptosis Response In Vitro

Discovery of tumoricidal DNA oligonucleotides by response-directed in vitro evolution

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