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• W1979641337 abstract "Background: The dysregulation of apoptosis is a defining characteristic of malignant cells where excessive concentration of BCL2 protein contributes to the anti-apoptotic phenotype, driving development and subsequent resistance to therapy. Chromosomal translocations, including the t(14;18) rearrangement, up-regulate BCL2 transcription, preventing tumor cell death in B-cell lymphomas. A new class of therapeutic agents, called DNA interference (DNAi) drugs, exert their therapeutic effect by selectively blocking the transcription of oncogenes. PNT2258 is the lead DNAi drug currently undergoing clinical evaluation in patients with hematological malignancies. PNT2258 contains PNT100, a single stranded, native sequence oligonucleotide targeted against BCL2, which is delivered to cancer cells in a protective liposomal transport system. We present data on the anti-tumor and immunomodulatory effects of PNT228 in mice compared with that observed in patients with advanced solid tumors treated with escalating doses of PNT2258. Material and Methods: Twenty-two patients received PNT2258 doses ranging from 1 to 150 mg/mˆ2 as part of a Phase I dose-escalation study in patients with advanced, treatment refractory solid tumors. Patient plasma specimens were analyzed using a 61-marker multiplex immunoassay. Balb/c and WSU-DLCL2 xenograft mice received PNT2258 or an encapsulated scrambled control (oligonucleotide) sequence at a dose of 20 mg/kg by intravenous infusion. Murine plasma was analyzed with a 37-marker multiplex immunoassay. Results: In the murine xenograft model, PNT2258 demonstrated sequence-specific anti-tumor and anti-BCL2 activity not observed with the scrambled control. Xenograft mice demonstrated a strong innate immune response that was very similar in magnitude for both PNT2258 and scrambled control. Balb/c mice exhibited a broad and relatively weak immune response to PNT2258 and a stronger response to the scrambled control suggesting activation of both adaptive and innate immune responses. In patients, PNT2258 did not produce clinical signs of immune stimulation. Multiplex immunoassay revealed a lack of significant drug-induced modulation of inflammatory biomarkers following treatment. PNT2258 did induce statistically significant dose-dependent changes in IP-10, leptin, MIP-1β, MCP-1, IL-17F, and IL-1RA consistent with a mechanistic response to BCL2 suppression. Conclusions: Biomarker response profiles of encapsulated human sequence-specific oligonucleotide therapeutics in mice are not predictive of responses in humans. PNT2258 is safe and well tolerated in patients with no evidence of an innate (TLR) response. The observed biomarker profile provides mechanistic confirmation of drug-induced BCL2 suppression at all doses tested. Leptin represents a unique biomarker that may be used to monitor PNT2258 anti-BCL2 activity in the clinic. Citation Format: Elzbieta Izbicka, Robert Streeper, Michael J. Wick, Drew Rasco, Amita Patnaik, Kyriakos P. Papadopoulos, Anthony W. Tolcher, Shari Gaylor, Michael J. Woolliscroft, Richard A. Messmann, Wendi V. Rodrigueza. Effect of PNT2258, an anti-BCL2 DNA-interference drug, on tumor growth and immunological markers in mice and humans. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3529. doi:10.1158/1538-7445.AM2013-3529" @default.
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• W1979641337 date "2013-04-15" @default.
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• W1979641337 title "Abstract 3529: Effect of PNT2258, an anti-BCL2 DNA-interference drug, on tumor growth and immunological markers in mice and humans." @default.
• W1979641337 doi "https://doi.org/10.1158/1538-7445.am2013-3529" @default.
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