566 ATOR-1017, a second generation 4–1BB antibody with potential to enhance efficacy of PD-1 therapies

BackgroundATOR-1017 is a Fcγ-receptor (FcγR) crosslinking dependent agonistic IgG4 antibody targeting the costimulatory receptor 4 1BB, designed for improved tolerability and efficacy. 4-1BB is highly expressed on tumor infiltrating CD8+ T effector cells (T effs) in several cancer indications. By binding to 4-1BB, ATOR-1017 enhances the activity of tumor reactive T effs and NK cells within the tumor and induces a potent anti-tumor response. 4-1BB is a promising candidate for immunotherapy and holds great potential for combination with other immunomodulatory antibodies, targeting e.g. the PD-1 pathway.MethodsHuman 4-1BB knock-in transgenic mice with established murine colon carcinoma MC38 tumors were used to demonstrate anti-tumor efficacy after systemic treatment with ATOR-1017 in combination with anti-PD-1. Further, the effect of combining ATOR-1017 with anti-PD-1 on T cell activation (measured as production of IFNγ) was evaluated in a mixed lymphocyte reaction (MLR) assay with human primary CD4+ T cells and mature monocyte-derived DCs (mDC) expressing endogenous levels of both 4-1BB and PD-1.ResultsATOR-1017 in combination with anti-PD-1 improved survival and reduced tumor growth signifcantly in human 4-1BB knock-in transgenic mice with established tumors compared with each monotherapy alone. The potential for combining ATOR-1017 and PD-1 was further supported by data from a MLR assay demonstrating that the combination of ATOR-1017 with anti-PD-1 induced a more potent CD4+ T cells activation than each monotherapy alone.The functional activation profile of ATOR-1017 is expected to minimize the risk of systemic immune activation and toxicity, by directing a potent immune response to immune cells in tumor tissue and tumor draining lymph nodes. This is supported by early data from the ongoing first-in-human phase I study where ATOR-1017 has been shown to be safe and tolerable.ConclusionsIn summary, these results support further clinical development of ATOR-1017 in combination with PD-1 antibodies. By combining ATOR-1017 with anti-PD-1, tumor infiltrating T cells can be more effectively activated and potentially increase the response rate in multiple indications.Ethics ApprovalAll animal procedures were in accordance to IACUC guidance

Poly(methacrylic Acid)-Cellulose Brushes as Anticancer Porphyrazine Carrier

The prospective strategy for treatment of cancer is based on the application of nano-sized macromolecular carriers, which are able penetrate inside and can be accumulated within tumor tissue. In this work graft copolymers of cellulose and poly(methacrylic acid) has been prepared and tested as a nanocontainers for the delivery of drug to tumor. For this purpose, two derivatives of porphyrazine suitable for photodynamic cancer therapy were loaded into prepared polymer brush. Fluorescence imaging was applied for monitoring of accumulation of porphyrazine in the CT26 murine colon carcinoma. The selective accumulation of cellulose brush loaded with porphyrazine in tumor was demonstrated by fluorescence intensity contrast between the tumor area and normal tissues. The tumor growth rate after photodynamic therapy were assessed and inhibition of its growth was revealed.

A Metabolic Change towards Fermentation Drives Cancer Cachexia in Myotubes

Cachexia is a disorder associated with several pathologies, including cancer. In this paper, we describe how cachexia is induced in myotubes by a metabolic shift towards fermentation, and the block of this metabolic modification prevents the onset of the cachectic phenotype. Cachectic myotubes, obtained by the treatment with conditioned medium from murine colon carcinoma cells CT26, show increased glucose uptake, decreased oxygen consumption, altered mitochondria, and increased lactate production. Interestingly, the block of glycolysis by 2-deoxy-glucose or lactate dehydrogenase inhibition by oxamate prevents the induction of cachexia, thus suggesting that this metabolic change is greatly involved in cachexia activation. The treatment with 2-deoxy-glucose or oxamate induces positive effects also in mitochondria, where mitochondrial membrane potential and pyruvate dehydrogenase activity became similar to control myotubes. Moreover, in myotubes treated with interleukin-6, cachectic phenotype is associated with a fermentative metabolism, and the inhibition of lactate dehydrogenase by oxamate prevents cachectic features. The same results have been achieved by treating myotubes with conditioned media from human colon HCT116 and human pancreatic MIAPaCa-2 cancer cell lines, thus showing that what has been observed with murine-conditioned media is a wide phenomenon. These findings demonstrate that cachexia induction in myotubes is linked with a metabolic shift towards fermentation, and inhibition of lactate formation impedes cachexia and highlights lactate dehydrogenase as a possible new tool for counteracting the onset of this pathology.

Oncolytic reovirus shows potentially anticancer effect against CT26 cell lines

Background: Reovirus type 3 Dearing (T3D) is a segmented double-stranded RNA that selectively replicates and triggers anticancer responses in the KRAS mutant cancer cells. Here, we examine the anticancer activity of ReoT3D against murine colon carcinoma cell line (CT26) with deferent in vitro experiments. Results: Our results showed that ReoT3D significantly induced oncolysis in the CT26 cells by induction of apoptosis, and cell cycle arrest in the G0/G1 and G2/M checkpoints and reduction of cell migration and colony forming ability. Conclusion: Present study confirmed that ReoT3D has strong anticancer impacts on CT26 cells which can be considered as a new approach against KRAS mutant cancer cell lines in laboratory investigation.