Venetoclax Increases Intratumoral Effector T Cells and Antitumor Efficacy in Combination with Immune Checkpoint Blockade.

The antiapoptotic protein BCL2 plays critical roles in regulating lymphocyte development and immune responses, and has also been implicated in tumorigenesis and tumor survival. However, it is unknown whether BCL2 is critical for antitumor immune responses. We evaluated whether venetoclax, a selective small-molecule inhibitor of BCL2, would influence the antitumor activity of immune checkpoint inhibitors (ICI). We demonstrate in mouse syngeneic tumor models that venetoclax can augment the antitumor efficacy of ICIs accompanied by the increase of PD-1+ T effector memory cells. Venetoclax did not impair human T-cell function in response to antigen stimuli in vitro and did not antagonize T-cell activation induced by anti-PD-1. Furthermore, we demonstrate that the antiapoptotic family member BCL-XL provides a survival advantage in effector T cells following inhibition of BCL2. Taken together, these data provide evidence that venetoclax should be further explored in combination with ICIs for cancer therapy. SIGNIFICANCE: The antiapoptotic oncoprotein BCL2 plays critical roles in tumorigenesis, tumor survival, lymphocyte development, and immune system regulation. Here we demonstrate that venetoclax, the first FDA/European Medicines Agency-approved BCL2 inhibitor, unexpectedly can be combined preclinically with immune checkpoint inhibitors to enhance anticancer immunotherapy, warranting clinical evaluation of these combinations.This article is highlighted in the In This Issue feature, p. 1.

Targeting Lineage-specific MITF Pathway in Human Melanoma Cell Lines by A-485, the Selective Small-molecule Inhibitor of p300/CBP.

Metastatic melanoma is responsible for approximately 80% of deaths from skin cancer. Microphthalmia-associated transcription factor (MITF) is a melanocyte-specific transcription factor that plays an important role in the differentiation, proliferation, and survival of melanocytes as well as in melanoma oncogenesis. MITF is amplified in approximately 15% of patients with metastatic melanoma. However, no small-molecule inhibitors of MITF currently exist. MITF was shown to associate with p300/CBP, members of the KAT3 family of histone acetyltransferase. p300 and CREB-binding protein (p300/CBP) regulate a wide range of cellular events such as senescence, apoptosis, cell cycle, DNA damage response, and cellular differentiation. p300/CBP act as transcriptional coactivators for multiple proteins in cancers, including oncogenic transcription factors such as MITF. In this study, we showed that our novel p300/CBP catalytic inhibitor, A-485, induces senescence in multiple melanoma cell lines, similar to silencing expression of EP300 (encodes p300) or MITF We did not observe apoptosis and increase invasiveness upon A-485 treatment. A-485 regulates the expression of MITF and its downstream signature genes in melanoma cell lines undergoing senescence. In addition, expression and copy number of MITF is significantly higher in melanoma cell lines that undergo A-485-induced senescence than resistant cell lines. Finally, we showed that A-485 inhibits histone-H3 acetylation but did not displace p300 at promoters of MITF and its putative downstream genes. Taken together, we provide evidence that p300/CBP inhibition suppressed the melanoma-driven transcription factor, MITF, and could be further exploited as a potential therapy for treating melanoma.

Final report of the amended safety assessment of sodium laureth sulfate and related salts of sulfated ethoxylated alcohols.

Sodium laureth sulfate is a member of a group of salts of sulfated ethoxylated alcohols, the safety of which was evaluated by the Cosmetic Ingredient Review (CIR) Expert Panel for use in cosmetics. Sodium and ammonium laureth sulfate have not evoked adverse responses in any toxicological testing. Sodium laureth sulfate was demonstrated to be a dermal and ocular irritant but not a sensitizer. The Expert Panel recognized that there are data gaps regarding use and concentration of these ingredients. However, the overall information available on the types of products in which these ingredients are used and at what concentrations indicates a pattern of use. The potential to produce irritation exists with these salts of sulfated ethoxylated alcohols, but in practice they are not regularly seen to be irritating because of the formulations in which they are used. These ingredients should be used only when they can be formulated to be nonirritating.

Final report on the safety assessment of PPG-2 methyl ether, PPG-3 methyl ether, and PPG-2 methyl ether acetate.

PPG-2 methyl ether, PPG-3 methyl ether, and PPG-2 methyl ether acetate are used in cosmetics as fragrance ingredients and/or solvents at concentrations of 0.4% to 2%. Propylene glycol ethers are rapidly absorbed and distributed throughout the body when introduced by inhalation or oral exposure, but the inhalation toxicity of PPG-2 methyl ether vapor, for example, is low. Aerosols, such as found with hair sprays, produce particle sizes that are not respirable. Because these ingredients are highly water-soluble, they are likely to be absorbed through the human skin only at slow rates, resulting in low blood concentrations and rapid removal by the kidney. These ingredients are not genotoxic and are not reproductive or developmental toxicants. Overall the data are sufficient to conclude that PPG-2 methyl ether, PPG-3 methyl ether, and PPG-2 methyl ether acetate are safe as used in cosmetics.

Final report on the safety assessment of Piper methysticum leaf/root/stem extract and Piper methysticum root extract.

Piper methysticum leaf/root/stem extract is the cosmetic ingredient name for a material derived from the leaves, roots, and stems of the Piper methysticum G. Forster plant, commonly known as kava kava. This and other kava-derived ingredients are used as skin-conditioning agents at concentrations from 0.0001% to 0.1%. The Food and Drug Administration issued a consumer advisory in 2002 expressing concern about liver damage in individuals who have ingested kava products. The available oral toxicity data support the concern about liver damage on ingestion but do not resolve the question, for example, whether these ingredients would be substantially absorbed through the skin. Other data needs are described, including toxicology data for yangonin, methysticin, and kavain, which may be present in kava-derived ingredients. Accordingly, the available data are insufficient to support the safety of these ingredients in cosmetics.

Amended safety assessment of tall oil acid, sodium tallate, potassium tallate, and ammonium tallate.

Tall oil acid is a mixture of oleic and linoleic acids (fatty acids) and rosin acids derived from tall oil, a by-product of pulp from resinous woods, used in cosmetic products as a surfactant at concentrations up to 8%. Ammonium, potassium, and sodium salts also are listed as cosmetic ingredients. In addition to the studies summarized in this report, extensive toxicity, genotoxicity, and carcinogenicity studies in animals are available for oleic, lauric, palmitic, myristic, and stearic fatty acids as published earlier by the Cosmetic Ingredient Review (CIR). These data may be extrapolated to tall oil acid and its salts. There are no reports of current uses or use concentration data for ammonium tallate, nor are use concentration data available for the other salts. The CIR Expert Panel found tall oil acid, ammonium tallate, potassium tallate, and sodium tallate to be safe cosmetic ingredients in the given practices of use and concentration.

Electron spin resonance study of phosphorus-nitroxides from 1,3-additions of silicon-phosphorus reagents to nitrones.

This article explores a new, convenient route to beta-phosphorus nitroxides. Specifically, the reaction sequence involves the novel 1,3-addition of trimethylsilyl phosphites (e.g. diethyl) or trimethylsilyl phosphines (e.g. diphenyl) to aldo-nitrones [e.g. alpha-phenyl-N-tert-butylnitrone (PBN) or 5,5-dimethyl-l-pyrroline-N-oxide (DMPO)] or keto-nitrones [e.g. 2-ethyl-5,5-dimethyl-1 pyrroline-N-oxide (2-Et-DMPO) or 2-phenyl-5,5-dimethyl-l-pyrroline-N-oxide (2-Ph-DMPO)] to form alpha-phosphityl- or alpha-phosphinyl-O-silylhydroxylamines. Acidic hydrolysis provides the corresponding hydroxylamines that are easily oxidized to the title beta-phosphorus-nitroxides. ESR spectroscopic analysis revealed some very large beta-phosphorus hyperfine splittings (i.e. in excess of 5 mT). For this reason and their remarkable stability (persistence) some of these nitroxides show promise as integral components in new, improved weak-field dynamic nuclear polarization (DNP) magnetometers.