Novel combinatorial strategies for boosting the efficacy of immune checkpoint inhibitors in advanced breast cancers

The year 2019 witnessed the first approval of an immune checkpoint inhibitor (ICI) for the management of triple negative breast cancers (TNBC) that are metastatic and programmed death ligand (PD)-L1 positive. Extensive research has focused on testing ICI-based combinatorial strategies, with the ultimate goal of enhancing the response of breast tumors to immunotherapy to increase the number of breast cancer patients benefiting from this transformative treatment. The promising investigational strategies included immunotherapy combinations with monoclonal antibodies (mAbs) against human epidermal growth factor receptor (HER)-2 for the HER2 + tumors versus cyclin-dependent kinase (CDK)4/6 inhibitors in the estrogen receptor (ER) + disease. Multiple approaches are showing signals of success in advanced TNBC include employing Poly (ADP-ribose) polymerase (PARP) inhibitors, tyrosine kinase inhibitors, MEK inhibitors, phosphatidylinositol 3‑kinase (PI3K)/protein kinase B (AKT) signaling inhibitors or inhibitors of adenosine receptor, in combination with the classical PD-1/PD-L1 immune checkpoint inhibitors. Co-treatment with chemotherapy, high intensity focused ultrasound (HIFU) or interleukin-2-βɣ agonist have also produced promising outcomes. This review highlights the latest combinatorial strategies under development for overcoming cancer immune evasion and enhancing the percentage of immunotherapy responders in the different subsets of advanced breast cancers (AU)

Novel combinatorial strategies for boosting the efficacy of immune checkpoint inhibitors in advanced breast cancers.

The year 2019 witnessed the first approval of an immune checkpoint inhibitor (ICI) for the management of triple negative breast cancers (TNBC) that are metastatic and programmed death ligand (PD)-L1 positive. Extensive research has focused on testing ICI-based combinatorial strategies, with the ultimate goal of enhancing the response of breast tumors to immunotherapy to increase the number of breast cancer patients benefiting from this transformative treatment. The promising investigational strategies included immunotherapy combinations with monoclonal antibodies (mAbs) against human epidermal growth factor receptor (HER)-2 for the HER2 + tumors versus cyclin-dependent kinase (CDK)4/6 inhibitors in the estrogen receptor (ER) + disease. Multiple approaches are showing signals of success in advanced TNBC include employing Poly (ADP-ribose) polymerase (PARP) inhibitors, tyrosine kinase inhibitors, MEK inhibitors, phosphatidylinositol 3­kinase (PI3K)/protein kinase B (AKT) signaling inhibitors or inhibitors of adenosine receptor, in combination with the classical PD-1/PD-L1 immune checkpoint inhibitors. Co-treatment with chemotherapy, high intensity focused ultrasound (HIFU) or interleukin-2-ßÉ£ agonist have also produced promising outcomes. This review highlights the latest combinatorial strategies under development for overcoming cancer immune evasion and enhancing the percentage of immunotherapy responders in the different subsets of advanced breast cancers.

Potentiation of the teratogenic effects induced by coadministration of retinoic acid or phytanic acid/phytol with synthetic retinoid receptor ligands.

Previous studies in our laboratory identified retinoid-induced defects that are mediated by RAR-RXR heterodimerization using interaction of synthetic ligands selective for the retinoid receptors RAR and RXR in mice (Elmazar et al. 1997, Toxicol Appl Pharmacol 146:21-28; Elmazar et al. 2001, Toxicol Appl Pharmacol 170:2-9; Nau and Elmazar 1999, Handbook of experimental pharmacology, vol 139, Retinoids, Springer-Verlag, pp 465-487). The present study was designed to investigate whether these RAR-RXR heterodimer-mediated defects can be also induced by interactions of natural and synthetic ligands for retinoid receptors. A non-teratogenic dose of the natural RXR agonist phytanic acid (100 mg/kg orally) or its precursor phytol (500 mg/kg orally) was coadministered with a synthetic RARalpha-agonist (Am580; 5 mg/kg orally) to NMRI mice on day 8.25 of gestation (GD8.25). Furthermore, a non-teratogenic dose of the synthetic RXR agonist LGD1069 (20 mg/kg orally) was also coadministered with the natural RAR agonist, all- trans-retinoic acid (atRA, 20 mg/kg orally) or its precursor retinol (ROH, 50 mg/kg orally) to NMRI mice on GD8.25. The teratogenic outcome was scored in day-18 fetuses. The incidence of Am580-induced resorptions, spina bifida aperta, micrognathia, anotia, kidney hypoplasia, dilated bladder, undescended testis, atresia ani, short and absent tail, fused ribs and fetal weight retardation were potentiated by coadministration of phytanic acid or its precursor phytol. Am580-induced exencephaly and cleft palate, which were not potentiated by coadministration with the synthetic RXR agonists, were also not potentiated by coadministration with either phytanic acid or its precursor phytol. LGD1069 potentiated atRA- and ROH-induced resorption, exencephaly, spina bifida, aperta, ear anotia and microtia, macroglossia, kidney hypoplasia, undescended testis, atresia ani, tail defects and fetal weight retardation, but not cleft palate. These results suggest that synergistic teratogenesis can be induced by coadministration of a natural RXR ligand (phytanic acid) with a synthetic RAR agonist (Am580). Thus, certain potentially useful therapeutic agents or nutritional factors such as phytanic acid should be tested for teratogenic risk by coadministration with other retinoid receptor agonists.

Effect of bioadhesive polymers, sodium salicylate, polyoxyethylene-9-lauryl ether, and method of preparation on the relative hypoglycemia produced by insulin enteric-coated capsules in diabetic beagle dogs.

The hypoglycemic effect of oral insulin capsules coated with pH-dependent Eudragit S100 and containing various absorption promoters was studied in hyperglycemic beagle dogs. The absorption enhancers used were bioadhesive polymers, sodium salicylate, and non-ionic surfactants. A comparative study of the bioadhesive polymers, polycarbophil (PC), hydroxypropyl methylcellulose (HPMC), and carbopol 934 in insulin-coated capsules revealed no significant difference between the insulin capsules containing these polymers, giving relative hypoglycemia (RH) values ranging from 4.3 +/- 2.3% to 6.5 +/- 5.1%. It was also found that the method of preparation of the mixture of the bioadhesive polymer with insulin either by physical mixing or freeze-drying did not affect the RH values obtained. Sodium salicylate, when used in insulin enteric-coated capsules (50 mg) mixed with insulin as a physical mixture, or prepared by wet granulation using 10% polyvinyl pyrollidone (PVP), or by freeze-drying, produced RH values ranging from 7.3 +/- 2.9% to 9.4 +/- 3.7%. When sodium salicylate (100 mg) was used with insulin in freeze-dried granules an RH value of 10 +/- 2.6% was produced. As the dose of insulin increased from 6 to 9 U/kg, the area under curve (AUC) of the enteric-coated capsules containing 50 mg sodium salicylate increased from 73.2 +/- 27.8% to 121.4 +/- 102.7% reduction, but the RH did not change significantly. Insulin capsules containing polyoxyethylene-9-lauryl ether (POELE) used in its optimum concentration (2%), found in these experiments, produced RH of 9.5 +/- 6.8% when prepared as granules by wetting with a few drops of absolute alcohol in the presence of PC (50 mg). Insulin capsules containing lower (1%) or higher (3%) concentrations of POELE and prepared with PC, 50 mg by wet granulation produced lower RH of about 6%. The enteric-coated oral insulin capsules containing insulin (6 or 9 U/kg) and sodium salicylate (50 mg) as an absorption promoter, together with the bioadhesive polymer polycarbophil (50 mg), and prepared either by wet granulation using ethanol or by freeze-drying, are the best formulations to be used. They achieved a reduction in plasma glucose levels of about 25-30% and RH of about 10%. Also insulin (9 U/kg) capsules containing 2% POELE produced a 28% reduction in plasma glucose levels and RH of 9.6 +/- 6.8%.