Autocrine-based selection of ligands for personalized CAR-T therapy of lymphoma.

We report the development of a novel platform to enhance the efficacy and safety of follicular lymphoma (FL) treatment. Since lymphoma is a clonal malignancy of a diversity system, every tumor has a different antibody on its cell surface. Combinatorial autocrine-based selection is used to rapidly identify specific ligands for these B cell receptors on the surface of FL tumor cells. The selected ligands are used in a chimeric antigen receptor T cell (CAR-T) format for redirection of human cytotoxic T lymphocytes. Essentially, the format is the inverse of the usual CAR-T protocol. Instead of being a guide molecule, the antibody itself is the target. Thus, these studies raise the possibility of personalized treatment of lymphomas using a private antibody binding ligand that can be obtained in a few weeks.

Soloxolone methyl inhibits influenza virus replication and reduces virus-induced lung inflammation.

Highly pathogenic influenza viruses pose a serious public health threat to humans. Although vaccines are available, new antivirals are needed to efficiently control disease progression and virus transmission due to the emergence of drug-resistant viral strains. In this study, we describe the anti-viral properties of Soloxolone methyl (SM) (methyl 2-cyano-3,12-dioxo-18ßH-olean-9(11),1(2)-dien-30-oate, a chemical derivative of glycyrrhetinic acid) against the flu virus. Anti-flu efficacy studies revealed that SM exhibits antiviral activity against the H1N1 influenza A virus in a dose-dependent manner causing a more than 10-fold decrease in virus titer and a reduction in the expression of NP and M2 viral proteins. In a time-of-addition study, SM was found to act at an early stage of infection to exhibit an inhibitory effect on both the attachment step and virus uptake into cells. Also, in infected cells SM downregulates the expression of the inflammatory cytokines IL-6 and TNF-α. In infected mice, SM administered intranasally prior to and after infection significantly decreases virus titers in the lung and prevents post-challenge pneumonia. Together, these results suggest that Soloxolone methyl might serve as an effective therapeutic agent to manage influenza outbreaks and virus-associated complications, and further preclinical and clinical investigation may be warranted.

The Toxic Effects of Polychemotherapy onto the Liver Are Accelerated by the Upregulated MDR of Lymphosarcoma.

Antitumor therapy of hematological malignancies is impeded due to the high toxicity of polychemotherapy toward liver and increasing multiple drug resistance (MDR) of tumor cells under the pressure of polychemotherapy. These two problems can augment each other and significantly reduce the efficiency of antineoplastic therapy. We studied the combined effect of polychemotherapy and upregulated MDR of lymphosarcoma RLS(40) onto the liver of experimental mice using two treatment schemes. Scheme 1 is artificial: the tumor was subjected to four courses of polychemotherapy while the liver of the tumor-bearing mice was exposed to only one. This was achieved by threefold tumor retransplantation taken from animals subjected to chemotherapy into intact animals. Scheme 2 displays "real-life" status of patients with MDR malignancies: both the tumor and the liver of tumor-bearing mice were subjected to three sequential courses of polychemotherapy. Our data show that the strengthening of MDR phenotype of RLS(40) under polychemotherapy and toxic pressure of polychemotherapy itself has a synergistic damaging effect on the liver that is expressed in the accumulation of destructive changes in the liver tissue, the reduction of the regeneration capacity of the liver, and increasing of Pgp expression on the surface of hepatocytes.