Low-dose carboplatin modifies the tumor microenvironment to augment CAR T cell efficacy in human prostate cancer models.

Chimeric antigen receptor (CAR) T cells have transformed the treatment landscape for hematological malignancies. However, CAR T cells are less efficient against solid tumors, largely due to poor infiltration resulting from the immunosuppressive nature of the tumor microenvironment (TME). Here, we assessed the efficacy of Lewis Y antigen (LeY)-specific CAR T cells in patient-derived xenograft (PDX) models of prostate cancer. In vitro, LeY CAR T cells directly killed organoids derived from androgen receptor (AR)-positive or AR-null PDXs. In vivo, although LeY CAR T cells alone did not reduce tumor growth, a single prior dose of carboplatin reduced tumor burden. Carboplatin had a pro-inflammatory effect on the TME that facilitated early and durable CAR T cell infiltration, including an altered cancer-associated fibroblast phenotype, enhanced extracellular matrix degradation and re-oriented M1 macrophage differentiation. In a PDX less sensitive to carboplatin, CAR T cell infiltration was dampened; however, a reduction in tumor burden was still observed with increased T cell activation. These findings indicate that carboplatin improves the efficacy of CAR T cell treatment, with the extent of the response dependent on changes induced within the TME.

Endogenous opioid effect on breathing during normoxia and hypoxia in developing swine.

In normoxia, the opioid antagonist naltrexone (3 mg/kg i.v.) increased respiratory drive (dITP/dt), frequency (f) and ventilation (V) and decreased tidal volume (Vt) in 1- to 4-day-old anesthetized piglets; it increased dITP/dt in 10- to 18-day-old piglets. During progressive and steady state hypoxia, naltrexone increased dITP/dt, f and V within each age was abolished by naltrexone. Thus, it appears that (1) endogenous opioids modulate breathing in young more than in older piglets during normoxia; (2) during hypoxia, opiates modulate breathing of both young and older piglets, and (3) the increase in hypoxic respiratory drive with age may be related to enhanced respiratory suppression by opioids during hypoxia in the youngest animals. Lastly, respiratory drive is a sensitive measure of subtle differences between two closely related age groups.

Effect of antacid on the bioavailabiity of lithium carbonate.

The effect of an antacid on the bioavailability of lithium carbonate was determined in six healthy men in a crossover study. The volunteers were given single 300-mg doses of lithium carbonate alone and with 30 ml of an antacid containing aluminum and magnesium hydroxides with simethicone. Blood samples were collected at various times for 0-24 hours after each dose. The plasma samples were analyzed for lithium using a spectrophotometer, and bioavailability variables were calculated from plasma lithium concentration-time curves. There were no significant differences in peak plasma lithium concentration, time to peak concentration, area under the concentration-time curve from 0 to 24 hours, first-order absorption rate constant, and first-order elimination rate constant between the two treatments. Concurrent administration of antacids and lithium carbonate should not affect lithium blood concentrations.