Anti-CD166/4-1BB chimeric antigen receptor T cell therapy for the treatment of osteosarcoma.

BACKGROUND: Chimeric antigen receptor (CAR)-engineered T cells have displayed outstanding performance in the treatment of patients with hematological malignancies. However, their efficacy against solid tumors has been largely limited. METHODS: In this study, human osteosarcoma cell lines were prepared, flow cytometry using antibodies against CD166 was performed on different cell samples. CD166-specific T cells were obtained by viral gene transfer of corresponding DNA plasmids and selectively expanded using IL-2 and IL-15. The ability of CD166.BBζ CAR-T cells to kill CD166+ osteosarcoma cells was evaluated in vitro and in vivo. RESULTS: CD166 was selectively expressed on four different human osteosarcoma cell lines, indicating its role as the novel target for CAR-T cell therapy. CD166.BBζ CAR-T cells killed osteosarcoma cell lines in vitro; the cytotoxicity correlated with the level of CD166 expression on the tumor cells. Intravenous injection of CD166.BBζ CAR-T cells into mice resulted in the regression of the tumor with no obvious toxicity. CONCLUSIONS: Together, the data suggest that CD166.BBζ CAR-T cells may serve as a new therapeutic strategy in the future clinical practice for the treatment of osteosarcoma.

Reelin supplementation recovers synaptic plasticity and cognitive deficits in a mouse model for Angelman syndrome.

The Reelin signaling pathway is implicated in processes controlling synaptic plasticity and hippocampus-dependent learning and memory. A single direct in vivo application of Reelin enhances long-term potentiation, increases dendritic spine density and improves associative and spatial learning and memory. Angelman syndrome (AS) is a neurological disorder that presents with an overall defect in synaptic function, including decreased long-term potentiation, reduced dendritic spine density, and deficits in learning and memory, making it an attractive model in which to examine the ability of Reelin to recover synaptic function and cognitive deficits. In this study, we investigated the effects of Reelin administration on synaptic plasticity and cognitive function in a mouse model of AS and demonstrated that bilateral, intraventricular injections of Reelin recover synaptic function and corresponding hippocampus-dependent associative and spatial learning and memory. Additionally, we describe alteration of the Reelin profile in tissue from both the AS mouse and post-mortem human brain.

Reelin has a preventive effect on phencyclidine-induced cognitive and sensory-motor gating deficits.

Reelin has recently attracted attention because of its connection to several neuropsychiatric diseases. We previously reported the finding that prior transplantation of GABAergic neuron precursor cells into the medial prefrontal cortex (mPFC) of mice significantly prevented the induction of cognitive and sensory-motor gating deficits induced by phencyclidine (PCP). The majority of the precursor cells transplanted into the mPFC of the recipient mice differentiated into members of a somatostatin/Reelin-expressing class of GABAergic interneurons. These findings raised the possibility that Reelin secreted by the transplanted cells plays an important role in preventing the deficits induced by PCP. In this study, we investigated whether Reelin itself has a preventive effect on PCP-induced behavioral phenotypes by injecting conditioned medium containing Reelin into the lateral ventricle of the brains of 6- to 7-week-old male mice before administrating PCP. Behavioral analyses showed that the prior Reelin injection had a preventive effect against induction of the cognitive and sensory-motor gating deficits associated with PCP. Moreover, one of the types of Reelin receptor was found to be expressed by neurons in the mPFC. The results of this study point to the Reelin signaling pathway as a candidate target for the pharmacologic treatment of neuropsychiatric diseases.

A peptide agonist of the neural cell adhesion molecule (NCAM), C3, protects against developmental defects induced by a teratogen pyrimethamine.

The neural cell adhesion molecule, NCAM, not only plays an important role in neuronal migration, differentiation and formation of connections in the developing nervous system, but also in the condensation of the mesodermal mesenchyme of the limb bud. Therefore, NCAM may be regarded as a target molecule for preventive strategies aimed at minimizing the effects of teratogens affecting the prenatal development of the nervous system and the skeleton. Treatment of fetuses with the teratogen pyrimethamine results in a reduced body weight, microcephaly and malformations of the hind limbs and forelimbs, e.g. micromelia, brachydactyly and adactyly. We here show that a peptide agonist of NCAM, C3, partly prevented the defects induced by this treatment. Although intra-amniotic administration of C3 at gestational day 14 had no effect on the pyrimethamine-induced reduction in body weight, it rescued the deficit in brain weight (microcephaly), partly reversed a decrease in thickness of the cortical plate, and significantly reduced the number of malformed fetuses. In vitro, C3 promoted survival of PC12-E2 cells treated with pyrimethamine. Since C3 is a peptide mimetic of NCAM, our data strongly suggest that stimulating of NCAM results in neuroprotection in vivo and in vitro.