We have induced in canines long-term immune tolerance to an allogeneic cell line derived from a spontaneous canine astrocytoma. Allogeneic astrocytoma cells were implanted endoscopically into the subcutaneous space of fetal dogs before the onset of immune competency (< 40th gestational day). At adulthood, dogs rendered tolerant successfully serve as recipients of intracranial transplants of their growing allogeneic, subcutaneous tumor. Transplanted dogs subsequently develop a solid brain tumor with histological features similar to the original astrocytoma. This model may allow rapid development and evaluation of new therapies for brain tumors, as well as afford tumor biology studies that are untenable in smaller, immune incompetent, or inbred animals harboring less representative tumors.
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http://dx.doi.org/10.1038/sj.neo.7900020 | DOI Listing |
Unlabelled: Cancer immunotherapy using immune checkpoint inhibitors and its combination with other anticancer therapies has emerged as a new standard of care because of the encouraging therapeutic effects in various solid cancers. Nonetheless, glioblastoma and pancreatic cancer remain resistant to immunotherapy and represent intractable cancers with the poorest prognosis. We investigated the therapeutic effects of next-generation chimeric antigen receptor (CAR) T cells producing IL7 and chemokine (C-C motif) ligand 19 (CCL19; referred to as 7 × 19 CAR-T) in these intractable cancers.
View Article and Find Full Text PDFInt J Mol Sci
May 2024
Department of Neurosurgery, Nara Medical University, Kashihara 634-8521, Japan.
Cytotherapy
October 2024
Center for Stem Cell and Translational Immunotherapy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA. Electronic address:
Highly malignant brain tumors, glioblastomas (GBM), are immunosuppressive, thereby limiting current promising immunotherapeutic approaches. In this study, we created interferon receptor 1 knockout allogeneic mesenchymal stem cells (MSC) to secrete dual-function pro-apoptotic and immunomodulatory interferon (IFN) β (MSC-IFNβ) using a single lentiviral vector CRISPR/Cas9 system. We show that MSC-IFNβ induces apoptosis in GBM cells and upregulates the cell surface expression of programmed death ligand-1 in tumor cells.
View Article and Find Full Text PDFInt J Mol Sci
May 2024
Department of Immunology, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo 05508-000, Brazil.
Glioblastomas (GBM) are the most common primary malignant brain tumors, comprising 2% of all cancers in adults. Their location and cellular and molecular heterogeneity, along with their highly infiltrative nature, make their treatment challenging. Recently, our research group reported promising results from a prospective phase II clinical trial involving allogeneic vaccination with dendritic cells (DCs).
View Article and Find Full Text PDFNat Commun
March 2024
Department of Industrial and Molecular Pharmaceutics, Purdue University, West Lafayette, IN, USA.
Severe heterogeneity within glioblastoma has spurred the notion that disrupting the interplay between multiple elements on immunosuppression is at the core of meaningful anti-tumor responses. T cell immunoreceptor with Ig and ITIM domains (TIGIT) and its glioblastoma-associated antigen, CD155, form a highly immunosuppressive axis in glioblastoma and other solid tumors, yet targeting of TIGIT, a functionally heterogeneous receptor on tumor-infiltrating immune cells, has largely been ineffective as monotherapy, suggesting that disruption of its inhibitory network might be necessary for measurable responses. It is within this context that we show that the usurpation of the TIGIT - CD155 axis via engineered synNotch-mediated activation of induced pluripotent stem cell-derived natural killer (NK) cells promotes transcription factor-mediated activation of a downstream signaling cascade that results in the controlled, localized blockade of CD73 to disrupt purinergic activity otherwise resulting in the production and accumulation of immunosuppressive extracellular adenosine.
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