CRISPR-Cas9 disruption of PD-1 enhances activity of universal EGFRvIII CAR T cells in a preclinical model of human glioblastoma

Journal for ImmunoTherapy of Cancer, Journal Year: 2019, Volume and Issue: 7(1)

Published: Nov. 14, 2019

Despite remarkable success in the treatment of hematological malignancies, CAR T-cell therapies for solid tumors have floundered, large part due to local immune suppression and effects prolonged stimulation leading dysfunction exhaustion. One mechanism by which gliomas other cancers can hamper T cells is through surface expression inhibitory ligands such as programmed cell death ligand 1 (PD-L1). Using CRIPSR-Cas9 system, we created universal resistant PD-1 inhibition multiplexed gene disruption endogenous receptor (TRAC), beta-2 microglobulin (B2M) (PDCD1). Triple gene-edited demonstrated enhanced activity preclinical glioma models. Prolonged survival mice bearing intracranial was achieved after intracerebral, but not intravenous administration. CRISPR-Cas9 gene-editing only provides a potential source allogeneic, donor cells, also enables simultaneous checkpoint signaling that otherwise impedes maximal antitumor functionality.

Language: Английский

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Understanding the glioblastoma immune microenvironment as basis for the development of new immunotherapeutic strategies

eLife, Journal Year: 2020, Volume and Issue: 9

Published: Feb. 4, 2020

Cancer immunotherapy by immune checkpoint blockade has proven its great potential saving the lives of a proportion late stage patients with immunogenic tumor types. However, even in these sensitive types, majority do not sufficiently respond to therapy. Furthermore, other including glioblastoma, remain largely refractory. The glioblastoma microenvironment is recognized as highly immunosuppressive, posing major hurdle for inducing immune-mediated destruction cancer cells. Scattered information available about presence and activity immunosuppressive or immunostimulatory cell types tumors, tumor-associated macrophages, tumor-infiltrating dendritic cells regulatory T These are heterogeneous at level ontogeny, spatial distribution functionality within compartment, providing insight complex cellular molecular interplay that determines refractory state glioblastoma. This knowledge may also yield next generation targets therapeutic intervention.

Language: Английский

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A review of glioblastoma immunotherapy

Journal of Neuro-Oncology, Journal Year: 2020, Volume and Issue: 151(1), P. 41 - 53

Published: April 6, 2020

Language: Английский

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Neoadjuvant Nivolumab for Patients With Resectable Merkel Cell Carcinoma in the CheckMate 358 Trial

Journal of Clinical Oncology, Journal Year: 2020, Volume and Issue: 38(22), P. 2476 - 2487

Published: April 23, 2020

PURPOSE Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer commonly driven by the polyomavirus (MCPyV). The programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) immunosuppressive pathway often upregulated in MCC, and advanced metastatic MCC frequently responds to PD-1 blockade. We report what we believe be first trial of anti–PD-1 neoadjuvant setting for resectable MCC. METHODS In phase I/II CheckMate 358 study virus-associated types, patients with received nivolumab 240 mg intravenously on days 15. Surgery was planned day 29. Tumor regression assessed radiographically microscopically. MCPyV status, PD-L1 expression, tumor mutational burden (TMB) were pretreatment biopsies. RESULTS Thirty-nine American Joint Committee Cancer stage IIA-IV ≥ dose. Three (7.7%) did not undergo surgery because progression (n = 1) or adverse events 2). Any-grade treatment-related occurred 18 (46.2%), grade 3-4 3 (7.7%), no unexpected toxicities. Among 36 who underwent surgery, 17 (47.2%) achieved pathologic complete response (pCR). 33 evaluable (54.5%) had reductions 30%. Responses observed regardless MCPyV, PD-L1, TMB status. At median follow-up 20.3 months, recurrence-free survival (RFS) overall reached. RFS significantly correlated pCR radiographic at time surgery. No patient relapse during observation. CONCLUSION Nivolumab administered approximately 4 weeks before generally tolerable induced pCRs regressions one half treated patients. These early markers predicted improved RFS. Additional investigation these promising findings warranted.

Language: Английский

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The Society for Immunotherapy of Cancer statement on best practices for multiplex immunohistochemistry (IHC) and immunofluorescence (IF) staining and validation

Journal for ImmunoTherapy of Cancer, Journal Year: 2020, Volume and Issue: 8(1), P. e000155 - e000155

Published: May 1, 2020

Objectives The interaction between the immune system and tumor cells is an important feature for prognosis treatment of cancer. Multiplex immunohistochemistry (mIHC) multiplex immunofluorescence (mIF) analyses are emerging technologies that can be used to help quantify cell subsets, their functional state, spatial arrangement within microenvironment. Methods Society Immunotherapy Cancer (SITC) convened a task force pathologists laboratory leaders from academic centers as well experts pharmaceutical diagnostic companies develop best practice guidelines optimization validation mIHC/mIF assays across platforms. Results Representative outputs advantages disadvantages approaches, such multiplexed chromogenic IHC, immunohistochemical consecutive staining on single slide, mIF (including multispectral approaches), tissue-based mass spectrometry, digital profiling discussed. Conclusions becoming standard tools biomarker studies likely enter routine clinical in near future. Careful assay will ensure robust comparable laboratories potentially Quantitative image analysis output data management considerations addressed complementary manuscript this force.

Language: Английский

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