Delivery technologies for cancer immunotherapy

Nature Reviews Drug Discovery, Journal Year: 2019, Volume and Issue: 18(3), P. 175 - 196

Published: Jan. 8, 2019

Language: Английский

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The Microenvironmental Landscape of Brain Tumors

Cancer Cell, Journal Year: 2017, Volume and Issue: 31(3), P. 326 - 341

Published: March 1, 2017

Language: Английский

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Mechanisms of resistance to immune checkpoint inhibitors

British Journal of Cancer, Journal Year: 2018, Volume and Issue: 118(1), P. 9 - 16

Published: Jan. 1, 2018

Immune checkpoint inhibitors (ICI) targeting CTLA-4 and the PD-1/PD-L1 axis have shown unprecedented clinical activity in several types of cancer are rapidly transforming practice medical oncology. Whereas cytotoxic chemotherapy small molecule ('targeted therapies') largely act on cells directly, immune reinvigorate anti-tumour responses by disrupting co-inhibitory T-cell signalling. While resistance routinely develops patients treated with conventional therapies targeted therapies, durable suggestive long-lasting immunologic memory commonly seen large subsets ICI. However, initial response appears to be a binary event, most non-responders single-agent ICI therapy progressing at rate consistent natural history disease. In addition, late relapses now emerging longer follow-up trial populations, suggesting emergence acquired resistance. As robust biomarkers predict and/or remain elusive, mechanisms underlying innate (primary) (secondary) inferred from pre-clinical studies correlative data. Improved understanding molecular (and resistance) may not only identify novel predictive prognostic biomarkers, but also ultimately guide optimal combination/sequencing clinic. Here we review data identifying inhibition.

Language: Английский

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Genetics and biology of prostate cancer

Genes & Development, Journal Year: 2018, Volume and Issue: 32(17-18), P. 1105 - 1140

Published: Sept. 1, 2018

Despite the high long-term survival in localized prostate cancer, metastatic cancer remains largely incurable even after intensive multimodal therapy. The lethality of advanced disease is driven by lack therapeutic regimens capable generating durable responses setting extreme tumor heterogeneity on genetic and cell biological levels. Here, we review available model systems, genome atlas, cellular functional microenvironment, tumor-intrinsic tumor-extrinsic mechanisms underlying resistance, technological advances focused detection management. These advances, along with an improved understanding adaptive to conventional therapies, anti-androgen therapy, immunotherapy, are catalyzing development more effective strategies for disease. In particular, knowledge heterotypic interactions between coevolution host cells microenvironment has illuminated novel combinations a strong potential eventual cures Improved management will also benefit from artificial intelligence-based expert decision support systems proper standard care, prognostic determinant biomarkers minimize overtreatment disease, new standards care accelerated next-generation clinical trials.

Language: Английский

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Turning the corner on therapeutic cancer vaccines

npj Vaccines, Journal Year: 2019, Volume and Issue: 4(1)

Published: Feb. 8, 2019

Abstract Recent advances in several areas are rekindling interest and enabling progress the development of therapeutic cancer vaccines. These have been made target selection, vaccine technology, methods for reversing immunosuppressive mechanisms exploited by cancers. Studies testing different tumor antigens revealed properties that yield high versus normal cell specificity adequate immunogenicity to affect clinical efficacy. A few tumor-associated antigens, host proteins abnormally expressed cells, demonstrated serve as good targets immunotherapies, although many do not possess needed or immunogenicity. Neoantigens, which arise from mutated truly cancer-specific can be highly immunogenic, though vast majority unique each patient’s thus require personalized therapies. Lessons previous expeditions teaching us type magnitude immune responses needed, well technologies achieve these responses. For example, we learning approaches elicit potent, balanced, durable CD4 plus CD8 T expansion necessary Exploration interactions between system has elucidated adaptations enable cells suppress evade attack. This led breakthroughs new drugs, and, subsequently, opportunities combine with vaccines dramatically increase patient Here review this recent progress, highlighting key steps bringing promise within reach.

Language: Английский

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DNA Damage and Repair Biomarkers of Immunotherapy Response

Cancer Discovery, Journal Year: 2017, Volume and Issue: 7(7), P. 675 - 693

Published: June 20, 2017

DNA-damaging agents are widely used in clinical oncology and exploit deficiencies tumor DNA repair. Given the expanding role of immune checkpoint blockade as a therapeutic strategy, interaction damage with system has recently come into focus, it is now clear that repair landscape an important driving response to blockade. Here, we summarize mechanisms by which genomic instability have been found shape antitumor describe efforts use biomarkers guide immune-directed therapies.

Language: Английский

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Defining the role of the tumor vasculature in antitumor immunity and immunotherapy

Cell Death and Disease, Journal Year: 2018, Volume and Issue: 9(2)

Published: Jan. 25, 2018

Abstract It is now well established that cancer cells co-exist within a complex environment with stromal and depend for their growth dissemination on tight plastic interactions components of the tumor microenvironment (TME). Cancer incite formation new blood lymphatic vessels from preexisting to cope high nutrient/oxygen demand favor outgrowth. Research over past decades has highlighted crucial role played by tumor-associated vasculature in supporting immunoevasion subverting T-cell-mediated immunosurveillance, which are main hallmarks cancers. The structurally functionally aberrant contributes protumorigenic immunosuppressive TME maintaining cell’s permissive characterized hypoxia, acidosis, interstitial pressure, while simultaneously generating physical barrier T cells' infiltration. Recent research moreover shown endothelial forming can actively suppress recruitment, adhesion, activity cells. Likewise, during tumorigenesis undergoes dramatic remodeling facilitates metastatic spreading immunosuppression. Beyond carcinogenesis, erratic been recently implicated mechanisms therapy resistance, including those limiting efficacy clinically approved immunotherapies, such as immune checkpoint blockers adoptive T-cell transfer. In this review, we discuss emerging evidence highlighting major thwarting immunosurveillance antitumor immunity. Moreover, also novel therapeutic approaches targeting potential help overcoming immunotherapy resistance.

Language: Английский

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Resistance to PD1/PDL1 checkpoint inhibition

Cancer Treatment Reviews, Journal Year: 2016, Volume and Issue: 52, P. 71 - 81

Published: Nov. 27, 2016

Language: Английский

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Regulatory circuits of T cell function in cancer

Nature reviews. Immunology, Journal Year: 2016, Volume and Issue: 16(10), P. 599 - 611

Published: Aug. 16, 2016

Language: Английский

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Overall Survival in Patients With Advanced Melanoma Who Received Nivolumab Versus Investigator’s Choice Chemotherapy in CheckMate 037: A Randomized, Controlled, Open-Label Phase III Trial

Journal of Clinical Oncology, Journal Year: 2017, Volume and Issue: 36(4), P. 383 - 390

Published: July 3, 2017

Purpose Until recently, limited options existed for patients with advanced melanoma who experienced disease progression while receiving treatment ipilimumab. Here, we report the coprimary overall survival (OS) end point of CheckMate 037, which has previously shown that nivolumab resulted in more achieving an objective response compared chemotherapy regimens ipilimumab-refractory melanoma. Patients and Methods were stratified by programmed death-ligand 1 expression, BRAF status, best prior cytotoxic T-lymphocyte antigen-4 therapy response, then randomly assigned 2:1 to 3 mg/kg intravenously every 2 weeks or investigator’s choice (ICC; dacarbazine 1,000 mg/m carboplatin area under curve 6 plus paclitaxel 175 weeks). treated until they unacceptable toxicity, follow-up approximately years. Results Two hundred seventy-two (99% treated) 133 ICC (77% treated). More nivolumab-treated had brain metastases (20% v 14%) increased lactate dehydrogenase levels (52% 38%) at baseline; 41% versus 11% received anti–programmed death agents after therapy. Median OS was 16 months 14 (hazard ratio, 0.95; 95.54% CI, 0.73 1.24); median progression-free 3.1 3.7 months, respectively 1.0; 95.1% 0.78 1.436). Overall rate (27% 10%) duration (32 13 months) notably higher ICC. Fewer grade 4 treatment-related adverse events observed on (14% 34%). Conclusion Nivolumab demonstrated higher, durable responses but no difference should be interpreted caution as it likely impacted dropout before treatment, led crossover group, proportion group poor prognostic factors.

Language: Английский

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