Immune Escape After Adoptive T-cell Therapy for Malignant Gliomas

Wildes, Tyler J.; Dyson, Kyle; Francis, CM; Wummer, Brandon; Yang, Changlin; Yegorov, Oleg; Shin, David; Grippin, Adam; Dean, Bayli DiVita; Abraham, Rebecca; Pham, Christina; Moore, Ginger; Kuizon, Carmelle; Mitchell, Duane A.; Flores, Catherine

doi:10.1158/1078-0432.ccr-20-1065

Cited by 32 publications

(18 citation statements)

References 59 publications

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“…It appears evident that an understanding of the biology of how the TME shapes the pattern and levels of immune-cell infiltration and exhaustion will be a key factor for the success of ACT. 162 This understanding could provide the biological knowledge to pharmacologically modulate the key pathways of immunoevasion prior to or during the administration of ACT to the patients. Furthermore, drugs could be administered to tumour fragments ex vivo during the manufacturing of the cell product to increase TIL expansion and activation.…”

Section: Ex Vivo Drug Modulation Modifications Of Culturing Conditionmentioning

confidence: 99%

Promises and challenges of adoptive T-cell therapies for solid tumours

et al. 2021

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Cancer is a leading cause of death worldwide and, despite new targeted therapies and immunotherapies, many patients with advanced-stage- or high-risk cancers still die, owing to metastatic disease. Adoptive T-cell therapy, involving the autologous or allogeneic transplant of tumour-infiltrating lymphocytes or genetically modified T cells expressing novel T-cell receptors or chimeric antigen receptors, has shown promise in the treatment of cancer patients, leading to durable responses and, in some cases, cure. Technological advances in genomics, computational biology, immunology and cell manufacturing have brought the aspiration of individualised therapies for cancer patients closer to reality. This new era of cell-based individualised therapeutics challenges the traditional standards of therapeutic interventions and provides opportunities for a paradigm shift in our approach to cancer therapy. Invited speakers at a 2020 symposium discussed three areas—cancer genomics, cancer immunology and cell-therapy manufacturing—that are essential to the effective translation of T-cell therapies in the treatment of solid malignancies. Key advances have been made in understanding genetic intratumour heterogeneity, and strategies to accurately identify neoantigens, overcome T-cell exhaustion and circumvent tumour immunosuppression after cell-therapy infusion are being developed. Advances are being made in cell-manufacturing approaches that have the potential to establish cell-therapies as credible therapeutic options. T-cell therapies face many challenges but hold great promise for improving clinical outcomes for patients with solid tumours.

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Section: Ex Vivo Drug Modulation Modifications Of Culturing Conditionmentioning

confidence: 99%

Promises and challenges of adoptive T-cell therapies for solid tumours

et al. 2021

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“…There are three general ways by which cancer cells evade the immune system (Wildes et al, 2020). First, cancer cells alter surface membrane molecules that fool cytotoxic T-cells into perceiving them as unsuitable prey.…”

Section: Anti-predator Adaptations In Cancermentioning

confidence: 99%

Ecology of Fear: Spines, Armor and Noxious Chemicals Deter Predators in Cancer and in Nature

et al. 2021

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In nature, many multicellular and unicellular organisms use constitutive defenses such as armor, spines, and noxious chemicals to keep predators at bay. These defenses render the prey difficult and/or dangerous to subdue and handle, which confers a strong deterrent for predators. The distinct benefit of this mode of defense is that prey can defend in place and continue activities such as foraging even under imminent threat of predation. The same qualitative types of armor-like, spine-like, and noxious defenses have evolved independently and repeatedly in nature, and we present evidence that cancer is no exception. Cancer cells exist in environments inundated with predator-like immune cells, so the ability of cancer cells to defend in place while foraging and proliferating would clearly be advantageous. We argue that these defenses repeatedly evolve in cancers and may be among the most advanced and important adaptations of cancers. By drawing parallels between several taxa exhibiting armor-like, spine-like, and noxious defenses, we present an overview of different ways these defenses can appear and emphasize how phenotypes that appear vastly different can nevertheless have the same essential functions. This cross-taxa comparison reveals how cancer phenotypes can be interpreted as anti-predator defenses, which can facilitate therapy approaches which aim to give the predators (the immune system) the upper hand. This cross-taxa comparison is also informative for evolutionary ecology. Cancer provides an opportunity to observe how prey evolve in the context of a unique predatory threat (the immune system) and varied environments.

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“…In glioma, recent studies have reported that immunotherapy such as anti-PD-1 and anti-VEGFA could predominantly prolong the survival of some glioma patients, but the response population was not stable, only a subset of patients could benefit from immunotherapy ( Sandmann et al, 2015 ; Lyon et al, 2017 ; Schalper et al, 2019 ). The immunotherapy limitation may be due to the high heterogeneity of gliomas and their complex immune escape mechanisms ( Jackson et al, 2019 ; Wildes et al, 2020 ). Thus, investigating the molecular heterogeneity and potential immune escape mechanisms of gliomas may contribute to the development of immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Molecular Analyses of a Novel Mutational Signature Classification System with Regard to Prognosis, Genomic Alterations, and Immune Landscape in Glioma

Wang

Liu

et al. 2021

Front. Mol. Biosci.

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Background: Glioma is the most common malignant brain tumor with complex carcinogenic process and poor prognosis. The current molecular classification cannot fully elucidate the molecular diversity of glioma.Methods: Using broad public datasets, we performed cluster analysis based on the mutational signatures and further investigated the multidimensional heterogeneity of the novel glioma molecular subtypes. The clinical significance and immune landscape of four clusters also investigated. The nomogram was developed using the mutational clusters and clinical characteristics.Results: Four heterogenous clusters were identified, termed C1, C2, C3, and C4, respectively. These clusters presented distinct molecular features: C1 was characterized by signature 1, PTEN mutation, chromosome seven amplification and chromosome 10 deletion; C2 was characterized by signature 8 and FLG mutation; C3 was characterized by signature 3 and 13, ATRX and TP53 mutations, and 11p15.1, 11p15.5, and 13q14.2 deletions; and C4 was characterized by signature 16, IDH1 mutation and chromosome 1p and 19q deletions. These clusters also varied in biological functions and immune status. We underlined the potential immune escape mechanisms: abundant stromal and immunosuppressive cells infiltration and immune checkpoints (ICPs) blockade in C1; lack of immune cells, low immunogenicity and antigen presentation defect in C2 and C4; and ICPs blockade in C3. Moreover, C4 possessed a better prognosis, and C1 and C3 were more likely to benefit from immunotherapy. A nomogram with excellent performance was also developed for assessing the prognosis of patients with glioma.Conclusion: Our results can enhance the mastery of molecular features and facilitate the precise treatment and clinical management of glioma.

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Immune Escape After Adoptive T-cell Therapy for Malignant Gliomas

Abstract: Purpose: Immunotherapy has been demonstrably effective against multiple cancers, yet tumor escape is common. It remains unclear how brain tumors escape immunotherapy and how to overcome this immune escape.

Cited by 32 publications

References 59 publications

Promises and challenges of adoptive T-cell therapies for solid tumours

Promises and challenges of adoptive T-cell therapies for solid tumours

Ecology of Fear: Spines, Armor and Noxious Chemicals Deter Predators in Cancer and in Nature

Comprehensive Molecular Analyses of a Novel Mutational Signature Classification System with Regard to Prognosis, Genomic Alterations, and Immune Landscape in Glioma

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