Cancer immunotherapy: exploiting neoepitopes

Platten, Michael; Offringa, Rienk

doi:10.1038/cr.2015.66

Cited by 21 publications

(9 citation statements)

References 14 publications

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“…However, their utility in tumors with lower mutational burden, such as those that occur in pediatric cancers, is less clear ( 37 ). The development of more targeted T cell based immunotherapies to treat cancer relies on understanding the molecular basis of neoepitope display on tumor cells, in addition to the initiation and regulation of cytotoxic CD8+ T cell responses ( 38 ). A current roadblock in the development of robust approaches across patients is that the HLA locus is extremely polymorphic, and an individual’s exact HLA haplotype sculpts the repertoire of epitopes displayed to the immune system ( 5 ).…”

Section: Discussionmentioning

confidence: 99%

A Recurrent Mutation in Anaplastic Lymphoma Kinase with Distinct Neoepitope Conformations

Toor

McShan

et al. 2018

Front. Immunol.

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The identification of recurrent human leukocyte antigen (HLA) neoepitopes driving T cell responses against tumors poses a significant bottleneck in the development of approaches for precision cancer therapeutics. Here, we employ a bioinformatics method, Prediction of T Cell Epitopes for Cancer Therapy, to analyze sequencing data from neuroblastoma patients and identify a recurrent anaplastic lymphoma kinase mutation (ALK R1275Q) that leads to two high affinity neoepitopes when expressed in complex with common HLA alleles. Analysis of the X-ray structures of the two peptides bound to HLA-B*15:01 reveals drastically different conformations with measurable changes in the stability of the protein complexes, while the self-epitope is excluded from binding due to steric hindrance in the MHC groove. To evaluate the range of HLA alleles that could display the ALK neoepitopes, we used structure-based Rosetta comparative modeling calculations, which accurately predict several additional high affinity interactions and compare our results with commonly used prediction tools. Subsequent determination of the X-ray structure of an HLA-A*01:01 bound neoepitope validates atomic features seen in our Rosetta models with respect to key residues relevant for MHC stability and T cell receptor recognition. Finally, MHC tetramer staining of peripheral blood mononuclear cells from HLA-matched donors shows that the two neoepitopes are recognized by CD8+ T cells. This work provides a rational approach toward high-throughput identification and further optimization of putative neoantigen/HLA targets with desired recognition features for cancer immunotherapy.

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Section: Discussionmentioning

confidence: 99%

A Recurrent Mutation in Anaplastic Lymphoma Kinase with Distinct Neoepitope Conformations

Toor

McShan

et al. 2018

Front. Immunol.

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“…Cancer cells, as a natural defense mechanism, upregulate checkpoint blockade ligands to shutdown T cells which may have had the potential to elicit an attack on the cancer cells initiated by their recognition of neo-antigens which had been recognized as ‘foreign’. This observation is well documented, particularly in cancers, such as NSCLC and melanoma, where mutational burden is quite high (27). In addition to preventing the activation of checkpoint blockade to promote CTL functionality, depleting T regulatory cells (T regs ) to reduce immunosuppression from the tumor microenvironment is touted as another potential therapeutic angle.…”

Section: Checkpoint Blockade Inhibitorsmentioning

confidence: 84%

“…Tumor vaccination relies upon the presence of highly immunogenic neo-antigens expressed by tumor-derived cells, and their capacity to elicit a long lasting anti-tumor, CTL-mediated response. Gliomas typically have a low mutational burden, relative to other cancers such as melanoma or non-squamous cell lung cancer (NSCLC), and thus the number of neo-antigens to vaccinate against are much lower (27). Moreover, gliomas typically vary widely in which mutations they carry, making genetic screening and personalized vaccination for each individual a necessity if therapy is to be efficacious.…”

Section: Vaccine Developmentmentioning

confidence: 99%

Advances in immunotherapeutic research for glioma therapy

Miyauchi

Tsirka

2017

J Neurol

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Gliomas are primary malignancies of the brain. Tumors are staged based on malignancy, nuclear atypia, and infiltration of the surrounding brain parenchyma. Tumors are often diagnosed once patients become symptomatic, at which time the lesion is sizable. Glioblastoma (grade IV glioma) is highly aggressive and difficult to treat. Most tumors are diagnosed de novo. The gold standard of therapy, implemented over a decade ago, consists of fractionated radiotherapy and temozolomide, but unfortunately, chemotherapeutic resistance arises. Recurrence is common after initial therapy. The tumor microenvironment plays a large role in cancer progression and its manipulation can repress progression. The advent and implementation of immunotherapy, via manipulation and activation of cytotoxic T cells, have had an outstanding impact on reducing morbidity and mortality associated with peripheral cancers under certain clinical circumstances. An arsenal of immunotherapeutics is currently under clinical investigation for safety and efficacy in the treatment of newly diagnosed and recurrent high grade gliomas. These immunotherapeutics encompass antibody-drug conjugates, autologous infusions of modified chimeric antigen receptor expressing T cells, peptide vaccines, autologous dendritic cell vaccines, immunostimulatory viruses, oncolytic viruses, checkpoint blockade inhibitors, and drugs which alter the behavior of innate immune cells. Effort is focusing on determining which patient populations will benefit the most from these treatments and why. Research addressing synergism between treatment options is gaining attention. While advances in the treatment of glioma stagnated in the past, we may see a considerable evolution in the management of the disease in the upcoming years.

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“…39 The more pertinent problem is that the induction of an efficacious antitumor immunity may be hampered by the expression of self-antigens in the thymus, resulting in central T cell tolerance and the development of antigen-specific suppressive T-regulatory cells. 40 Hence, many current clinical trials targeting self-antigens combine multiple epitopes. Some approaches select one or multiple vaccines from a warehouse of vaccines based on individual antigen expression, antigen presentation, and/or preexisting immune responses.…”

Section: Vaccination Strategiesmentioning

confidence: 99%

Concepts for Immunotherapies in Gliomas

Platten

Reardon

2018

Semin Neurol

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Strategies to empower the immune system to successfully attack cancers, including vaccination approaches, adaptive T cell therapies, and immune checkpoint modulators, have recently achieved remarkable success across a spectrum of cancer indications. Nonetheless, with rare exception, only a minority of patients with a given type of cancer respond to an immunotherapeutic when administered as single-agent therapy. Although under extensive laboratory and clinical investigation, the role of these approaches for glioma patients remains to be determined. While the central nervous system (CNS) is no longer regarded as an immunoprivileged sanctuary, nuances regarding immune responses in the CNS may impact on the activity of immunotherapy treatments of brain tumor patients. Furthermore, many common CNS tumors such as World Health Organization grade III and IV (high grade) gliomas utilize myriad, nonoverlapping strategies to dampen or extinguish antitumor immune responses. For these reasons, critical research efforts are focused on identifying biomarkers that predict patients with a heightened likelihood of therapeutic benefit as well as evaluating rationally designed combinatorial immunotherapy approaches with potentially complementary mechanisms of immune-activation for brain cancer patients.

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Cancer immunotherapy: exploiting neoepitopes

Cited by 21 publications

References 14 publications

A Recurrent Mutation in Anaplastic Lymphoma Kinase with Distinct Neoepitope Conformations

A Recurrent Mutation in Anaplastic Lymphoma Kinase with Distinct Neoepitope Conformations

Advances in immunotherapeutic research for glioma therapy

Concepts for Immunotherapies in Gliomas

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