Rapid tumor regression in an Asian lung cancer patient following personalized neo-epitope peptide vaccination

Li, Fenge; Chen, Caixia; Ju, Tao; Gao, Jun-Qin; Yan, Jun; Wang, Peng; Xu, Qiang; Hwu, Patrick; Du, Xueming; Lizée, Gregory

doi:10.1080/2162402x.2016.1238539

Cited by 21 publications

(25 citation statements)

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“…NetMHCpan (http://www.cbs.dtu.dk/services/NetMHCpan/) is widely used for peptide prediction (38,(42)(43)(44)(45)(46). Based on previous knowledge, peptide prediction using NetMHCpan showed that the P motif of HLA-A * 30:01-binding peptides was biased toward both A1 supertype-preferred residues (Ile and Leu), and A3 supertype-preferred residues (Arg and Lys) ( Figure 7A).…”

Section: Discussionmentioning

confidence: 99%

“…Screening of immunogenic peptides which are presented by specific MHC I molecules is crucial for the development of vaccines for infection diseases or cancer immunotherapy and for T-cell immune response evaluation (45)(46)(47)(48)(49)(50)(51). Recently, several pre-clinical and clinical studies have shown that vaccines targeting predicted personal tumor neoantigens are feasibility, safety, and immunogenicity (45,50,(52)(53)(54)(55).…”

Section: Discussionmentioning

confidence: 99%

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Divergent Peptide Presentations of HLA-A*30 Alleles Revealed by Structures With Pathogen Peptides

et al. 2019

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Human leukocyte antigen (HLA) alleles have a high degree of polymorphism, which determines their peptide-binding motifs and subsequent T-cell receptor recognition. The simplest way to understand the cross-presentation of peptides by different alleles is to classify these alleles into supertypes. A1 and A3 HLA supertypes are widely distributed in humans. However, direct structural and functional evidence for peptide presentation features of key alleles (e.g., HLA-A * 30:01 and -A * 30:03) are lacking. Herein, the molecular basis of peptide presentation of HLA-A * 30:01 and -A * 30:03 was demonstrated by crystal structure determination and thermostability measurements of complexes with T-cell epitopes from influenza virus (NP44), human immunodeficiency virus (RT313), and Mycobacterium tuberculosis (MTB). When binding to the HIV peptide, RT313, the PΩ-Lys anchoring modes of HLA-A * 30:01, and -A * 30:03 were similar to those of HLA-A * 11:01 in the A3 supertype. However, HLA-A * 30:03, but not -A * 30:01, also showed binding with the HLA * 01:01-favored peptide, NP44, but with a specific structural conformation. Thus, different from our previous understanding, HLA-A * 30:01 and -A * 30:03 have specific peptide-binding characteristics that may lead to their distinct supertype-featured binding peptide motifs. Moreover, we also found that residue 77 in the F pocket was one of the key residues for the divergent peptide presentation characteristics of HLA-A * 30:01 and -A * 30:03. Interchanging residue 77 between HLA-A * 30:01 and HLA-A * 30:03 switched their presented peptide profiles. Our results provide important recommendations for screening virus and tumor-specific peptides among the population with prevalent HLA supertypes for vaccine development and immune interventions.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Divergent Peptide Presentations of HLA-A*30 Alleles Revealed by Structures With Pathogen Peptides

et al. 2019

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“…Li et al designed a saline-based multi-epitope peptide vaccine and demonstrated rapid tumour shrinkage of multiple lung tumour nodules in a lung cancer patient following administration 63 . However, eight weeks following the initiation of vaccination, the patient died from complications due to the progression of liver metastases.…”

Section: Future Perspectives Of Neoantigen Vaccinesmentioning

confidence: 99%

Personalized cancer neoantigen vaccines come of age

Chu¹,

Liu²,

Wei³

et al. 2018

Theranostics

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Cancer vaccines have encountered their ideal personalized partner along with evidence for great breakthroughs in the identification and synthesis of neoantigens. Individual cancer neoantigen vaccines are capable of eliciting robust T-cell responses and have been demonstrated to achieve striking clinical efficacy due to their high immunogenicity and central thymic tolerance escape of neoantigens. Two recent phase I clinical trials have provided support for the hypothesis and have heralded a nascent era of personalized vaccines in the field of immunotherapy. This review aims to address the identification of neoepitopes and describes advances made in personalized vaccines. In addition, this review discusses the challenges related to the exploitation of vaccine therapy, and provides potential thoughts for the improvement of vaccine design and applications.

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“…Naturally occurring tumor infiltrating lymphocytes (TILs) are mostly directed towards neoantigens, their frequency correlates to the tumor mutational burden and associate with increased survival [ 5 – 8 ]. Therapeutic cancer vaccines based on mutated neoantigens are currently evaluated in clinical trials showing significant prolonged patients’ survival, including also synthetic long peptide vaccines which are capable of inducing both CD8+ and CD4+ neoantigen-specific T-cell responses [ 9 – 12 ]. Moreover, clinical benefit of melanoma and lung cancer patients treated with checkpoint inhibitors (anti-CTLA-4 and PD-1) has been found to correlate not only with pre-existing T-cell infiltration and PD-L1 expression in tumors [ 13 ], but also with the mutational burden of treated tumors [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Unique true predicted neoantigens (TPNAs) correlates with anti-tumor immune control in HCC patients

et al. 2018

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BackgroundA novel prediction algorithm is needed for the identification of effective tumor associated mutated neoantigens. Only those with no homology to self wild type antigens are true predicted neoantigens (TPNAs) and can elicit an antitumor T cell response, not attenuated by central tolerance. To this aim, the mutational landscape was evaluated in HCV-associated hepatocellular carcinoma.MethodsLiver tumor biopsies and adjacent non-tumor liver tissues were obtained from 9 HCV-chronically infected subjects and subjected to RNA-Seq analysis. Mutant peptides were derived from single nucleotide variations and TPNAs were predicted using two prediction servers (e.g. NetTepi and NetMHCstabpan) by comparison with corresponding wild-type sequences, non-related self and pathogen-related antigens. Immunological confirmation was obtained in preclinical as well as clinical setting.ResultsThe development of such an improved algorithm resulted in a handful of TPNAs despite the large number of predicted neoantigens. Furthermore, TPNAs may share homology to pathogen’s antigens and be targeted by a pre-existing T cell immunity. Cross-reactivity between such antigens was confirmed in an experimental pre-clinical setting. Finally, TPNAs homologous to pathogen’s antigens were found in the only HCC long-term survival patient, suggesting a correlation between the pre-existing T cell immunity specific for these TPNAs and the favourable clinical outcome.ConclusionsThe new algorithm allowed the identification of the very few TPNAs in cancer cells, and those targeted by a pre-existing immunity strongly correlated with long-term survival. Only such TPNAs represent the optimal candidates for immunotherapy strategies.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1662-9) contains supplementary material, which is available to authorized users.

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Rapid tumor regression in an Asian lung cancer patient following personalized neo-epitope peptide vaccination

Cited by 21 publications

References 40 publications

Divergent Peptide Presentations of HLA-A*30 Alleles Revealed by Structures With Pathogen Peptides

Divergent Peptide Presentations of HLA-A*30 Alleles Revealed by Structures With Pathogen Peptides

Personalized cancer neoantigen vaccines come of age

Unique true predicted neoantigens (TPNAs) correlates with anti-tumor immune control in HCC patients

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