Novel tools to assist neoepitope targeting in personalized cancer immunotherapy

Saini, Sunil Kumar; Rekers, Nicolle H.; Hadrup, Sine Reker

doi:10.1093/annonc/mdx544

Cited by 28 publications

(19 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Efforts to reverse exhaustion may assist in generation of functional TIL products from such populations, and may include cytokines (eg, IL‐21), agonistic antibodies or epigenetic modifiers . Although potentially not as efficient, reversal of exhaustion in vitro may be possible with current methods of rapid expansion, given the ability of several groups to detect neo‐antigen reactivity in expanded products, though it is uncertain if these cells were Tex or functional ex vivo . Engineering of exhaustion‐resistant TILs (ie, use of CRISPR technology to remove TCIRs) for adoptive cell therapy, or combining adoptive cell therapy with checkpoint blockade may avoid recrudescence of T cell dysfunction and improve the efficacy of cellular cancer therapeutics …”

Section: Outstanding Questionsmentioning

confidence: 99%

The function and dysfunction of memory CD8⁺ T cells in tumor immunity

Reading

Gálvez-Cancino

Swanton

et al. 2018

Immunological Reviews

128

107

View full text Add to dashboard Cite

The generation and maintenance of CD8 T cell memory is crucial to long-term host survival, yet the basic tenets of CD8 T cell immunity are still being established. Recent work has led to the discovery of tissue-resident memory cells and refined our understanding of the transcriptional and epigenetic basis of CD8 T cell differentiation and dysregulation. In parallel, the unprecedented clinical success of immunotherapy has galvanized an intense, global research effort to decipher and de-repress the anti-tumor response. However, the progress of immunotherapy is at a critical juncture, since the efficacy of immuno-oncology agents remains confined to a fraction of patients and often fails to provide durable benefit. Unlocking the potential of immunotherapy requires the design of strategies that both induce a potent effector response and reliably forge stable, functional memory T cell pools capable of protecting from recurrence or relapse. It is therefore essential that basic and emerging concepts of memory T cell biology are rapidly and faithfully transposed to advance therapeutic development in cancer immunotherapy. This review highlights seminal and recent reports in CD8 T cell memory and tumor immunology, and evaluates recent data from solid cancer specimens in the context of the key paradigms from preclinical models. We elucidate the potential significance of circulating effector cells poised downstream of neoantigen recognition and upstream of T cell dysfunction and propose that cells in this immunological 'sweet spot' may be key anti-tumor effectors.

show abstract

Section: Outstanding Questionsmentioning

confidence: 99%

The function and dysfunction of memory CD8⁺ T cells in tumor immunity

Reading

Gálvez-Cancino

Swanton

et al. 2018

Immunological Reviews

128

107

View full text Add to dashboard Cite

show abstract

“…The progress in analyzing T cell receptor (TCR) repertoires in cancer tissues made it possible to evaluate the diversity of T cell clonotypes and the extent of clonal T cell expansion, and to characterize neoantigen‐specific TCR . Detailed information on the tumor microenvironment may serve as a predictive marker for immunomodulatory therapies and may also be useful for development of new treatment strategies, including personalized T cell‐mediated cancer immunotherapy and neoantigen vaccine therapy . TCR repertoire analyses could be used to monitor the dynamics of T cell clonality and the individual tumor‐reactive T cell clones in cancer patients treated with ICI .…”

Section: Introductionmentioning

confidence: 99%

Significant differences in T cell receptor repertoires in lung adenocarcinomas with and without epidermal growth factor receptor mutations

et al. 2019

View full text Add to dashboard Cite

Recent clinical trials of non‐small cell lung cancer with immune checkpoint inhibitors revealed that patients with epidermal growth factor receptor (EGFR) mutations had more unfavorable outcomes compared with those with wild‐type EGFR. However, the underlying mechanism for the link between EGFR mutations and immune resistance remains unclear. We performed T cell receptor (TCR) repertoire analysis of resected lung adenocarcinoma tissues with and without EGFR mutations to investigate the characteristics of TCR repertoires. We collected a total of 39 paired (normal and tumor) lung tissue samples (20 had EGFR mutations) and conducted TCR repertoire analysis as well as whole‐exome sequencing (WES) and transcriptome analysis. The TCR diversity index in EGFR‐mutant tumors was significantly higher than that in EGFR‐wild‐type tumors (median [range] 552 [162‐1,135] vs 230 [30‐764]; P < .01), suggesting higher T cell clonal expansion in EGFR‐wild‐type tumors than in EGFR‐mutant tumors. In WES, EGFR‐mutant tumors showed lower numbers of non‐synonymous mutations and predicted neoantigens than EGFR‐wild‐type tumors (P < .01, P = .03, respectively). The number of non‐synonymous mutations revealed a positive correlation with the sum of frequencies of the TCRβ clonotypes of 1% or higher in tumors (r = .52, P = .04). The present study demonstrates significant differences in TCR repertoires and the number of predicted neoantigens between EGFR‐mutant and wild‐type lung tumors. Our findings provide important information for understanding the molecular mechanism behind EGFR‐mutant patients showing unfavorable responses to immune checkpoint inhibitors.

show abstract

“…Thus, mutation of either passenger or cancer-driving genes generates novel neoepitopes presented by tumor cells. These neoepitopes may be sufficiently different from the unmutated, self-epitopes to prime, and activate, pre-existing T cells which have not been tolerized, or deleted, and which can lead to potentially clearative antitumor T-cell responses [21][22][23][24] . Neoepitopes are encoded by nonsynonymous mutations, splice variants, or genome rearrangements that transform a self-peptide into a nonself peptide, and their identification, and approaches to specifically activate their cognate T cells, have provided effective clinical therapy 25 .…”

mentioning

confidence: 99%

APOBEC3B-mediated corruption of the tumor cell immunopeptidome induces heteroclitic neoepitopes for cancer immunotherapy

et al. 2020

View full text Add to dashboard Cite

APOBEC3B, an anti-viral cytidine deaminase which induces DNA mutations, has been implicated as a mediator of cancer evolution and therapeutic resistance. Mutational plasticity also drives generation of neoepitopes, which prime anti-tumor T cells. Here, we show that overexpression of APOBEC3B in tumors increases resistance to chemotherapy, but simultaneously heightens sensitivity to immune checkpoint blockade in a murine model of melanoma. However, in the vaccine setting, APOBEC3B-mediated mutations reproducibly generate heteroclitic neoepitopes in vaccine cells which activate de novo T cell responses. These cross react against parental, unmodified tumors and lead to a high rate of cures in both subcutaneous and intra-cranial tumor models. Heteroclitic Epitope Activated Therapy (HEAT) dispenses with the need to identify patient specific neoepitopes and tumor reactive T cells ex vivo. Thus, actively driving a high mutational load in tumor cell vaccines increases their immunogenicity to drive anti-tumor therapy in combination with immune checkpoint blockade.

show abstract

Novel tools to assist neoepitope targeting in personalized cancer immunotherapy

Cited by 28 publications

References 65 publications

The function and dysfunction of memory CD8⁺ T cells in tumor immunity

The function and dysfunction of memory CD8⁺ T cells in tumor immunity

Significant differences in T cell receptor repertoires in lung adenocarcinomas with and without epidermal growth factor receptor mutations

APOBEC3B-mediated corruption of the tumor cell immunopeptidome induces heteroclitic neoepitopes for cancer immunotherapy

Contact Info

Product

Resources

About

Novel tools to assist neoepitope targeting in personalized cancer immunotherapy

Cited by 28 publications

References 65 publications

The function and dysfunction of memory CD8+ T cells in tumor immunity

The function and dysfunction of memory CD8+ T cells in tumor immunity

Significant differences in T cell receptor repertoires in lung adenocarcinomas with and without epidermal growth factor receptor mutations

APOBEC3B-mediated corruption of the tumor cell immunopeptidome induces heteroclitic neoepitopes for cancer immunotherapy

Contact Info

Product

Resources

About

The function and dysfunction of memory CD8⁺ T cells in tumor immunity

The function and dysfunction of memory CD8⁺ T cells in tumor immunity