Boosting Antitumor Immunity with an Expanded Neoepitope Landscape

Nagel, Remco; Pataskar, Abhijeet; Champagne, Julien; Agami, Reuven

doi:10.1158/0008-5472.can-22-1525

Cited by 7 publications

(15 citation statements)

References 202 publications

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“…Tumors that fail to respond to immunotherapy have most likely less neoantigens regardless of the cancer type ( Fang et al, 2022 ). Cancer cells that only express tumor associated antigens or overexpress normal molecules are also less likely to respond to immunotherapy since they do not activate anti-tumor immunity ( Nagel et al, 2022 ). Interestingly, modest responses to PD-1/PD-L1 blockade in patients with non-small cell lung cancer (NSCLC) is strongly associated with weak formation of neoantigens ( Anagnostou et al, 2017a ).…”

Section: Dna-damage Agent Induces Immune System Activationmentioning

confidence: 99%

Destabilizing the genome as a therapeutic strategy to enhance response to immune checkpoint blockade: a systematic review of clinical trials evidence from solid and hematological tumors

Alotaibi,

Alshammari,

Alotaibi

et al. 2024

Front. Pharmacol.

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Background: Genomic instability is increased alterations in the genome during cell division and is common among most cancer cells. Genome instability enhances the risk of initial carcinogenic transformation, generating new clones of tumor cells, and increases tumor heterogeneity. Although genome instability contributes to malignancy, it is also an “Achilles’ heel” that constitutes a therapeutically-exploitable weakness—when sufficiently advanced, it can intrinsically reduce tumor cell survival by creating DNA damage and mutation events that overwhelm the capacity of cancer cells to repair those lesions. Furthermore, it can contribute to extrinsic survival-reducing events by generating mutations that encode new immunogenic antigens capable of being recognized by the immune system, particularly when anti-tumor immunity is boosted by immunotherapy drugs. Here, we describe how genome-destabilization can induce immune activation in cancer patients and systematically review the induction of genome instability exploited clinically, in combination with immune checkpoint blockade.Methods: We performed a systematic review of clinical trials that exploited the combination approach to successfully treat cancers patients. We systematically searched PubMed, Cochrane Central Register of Controlled Trials, Clinicaltrials.gov, and publication from the reference list of related articles. The most relevant inclusion criteria were peer-reviewed clinical trials published in English.Results: We identified 1,490 studies, among those 164 were clinical trials. A total of 37 clinical trials satisfied the inclusion criteria and were included in the study. The main outcome measurements were overall survival and progression-free survival. The majority of the clinical trials (30 out of 37) showed a significant improvement in patient outcome.Conclusion: The majority of the included clinical trials reported the efficacy of the concept of targeting DNA repair pathway, in combination with immune checkpoint inhibitors, to create a “ring of synergy” to treat cancer with rational combinations.

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Section: Dna-damage Agent Induces Immune System Activationmentioning

confidence: 99%

Destabilizing the genome as a therapeutic strategy to enhance response to immune checkpoint blockade: a systematic review of clinical trials evidence from solid and hematological tumors

Alotaibi,

Alshammari,

Alotaibi

et al. 2024

Front. Pharmacol.

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“…Other than classical tumor-associated antigens and neoAgs generated by mutations described above, 137 novel tumor antigens can derive from additional alterations or changes in RNA maturation and translation or in protein processing (reviewed in Xie et al and Nagel et al 19 , 138 ) Antigens deriving from transposable elements have also been described, but they are not discussed in this review. 139 …”

Section: Non-classical Tumor Antigensmentioning

confidence: 99%

Relevance of mutation-derived neoantigens and non-classical antigens for anticancer therapies

Aparicio,

Theunissen,

Hervas-Stubbs

et al. 2024

Human Vaccines & Immunotherapeutics

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Efficacy of cancer immunotherapies relies on correct recognition of tumor antigens by lymphocytes, eliciting thus functional responses capable of eliminating tumor cells. Therefore, important efforts have been carried out in antigen identification, with the aim of understanding mechanisms of response to immunotherapy and to design safer and more efficient strategies. In addition to classical tumor-associated antigens identified during the last decades, implementation of next-generation sequencing methodologies is enabling the identification of neoantigens (neoAgs) arising from mutations, leading to the development of new neoAg-directed therapies. Moreover, there are numerous non-classical tumor antigens originated from other sources and identified by new methodologies. Here, we review the relevance of neoAgs in different immunotherapies and the results obtained by applying neoAg-based strategies. In addition, the different types of non-classical tumor antigens and the best approaches for their identification are described. This will help to increase the spectrum of targetable molecules useful in cancer immunotherapies.

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“…With the in-depth study of neoantigens, many previously unnoticed neoantigens have been discovered [ 4 ], such as neoantigens arising from post-translational modifications and RNA editing. These neoantigens do not result from alterations at the gene level and cannot be identified by relying on sequencing technology or MS-based analysis.…”

Section: The Development History Of Neoantigen Identificationmentioning

confidence: 99%

“…The content about tumor neoantigens has been evolving, and with continuous research, many types of neoantigens have been identified. Tumor neoantigens can be divided into two categories: classical neoantigens and noncanonical neoepitopes [ 4 ]. Among these, classical neoantigens are derived from cancer-specific genetically hardwired alterations, including oncogenic missense mutations, frameshift mutations, splice sites, gene fusions, and long noncoding RNA-derived neoantigens.…”

Section: Introductionmentioning

confidence: 99%

“…Among these, classical neoantigens are derived from cancer-specific genetically hardwired alterations, including oncogenic missense mutations, frameshift mutations, splice sites, gene fusions, and long noncoding RNA-derived neoantigens. Noncanonical neoepitopes are not derived from genetic alterations, encompassing neoepitopes originating from alternative splicing, post-translational modifications, RNA editing, and aberrant mRNA translation [ 4 , 5 ]. Cancer immunotherapies developed against neoantigens have developed rapidly in recent decades [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Value of Microbes in Cancer Neoantigen Immunotherapy

Jing

2023

Pharmaceutics

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Tumor neoantigens are widely used in cancer immunotherapy, and a growing body of research suggests that microbes play an important role in these neoantigen-based immunotherapeutic processes. The human body and its surrounding environment are filled with a large number of microbes that are in long-term interaction with the organism. The microbiota can modulate our immune system, help activate neoantigen-reactive T cells, and play a great role in the process of targeting tumor neoantigens for therapy. Recent studies have revealed the interconnection between microbes and neoantigens, which can cross-react with each other through molecular mimicry, providing theoretical guidance for more relevant studies. The current applications of microbes in immunotherapy against tumor neoantigens are mainly focused on cancer vaccine development and immunotherapy with immune checkpoint inhibitors. This article summarizes the related fields and suggests the importance of microbes in immunotherapy against neoantigens.

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Boosting Antitumor Immunity with an Expanded Neoepitope Landscape

Cited by 7 publications

References 202 publications

Destabilizing the genome as a therapeutic strategy to enhance response to immune checkpoint blockade: a systematic review of clinical trials evidence from solid and hematological tumors

Destabilizing the genome as a therapeutic strategy to enhance response to immune checkpoint blockade: a systematic review of clinical trials evidence from solid and hematological tumors

Relevance of mutation-derived neoantigens and non-classical antigens for anticancer therapies

The Value of Microbes in Cancer Neoantigen Immunotherapy

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