Indication-specific tumor evolution and its impact on neoantigen targeting and biomarkers for individualized cancer immunotherapies

Lo, Amy A.; Wallace, Andrew; Oreper, Daniel; Lounsbury, Nicolas; Havnar, Charles; Pechuan-Jorge, Ximo; Wu, Thomas D.; Bourgon, Richard; Jones, Ryan D.; Krogh, Katrina; Yang, Guang–Yu; Zill, Oliver A.

doi:10.1136/jitc-2021-003001

Cited by 10 publications

(12 citation statements)

References 59 publications

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“…We observed 1% complete response (CR), 29% partial response (PR), 48% stable disease (SD), and 22% progressive disease (PD) at 54 weeks per RECIST v1.1 (Figure 3B-D) [24]. These outcomes were consistent with pooled results from 4 anti-PD-1 monotherapy arms in trials of previously untreated late-stage NSCLC [19][20][21][22].…”

Section: Neoantigen Burden Correlates With Ici Responsesupporting

confidence: 84%

“…We simulated the growth of 100 NSCLC tumors and characterized their neoantigen clonal architectures using parameters derived from previous literature (Figure 1A, Table S1). To model the oligoclonality of anti-tumor adaptive immunity, the two most clonally expressed and immunogenic neoantigens at any given time were deemed TDAs, such that only cells harboring TDAs were at greater propensity to be eliminated[2, 22].…”

Section: Resultsmentioning

confidence: 99%

“…We allowed simulated tumors to grow until pre-determined sizes to approximate the TRACERx 100 cohort of 26 stage I, 36 stage IB, 13 stage IIA, and 25 stage IIB/IIIA/IIIB tumors (Figure 1C) [23]. As they grew, clones within a tumor were allowed to modify their presentomes by acquiring new neoantigens, losing extant neoantigens, and losing HLA alleles [22]. Loss of an HLA allele reduced the immunogenicity of all neoantigens presented by that allele to 0.…”

Section: Simulations Recapitulate Early-stage Nsclc Neoantigen Archit...mentioning

confidence: 99%

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A multispecies framework for modeling adaptive immunity and immunotherapy in cancer

Vincent

Cao

2022

Preprint

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Neoantigen clonal architecture influences the efficacy of immunotherapy. The longitudinal dynamics of clonal neoantigen immunodominance over a canvas of heterogeneous subclonal neoantigens is critical to response durability, but challenging to characterize clinically and experimentally. We developed a computational model of neoantigen evolution that longitudinally tracks the "presentome" - that is, a cell's aggregate neoantigen repertoire and HLA status - of simulated non-small cell lung cancer (NSCLC) prior to and during treatment with checkpoint blockade. Using well-established neoantigen immunogenicity parameters, we first recapitulated the clinically observed presentomes of early-stage NSCLC tumors. After validating simulated neoantigen burden in an independent cohort, we simulated response to PD-1 blockade in silico. In addition to recapitulating known phenomena, such as the correlation of pre-treatment clonal neoantigen burden with response to PD-1 blockade, we found several additional salient features of response, including a profound clonal collapse among completely responding tumors and an insensitivity of response to increased oligoclonality of anti-neoantigen-presenting cell cytotoxicity. Our work can be adapted to longitudinally model the neoantigen architecture of other cancers, modalities of immunotherapy, and preclinical tumor models, ultimately informing cognizant strategies for future therapeutic development.

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Section: Neoantigen Burden Correlates With Ici Responsesupporting

confidence: 84%

Section: Resultsmentioning

confidence: 99%

Section: Simulations Recapitulate Early-stage Nsclc Neoantigen Archit...mentioning

confidence: 99%

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A multispecies framework for modeling adaptive immunity and immunotherapy in cancer

Vincent

Cao

2022

Preprint

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“…The direct utilization of neoantigens as biomarkers would rely on the development of assays and algorithms that can precisely detect both the quantity and quality of neoantigens within a tumor. 411 …”

Section: Biomarkers For Immunotherapy—lessons From Icb and Car-t Cellsmentioning

confidence: 99%

Therapeutic targets and biomarkers of tumor immunotherapy: response versus non-response

Wang

Sun

2022

Sig Transduct Target Ther

226

114

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Cancers are highly complex diseases that are characterized by not only the overgrowth of malignant cells but also an altered immune response. The inhibition and reprogramming of the immune system play critical roles in tumor initiation and progression. Immunotherapy aims to reactivate antitumor immune cells and overcome the immune escape mechanisms of tumors. Represented by immune checkpoint blockade and adoptive cell transfer, tumor immunotherapy has seen tremendous success in the clinic, with the capability to induce long-term regression of some tumors that are refractory to all other treatments. Among them, immune checkpoint blocking therapy, represented by PD-1/PD-L1 inhibitors (nivolumab) and CTLA-4 inhibitors (ipilimumab), has shown encouraging therapeutic effects in the treatment of various malignant tumors, such as non-small cell lung cancer (NSCLC) and melanoma. In addition, with the advent of CAR-T, CAR-M and other novel immunotherapy methods, immunotherapy has entered a new era. At present, evidence indicates that the combination of multiple immunotherapy methods may be one way to improve the therapeutic effect. However, the overall clinical response rate of tumor immunotherapy still needs improvement, which warrants the development of novel therapeutic designs as well as the discovery of biomarkers that can guide the prescription of these agents. Learning from the past success and failure of both clinical and basic research is critical for the rational design of studies in the future. In this article, we describe the efforts to manipulate the immune system against cancer and discuss different targets and cell types that can be exploited to promote the antitumor immune response.

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“…Thus, neoantigens binding to multiple HLA may offer a therapeutic advantage. In addition, potent and dominant neoantigen-specific T cell response may favor the loss of neoantigen expression due to immune pressure [ 162 ]. Therefore, it remains to be shown that immunotherapy targeting neoantigens derived from more disruptive aberrations would generate long and lasting memory T cell responses.…”

Section: Discussionmentioning

confidence: 99%

Sources of Cancer Neoantigens beyond Single-Nucleotide Variants

Capietto¹,

Hoshyar²,

Delamarre³

2022

IJMS

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The success of checkpoint blockade therapy against cancer has unequivocally shown that cancer cells can be effectively recognized by the immune system and eliminated. However, the identity of the cancer antigens that elicit protective immunity remains to be fully explored. Over the last decade, most of the focus has been on somatic mutations derived from non-synonymous single-nucleotide variants (SNVs) and small insertion/deletion mutations (indels) that accumulate during cancer progression. Mutated peptides can be presented on MHC molecules and give rise to novel antigens or neoantigens, which have been shown to induce potent anti-tumor immune responses. A limitation with SNV-neoantigens is that they are patient-specific and their accurate prediction is critical for the development of effective immunotherapies. In addition, cancer types with low mutation burden may not display sufficient high-quality [SNV/small indels] neoantigens to alone stimulate effective T cell responses. Accumulating evidence suggests the existence of alternative sources of cancer neoantigens, such as gene fusions, alternative splicing variants, post-translational modifications, and transposable elements, which may be attractive novel targets for immunotherapy. In this review, we describe the recent technological advances in the identification of these novel sources of neoantigens, the experimental evidence for their presentation on MHC molecules and their immunogenicity, as well as the current clinical development stage of immunotherapy targeting these neoantigens.

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Indication-specific tumor evolution and its impact on neoantigen targeting and biomarkers for individualized cancer immunotherapies

Cited by 10 publications

References 59 publications

A multispecies framework for modeling adaptive immunity and immunotherapy in cancer

A multispecies framework for modeling adaptive immunity and immunotherapy in cancer

Therapeutic targets and biomarkers of tumor immunotherapy: response versus non-response

Sources of Cancer Neoantigens beyond Single-Nucleotide Variants

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