Identification of neoantigen-reactive T cells in hepatocellular carcinoma: implication in adoptive T cell therapy

Vercher, Enric; Tamayo, Ibón; Mancheño, Uxua; Elizalde, Edurne; Conde, Enrique Álvarez; Repáraz, David; Lasarte, Juan J.; Villar, Virginia; Iñarrairaegui, Mercedes; Sangro, Bruno; Sarobe, Pablo; Hervás-Stubbs, Sandra

doi:10.1016/s0168-8278(20)30630-9

Cited by 6 publications

(6 citation statements)

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“…Ongoing studies by our group show that mutations found in patients with HCC might originate peptides with a higher HLA-binding capacity than non-mutated wild-type sequences. These peptides are immunogenic in HLA transgenic mice and induce T cells that selectively recognize the mutated, but not the wild-type, sequence, suggesting that this strategy might also be suitable as a vaccine in HCC 196 .…”

Section: Other Hcc Immunotherapiesmentioning

confidence: 99%

Advances in immunotherapy for hepatocellular carcinoma

Sangro

Sarobe

Hervás-Stubbs

et al. 2021

Nat Rev Gastroenterol Hepatol

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Hepatocellular carcinoma (HCC) is a prevalent disease with a progression that is modulated by the immune system. Systemic therapy is used in the advanced stage and until 2017 consisted only of antiangiogenic tyrosine kinase inhibitors (TKIs). Immunotherapy with checkpoint inhibitors has shown strong anti-tumour activity in a subset of patients and the combination of the anti-PDL1 antibody atezolizumab and the VEGF-neutralizing antibody bevacizumab has or will soon become the standard of care as a first-line therapy for HCC, whereas the anti-PD1 agents nivolumab and pembrolizumab are used after TKIs in several regions. Other immune strategies such as adoptive T-cell transfer, vaccination or virotherapy have not yet demonstrated consistent clinical activity. Major unmet challenges in HCC checkpoint immunotherapy are the discovery and validation of predictive biomarkers, advancing treatment to earlier stages of the disease, applying the treatment to patients with liver dysfunction and the discovery of more effective combinatorial or sequential approaches. Combinations with other systemic or local treatments are perceived as the most promising opportunities in HCC and some are already under evaluation in large-scale clinical trials. This Review provides up-to-date information on the best use of currently available immunotherapies in HCC and the therapeutic strategies under development.

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Section: Other Hcc Immunotherapiesmentioning

confidence: 99%

Advances in immunotherapy for hepatocellular carcinoma

Sangro

Sarobe

Hervás-Stubbs

et al. 2021

Nat Rev Gastroenterol Hepatol

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808

571

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“…Most confirmation assays are restricted to recognition by T cells. Indeed, in addition to our recent study showing that TILs are able to recognize predicted neoAgs of autologous tumors [133], neoAg-reactive T cells have been successfully isolated from tumors and peripheral blood in HCC patients, suggesting the ability of current neoAg identification pipelines to identify these epitopes [134].…”

Section: Mutations In Hcc As Elements For Neoag-based Vaccinesmentioning

confidence: 88%

Therapeutic Vaccines against Hepatocellular Carcinoma in the Immune Checkpoint Inhibitor Era: Time for Neoantigens?

Repáraz

Aparicio

Llópiz

et al. 2022

IJMS

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Immune checkpoint inhibitors (ICI) have been used as immunotherapy for hepatocellular carcinoma (HCC) with promising but still limited results. Identification of immune elements in the tumor microenvironment of individual HCC patients may help to understand the correlations of responses, as well as to design personalized therapies for non-responder patients. Immune-enhancing strategies, such as vaccination, would complement ICI in those individuals with poorly infiltrated tumors. The prominent role of responses against mutated tumor antigens (neoAgs) in ICI-based therapies suggests that boosting responses against these epitopes may specifically target tumor cells. In this review we summarize clinical vaccination trials carried out in HCC, the available information on potentially immunogenic neoAgs in HCC patients, and the most recent results of neoAg-based vaccines in other tumors. Despite the low/intermediate mutational burden observed in HCC, data obtained from neoAg-based vaccines in other tumors indicate that vaccines directed against these tumor-specific antigens would complement ICI in a subset of HCC patients.

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“…35 Moreover, our results using tumor infiltrating lymphocytes from HCC patients have allowed us to detect neoAg-specific T cells. 45 Although many efforts have been traditionally done to develop vaccination strategies aimed at activating CD8 T-cells, CD4 T-cells have emerged as important players, by mediating direct and indirect antitumor immunity, 25 46 suggesting the inclusion of CD4 epitopes in polyvalent vaccines. Unfortunately, we did not have any patient expressing HLA-A*02.01 and HLA-DRB1*01.…”

Section: Discussionmentioning

confidence: 99%

“… 35 Moreover, our results using tumor infiltrating lymphocytes from HCC patients have allowed us to detect neoAg-specific T cells. 45 …”

Section: Discussionmentioning

confidence: 99%

Neoantigens as potential vaccines in hepatocellular carcinoma

Repáraz

Ruiz

Llópiz

et al. 2022

J Immunother Cancer

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BackgroundNeoantigens, new immunogenic sequences arising from tumor mutations, have been associated with response to immunotherapy and are considered potential targets for vaccination. Hepatocellular carcinoma (HCC) is a moderately mutated tumor, where the neoantigen repertoire has not been investigated. Our aim was to analyze whether tumors in HCC patients contain immunogenic neoantigens suitable for future use in therapeutic vaccination.MethodsWhole-exome sequencing and RNAseq were performed in a cohort of fourteen HCC patients submitted to surgery or liver transplant. To identify mutations, single-nucleotide variants (SNV) originating non-synonymous changes that were confirmed at the RNA level were analyzed. Immunogenicity of putative neoAgs predicted by HLA binding algorithms was confirmed by using in vitro HLA binding assays and T-cell stimulation experiments, the latter in vivo, by immunizing HLA-A*02.01/HLA-DRB1*01 (HHD-DR1) transgenic mice, and in in vitro, using human lymphocytes.ResultsSequencing led to the identification of a median of 1217 missense somatic SNV per patient, narrowed to 30 when filtering by using RNAseq data. A median of 13 and 5 peptides per patient were predicted as potential binders to HLA class I and class II molecules, respectively. Considering only HLA-A*02.01- and HLA-DRB1*01-predicted binders, 70% demonstrated HLA-binding capacity and about 50% were immunogenic when tested in HHD-DR1 mice. These peptides induced polyfunctional T cells that specifically recognized the mutated but not the wild-type sequence as well as neoantigen-expressing cells. Moreover, coimmunization experiments combining CD8 and CD4 neoantigen epitopes resulted in stronger CD8 T cell responses. Finally, responses against neoantigens were also induced in vitro using human cells.ConclusionThese results show that mutations in HCC tumors may generate immunogenic neoantigens with potential applicability for future combinatorial therapeutic strategies.

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Identification of neoantigen-reactive T cells in hepatocellular carcinoma: implication in adoptive T cell therapy

Cited by 6 publications

References 0 publications

Advances in immunotherapy for hepatocellular carcinoma

Advances in immunotherapy for hepatocellular carcinoma

Therapeutic Vaccines against Hepatocellular Carcinoma in the Immune Checkpoint Inhibitor Era: Time for Neoantigens?

Neoantigens as potential vaccines in hepatocellular carcinoma

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