Evaluation of T-Cell Responses Against Shared Melanoma Associated Antigens and Predicted Neoantigens in Cutaneous Melanoma Patients Treated With the CSF-470 Allogeneic Cell Vaccine Plus BCG and GM-CSF

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Abstract

The CSF-470 vaccine consists of lethally-irradiated allogeneic cells derived from four cutaneous melanoma cell lines administered plus BCG and GM-CSF as adjuvants. In an adjuvant phase II study vs. IFN-α2b, the vaccine significantly prolonged the distant metastasis-free survival (DMFS) of stages IIB-IIC-III melanoma patients with evidence of the induction of immune responses against vaccine cells.

Purpose: The aim of this study was to analyze the antigens against which the immune response was induced, as well as the T-helper profile and lytic ability of immune cells after CSF-470 treatment.

Methods: HLA-restricted peptides from tumor-associated antigens (TAAs) were selected from TANTIGEN database for 13 evaluable vaccinated patients. In addition, for patient #006 (pt#006), tumor somatic variants were identified by NGS and candidate neoAgs were selected by predicted HLA binding affinity and similarity between wild type (wt) and mutant peptides. The patient‘s PBMC reactivity against selected peptides was detected by IFNγ-ELISPOT. T-helper transcriptional profile was determined by quantifying GATA-3, T-bet, and FOXP3 mRNA by RT-PCR, and intracellular cytokines were analyzed by flow cytometry. Autologous tumor cell lysis by PBMC was assessed in an in vitro calcein release assay.

Results: Vaccinated patient‘s PBMC reactivity against selected TAAs derived peptides showed a progressive increase in the number of IFNγ-producing cells throughout the 2-yr vaccination protocol. ELISPOT response correlated with delayed type hypersensitivity (DTH) reaction to CSF-470 vaccine cells. Early upregulation of GATA-3 and Foxp3 mRNA, as well as an increase in CD4+IL4+cells, was associated with a low DMFS. Also, IFNγ response against 9/73 predicted neoAgs was evidenced in the case of pt#006; 7/9 emerged after vaccination. We verified in pt# 006 that post-vaccination PBMC boosted in vitro with the vaccine lysate were able to lyse autologous tumor cells.

Conclusions: A progressive increase in the immune response against TAAs expressed in the vaccine and in the patient's tumor was induced by CSF-470 vaccination. In pt#006, we demonstrated immune recognition of patient's specific neoAgs, which emerged after vaccination. These results suggest that an initial response against shared TAAs could further stimulate an immune response against autologous tumor neoAgs.

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Most cited references 28

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NetMHCpan-4.0: Improved Peptide-MHC Class I Interaction Predictions Integrating Eluted Ligand and Peptide Binding Affinity Data.

Morten Nielsen, Vanessa Jurtz, Sinu Paul … (2017)

Cytotoxic T cells are of central importance in the immune system's response to disease. They recognize defective cells by binding to peptides presented on the cell surface by MHC class I molecules. Peptide binding to MHC molecules is the single most selective step in the Ag-presentation pathway. Therefore, in the quest for T cell epitopes, the prediction of peptide binding to MHC molecules has attracted widespread attention. In the past, predictors of peptide-MHC interactions have primarily been trained on binding affinity data. Recently, an increasing number of MHC-presented peptides identified by mass spectrometry have been reported containing information about peptide-processing steps in the presentation pathway and the length distribution of naturally presented peptides. In this article, we present NetMHCpan-4.0, a method trained on binding affinity and eluted ligand data leveraging the information from both data types. Large-scale benchmarking of the method demonstrates an increase in predictive performance compared with state-of-the-art methods when it comes to identification of naturally processed ligands, cancer neoantigens, and T cell epitopes.

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Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing.

Mahesh Yadav, Suchit Jhunjhunwala, Qui Phung … (2014)

Human tumours typically harbour a remarkable number of somatic mutations. If presented on major histocompatibility complex class I molecules (MHCI), peptides containing these mutations could potentially be immunogenic as they should be recognized as 'non-self' neo-antigens by the adaptive immune system. Recent work has confirmed that mutant peptides can serve as T-cell epitopes. However, few mutant epitopes have been described because their discovery required the laborious screening of patient tumour-infiltrating lymphocytes for their ability to recognize antigen libraries constructed following tumour exome sequencing. We sought to simplify the discovery of immunogenic mutant peptides by characterizing their general properties. We developed an approach that combines whole-exome and transcriptome sequencing analysis with mass spectrometry to identify neo-epitopes in two widely used murine tumour models. Of the >1,300 amino acid changes identified, ∼13% were predicted to bind MHCI, a small fraction of which were confirmed by mass spectrometry. The peptides were then structurally modelled bound to MHCI. Mutations that were solvent-exposed and therefore accessible to T-cell antigen receptors were predicted to be immunogenic. Vaccination of mice confirmed the approach, with each predicted immunogenic peptide yielding therapeutically active T-cell responses. The predictions also enabled the generation of peptide-MHCI dextramers that could be used to monitor the kinetics and distribution of the anti-tumour T-cell response before and after vaccination. These findings indicate that a suitable prediction algorithm may provide an approach for the pharmacodynamic monitoring of T-cell responses as well as for the development of personalized vaccines in cancer patients.

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The mechanism of action of BCG therapy for bladder cancer--a current perspective.

Gil Redelman-Sidi, Michael S Glickman, Bernard Bochner (2014)

Bacillus Calmette-Guérin (BCG) has been used to treat non-muscle-invasive bladder cancer for more than 30 years. It is one of the most successful biotherapies for cancer in use. Despite long clinical experience with BCG, the mechanism of its therapeutic effect is still under investigation. Available evidence suggests that urothelial cells (including bladder cancer cells themselves) and cells of the immune system both have crucial roles in the therapeutic antitumour effect of BCG. The possible involvement of bladder cancer cells includes attachment and internalization of BCG, secretion of cytokines and chemokines, and presentation of BCG and/or cancer cell antigens to cells of the immune system. Immune system cell subsets that have potential roles in BCG therapy include CD4(+) and CD8(+) lymphocytes, natural killer cells, granulocytes, macrophages, and dendritic cells. Bladder cancer cells are killed through direct cytotoxicity by these cells, by secretion of soluble factors such as TRAIL (tumour necrosis factor-related apoptosis-inducing ligand), and, to some degree, by the direct action of BCG. Several gaps still exist in our knowledge that should be addressed in future efforts to understand this biotherapy of cancer.

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Author and article information

Contributors

Enrique Podaza: URI : http://loop.frontiersin.org/people/565897/overview

Ibel Carri: URI : http://loop.frontiersin.org/people/511987/overview

Mariana Aris: URI : http://loop.frontiersin.org/people/166258/overview

Erika von Euw: URI : http://loop.frontiersin.org/people/989188/overview

Alicia Inés Bravo: URI : http://loop.frontiersin.org/people/439472/overview

Paula Blanco: URI : http://loop.frontiersin.org/people/411162/overview

Juan Manuel Ortiz Wilczyñski: URI : http://loop.frontiersin.org/people/523307/overview

Daniel Koile: URI : http://loop.frontiersin.org/people/512712/overview

Patricio Yankilevich: URI : http://loop.frontiersin.org/people/543679/overview

Morten Nielsen: URI : http://loop.frontiersin.org/people/479847/overview

José Mordoh: URI : http://loop.frontiersin.org/people/39471/overview

María Marcela Barrio: URI : http://loop.frontiersin.org/people/41146/overview

Journal

Journal ID (nlm-ta): Front Immunol

Journal ID (iso-abbrev): Front Immunol

Journal ID (publisher-id): Front. Immunol.

Title: Frontiers in Immunology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 1664-3224

Publication date (Electronic): 05 June 2020

Publication date Collection: 2020

Volume: 11

Electronic Location Identifier: 1147

Affiliations

[1] ¹Centro de Investigaciones Oncológicas, Fundación Cáncer , Buenos Aires, Argentina

[2] ²IIBIO, UNSAM, San Martín , Buenos Aires, Argentina

[3] ³UCLA JCCC-Translational Oncology Research Labs , Los Angeles, CA, United States

[4] ⁴T-Cure Bioscience Inc. , Los Angeles, CA, United States

[5] ⁵Centro de Excelencia en Medicina Translacional, Hospital El Cruce , Buenos Aires, Argentina

[6] ⁶Laboratorio de Trombosis Experimental- IMEX-ANM , Buenos Aires, Argentina

[7] ⁷Plataforma Bioinformática, INBioBA-MPSP , Buenos Aires, Argentina

[8] ⁸Department of Health Technology, The Technical University of Denmark , Lyngby, Denmark

[9] ⁹IIBBA-CONICET, Fundación Instituto Leloir , Buenos Aires, Argentina

[10] ¹⁰Instituto Alexander Fleming , Buenos Aires, Argentina

Author notes

Edited by: Brian J. Czerniecki, Moffitt Cancer Center, United States

Reviewed by: Hongbin Wang, California Northstate University, United States; Sherry Wu, The University of Queensland, Australia

*Correspondence: María Marcela Barrio barrio.marcela@ 123456gmail.com

This article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Immunology

Article

DOI: 10.3389/fimmu.2020.01147

PMC ID: 7290006

PubMed ID: 32582212

SO-VID: b48a08f2-1886-42db-afd9-de1653493789

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 22 February 2020

Date accepted : 11 May 2020

Page count

Figures: 6, Tables: 0, Equations: 0, References: 45, Pages: 15, Words: 9044

Funding

Funded by: Instituto Nacional del Cáncer 10.13039/501100008478

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Evaluation of T-Cell Responses Against Shared Melanoma Associated Antigens and Predicted Neoantigens in Cutaneous Melanoma Patients Treated With the CSF-470 Allogeneic Cell Vaccine Plus BCG and GM-CSF

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Most cited references 28

NetMHCpan-4.0: Improved Peptide-MHC Class I Interaction Predictions Integrating Eluted Ligand and Peptide Binding Affinity Data.

Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing.

The mechanism of action of BCG therapy for bladder cancer--a current perspective.

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