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
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...
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Frontiers Media S.A.
2020-06-01
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Series: | Frontiers in Immunology |
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Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.01147/full |
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Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Enrique Podaza Ibel Carri Mariana Aris Erika von Euw Erika von Euw Alicia Inés Bravo Paula Blanco Juan Manuel Ortiz Wilczyñski Daniel Koile Patricio Yankilevich Morten Nielsen Morten Nielsen José Mordoh José Mordoh José Mordoh María Marcela Barrio |
spellingShingle |
Enrique Podaza Ibel Carri Mariana Aris Erika von Euw Erika von Euw Alicia Inés Bravo Paula Blanco Juan Manuel Ortiz Wilczyñski Daniel Koile Patricio Yankilevich Morten Nielsen Morten Nielsen José Mordoh José Mordoh José Mordoh María Marcela Barrio 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 Frontiers in Immunology cutaneous melanoma CSF-470 allogeneic cell vaccine neoantigens tumor associated antigens melanoma immunotherapy |
author_facet |
Enrique Podaza Ibel Carri Mariana Aris Erika von Euw Erika von Euw Alicia Inés Bravo Paula Blanco Juan Manuel Ortiz Wilczyñski Daniel Koile Patricio Yankilevich Morten Nielsen Morten Nielsen José Mordoh José Mordoh José Mordoh María Marcela Barrio |
author_sort |
Enrique Podaza |
title |
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 |
title_short |
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 |
title_full |
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 |
title_fullStr |
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 |
title_full_unstemmed |
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 |
title_sort |
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 |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2020-06-01 |
description |
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. |
topic |
cutaneous melanoma CSF-470 allogeneic cell vaccine neoantigens tumor associated antigens melanoma immunotherapy |
url |
https://www.frontiersin.org/article/10.3389/fimmu.2020.01147/full |
work_keys_str_mv |
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doaj-8566c44582ab4163a12b6169f269e3dc2020-11-25T03:31:55ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-06-011110.3389/fimmu.2020.01147537185Evaluation 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-CSFEnrique Podaza0Ibel Carri1Mariana Aris2Erika von Euw3Erika von Euw4Alicia Inés Bravo5Paula Blanco6Juan Manuel Ortiz Wilczyñski7Daniel Koile8Patricio Yankilevich9Morten Nielsen10Morten Nielsen11José Mordoh12José Mordoh13José Mordoh14María Marcela Barrio15Centro de Investigaciones Oncológicas, Fundación Cáncer, Buenos Aires, ArgentinaIIBIO, UNSAM, San Martín, Buenos Aires, ArgentinaCentro de Investigaciones Oncológicas, Fundación Cáncer, Buenos Aires, ArgentinaUCLA JCCC-Translational Oncology Research Labs, Los Angeles, CA, United StatesT-Cure Bioscience Inc., Los Angeles, CA, United StatesCentro de Excelencia en Medicina Translacional, Hospital El Cruce, Buenos Aires, ArgentinaCentro de Investigaciones Oncológicas, Fundación Cáncer, Buenos Aires, ArgentinaLaboratorio de Trombosis Experimental- IMEX-ANM, Buenos Aires, ArgentinaPlataforma Bioinformática, INBioBA-MPSP, Buenos Aires, ArgentinaPlataforma Bioinformática, INBioBA-MPSP, Buenos Aires, ArgentinaIIBIO, UNSAM, San Martín, Buenos Aires, ArgentinaDepartment of Health Technology, The Technical University of Denmark, Lyngby, DenmarkCentro de Investigaciones Oncológicas, Fundación Cáncer, Buenos Aires, ArgentinaIIBBA-CONICET, Fundación Instituto Leloir, Buenos Aires, Argentina0Instituto Alexander Fleming, Buenos Aires, ArgentinaCentro de Investigaciones Oncológicas, Fundación Cáncer, Buenos Aires, ArgentinaThe 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.https://www.frontiersin.org/article/10.3389/fimmu.2020.01147/fullcutaneous melanomaCSF-470 allogeneic cell vaccineneoantigenstumor associated antigensmelanoma immunotherapy |