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评估 CSF-470 同种异体细胞疫苗联合 BCG 和 GM-CSF 治疗的皮肤黑素瘤患者对共享黑色素瘤相关抗原和预测的新抗原的 T 细胞反应。

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.

机构信息

Centro de Investigaciones Oncológicas, Fundación Cáncer, Buenos Aires, Argentina.

IIBIO, UNSAM, San Martín, Buenos Aires, Argentina.

出版信息

Front Immunol. 2020 Jun 5;11:1147. doi: 10.3389/fimmu.2020.01147. eCollection 2020.

DOI:10.3389/fimmu.2020.01147
PMID:32582212
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7290006/
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. 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. 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 calcein release assay. 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 with the vaccine lysate were able to lyse autologous tumor cells. 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.

摘要

CSF-470 疫苗由来自四种皮肤黑色素瘤细胞系的致死性辐照同种异体细胞组成，与卡介苗和 GM-CSF 联合使用作为佐剂。在一项与 IFN-α2b 的辅助 II 期研究中，该疫苗显著延长了 IIB-IIC-III 期黑色素瘤患者的无远处转移生存（DMFS），证据表明疫苗细胞诱导了免疫反应。本研究旨在分析诱导免疫反应的抗原，以及 CSF-470 治疗后免疫细胞的辅助性 T 细胞特征和溶细胞能力。从 TANTIGEN 数据库中为 13 名可评估的接种患者选择了来自肿瘤相关抗原（TAA）的 HLA 限制性肽。此外，对于患者#006（pt#006），通过 NGS 鉴定了肿瘤体细胞变异体，并通过预测 HLA 结合亲和力和野生型（wt）与突变肽之间的相似性选择候选新抗原。通过 IFNγ-ELISPOT 检测患者 PBMC 对选定肽的反应性。通过 RT-PCR 定量 GATA-3、T-bet 和 FOXP3 mRNA 来确定辅助性 T 细胞转录谱，并通过流式细胞术分析细胞内细胞因子。通过 calcein 释放测定评估 PBMC 对自体肿瘤细胞的溶解。接种患者 PBMC 对所选 TAA 衍生肽的反应性在整个 2 年疫苗接种方案中呈逐渐增加产生 IFNγ 的细胞数。ELISPOT 反应与 CSF-470 疫苗细胞的迟发型超敏反应（DTH）反应相关。GATA-3 和 Foxp3 mRNA 的早期上调以及 CD4+IL4+细胞的增加与低 DMFS 相关。此外，在 pt#006 中，证据表明针对 9/73 个预测的新抗原产生了 IFNγ 反应；其中 7/9 出现在疫苗接种后。我们在 pt#006 中证实，用疫苗裂解物增强的接种后 PBMC 能够裂解自体肿瘤细胞。CSF-470 疫苗接种诱导了对疫苗和患者肿瘤中表达的 TAA 的免疫反应逐渐增加。在 pt#006 中，我们证明了对患者特异性新抗原的免疫识别，这些新抗原在疫苗接种后出现。这些结果表明，对共享 TAA 的初始反应可能进一步刺激对自体肿瘤新抗原的免疫反应。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76a3/7290006/b42eedc1c9fb/fimmu-11-01147-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76a3/7290006/611674808e8c/fimmu-11-01147-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76a3/7290006/a14ab65ad471/fimmu-11-01147-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76a3/7290006/631da72a5edf/fimmu-11-01147-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76a3/7290006/61f78f403095/fimmu-11-01147-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76a3/7290006/99163d4f1c92/fimmu-11-01147-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76a3/7290006/b42eedc1c9fb/fimmu-11-01147-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76a3/7290006/611674808e8c/fimmu-11-01147-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76a3/7290006/a14ab65ad471/fimmu-11-01147-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76a3/7290006/631da72a5edf/fimmu-11-01147-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76a3/7290006/61f78f403095/fimmu-11-01147-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76a3/7290006/99163d4f1c92/fimmu-11-01147-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76a3/7290006/b42eedc1c9fb/fimmu-11-01147-g0006.jpg

相似文献

[1]
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.

Front Immunol. 2020

[2]
Dissecting the Immune Stimulation Promoted by CSF-470 Vaccine Plus Adjuvants in Cutaneous Melanoma Patients: Long Term Antitumor Immunity and Short Term Release of Acute Inflammatory Reactants.

Front Immunol. 2018-11-2

[3]
Immunization With the CSF-470 Vaccine Plus BCG and rhGM-CSF Induced in a Cutaneous Melanoma Patient a TCRβ Repertoire Found at Vaccination Site and Tumor Infiltrating Lymphocytes That Persisted in Blood.

Front Immunol. 2019-9-18

[4]
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[5]
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[6]
Effect of granulocyte/macrophage colony-stimulating factor on circulating CD8+ and CD4+ T-cell responses to a multipeptide melanoma vaccine: outcome of a multicenter randomized trial.

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[7]
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[8]
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[4]
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[5]
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[7]
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本文引用的文献

[1]
Immunization With the CSF-470 Vaccine Plus BCG and rhGM-CSF Induced in a Cutaneous Melanoma Patient a TCRβ Repertoire Found at Vaccination Site and Tumor Infiltrating Lymphocytes That Persisted in Blood.

Front Immunol. 2019-9-18

[2]
Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma.

N Engl J Med. 2019-9-28

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The adjuvant treatment revolution for high-risk melanoma patients.

Semin Cancer Biol. 2019-8-21

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Ther Adv Vaccines Immunother. 2019-8-1

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Natural T cell autoreactivity to melanoma antigens: clonally expanded melanoma-antigen specific CD8 + memory T cells can be detected in healthy humans.

Cancer Immunol Immunother. 2019-2-19

[6]
Dissecting the Immune Stimulation Promoted by CSF-470 Vaccine Plus Adjuvants in Cutaneous Melanoma Patients: Long Term Antitumor Immunity and Short Term Release of Acute Inflammatory Reactants.

Front Immunol. 2018-11-2

[7]
Changes in the TCRβ Repertoire and Tumor Immune Signature From a Cutaneous Melanoma Patient Immunized With the CSF-470 Vaccine: A Case Report.

Front Immunol. 2018-5-3

[8]
Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma.

N Engl J Med. 2018-4-15

[9]
Improved methods for predicting peptide binding affinity to MHC class II molecules.

Immunology. 2018-2-6

[10]
NetMHCpan-4.0: Improved Peptide-MHC Class I Interaction Predictions Integrating Eluted Ligand and Peptide Binding Affinity Data.

J Immunol. 2017-11-1

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