mRNA vaccine-induced neoantigen-specific T cell immunity in patients with gastrointestinal cancer

被引：289

作者：

Cafri, Gal ^{[1
,2
]}

Gartner, Jared J. ^{[1
]}

Zaks, Tal ^{[3
]}

Hopson, Kristen ^{[3
]}

Levin, Noam ^{[1
]}

Paria, Biman C. ^{[1
]}

Parkhurst, Maria R. ^{[1
]}

Yossef, Rami ^{[1
]}

Lowery, Frank J. ^{[1
]}

Jafferji, Mohammad S. ^{[1
]}

Prickett, Todd D. ^{[1
]}

Goff, Stephanie L. ^{[1
]}

McGowan, Christine T. ^{[1
]}

Seitter, Samantha ^{[1
]}

Shindorf, Mackenzie L. ^{[1
]}

Parikh, Anup ^{[1
]}

Chatani, Praveen D. ^{[1
]}

Robbins, Paul F. ^{[1
]}

Rosenberg, Steven A. ^{[1
]}

机构：

[1] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA

[2] Sheba Med Ctr, Derech Sheba 2, Ramat Gan, Israel

[3] Moderna Inc, Cambridge, MA USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2020年 / 130卷 / 11期

关键词：

TUMOR; IDENTIFICATION; LYMPHOCYTES;

D O I：

10.1172/JCI134915

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

BACKGROUND. Therapeutic vaccinations against cancer have mainly targeted differentiation antigens, cancer-testis antigens, and overexpressed antigens and have thus far resulted in little clinical benefit. Studies conducted by multiple groups have demonstrated that T cells recognizing neoantigens are present in most cancers and offer a specific and highly immunogenic target for personalized vaccination. METHODS. We recently developed a process using tumor-infiltrating lymphocytes to identify the specific immunogenic mutations expressed in patients' tumors. Here, validated, defined neoantigens, predicted neoepitopes, and mutations of driver genes were concatenated into a single mRNA construct to vaccinate patients with metastatic gastrointestinal cancer. RESULTS. The vaccine was safe and elicited mutation-specific T cell responses against predicted neoepitopes not detected before vaccination. Furthermore, we were able to isolate and verify T cell receptors targeting KRAS(G12D) mutation. We observed no objective clinical responses in the 4 patients treated in this trial. CONCLUSION. This vaccine was safe, and potential future combination of such vaccines with checkpoint inhibitors or adoptive T cell therapy should be evaluated for possible clinical benefit in patients with common epithelial cancers.

引用

页码：5976 / 5988

页数：13

共 21 条

[21] Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer [J].

Zacharakis, Nikolaos ;

Chinnasamy, Harshini ;

Black, Mary ;

Xu, Hui ;

Lu, Yong-Chen ;

Zheng, Zhili ;

Pasetto, Anna ;

Langhan, Michelle ;

Shelton, Thomas ;

Prickett, Todd ;

Gartner, Jared ;

Jia, Li ;

Trebska-McGowan, Katarzyna ;

Somerville, Robert P. ;

Robbins, Paul F. ;

Rosenberg, Steven A. ;

Goff, Stephanie L. ;

Feldman, Steven A. .

NATURE MEDICINE, 2018, 24 (06) :724-+

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