Neoantigen-specific stimulation of tumor-infiltrating lymphocytes enables effective TCR isolation and expansion while preserving stem-like memory phenotypes

被引：7

作者：

Levin, Noam ^{[1
]}

Kim, Sanghyun P. ^{[1
]}

Marquardt, Charles A. ^{[1
]}

Vale, Nolan R. ^{[1
]}

Yu, Zhiya ^{[1
]}

Sindiri, Sivasish ^{[1
]}

Gartner, Jared J. ^{[1
]}

Parkhurst, Maria ^{[1
]}

Krishna, Sri ^{[1
]}

Lowery, Frank J. ^{[1
]}

Zacharakis, Nikolaos ^{[1
]}

Levy, Lior ^{[1
]}

Prickett, Todd D. ^{[1
]}

Benzine, Tiffany ^{[1
]}

Ray, Satyajit ^{[1
]}

Masi, Robert, V ^{[1
]}

Gasmi, Billel ^{[1
]}

Li, Yong ^{[1
]}

Islam, Rafiqul ^{[1
]}

Bera, Alakesh ^{[1
]}

Goff, Stephanie L. ^{[1
]}

Robbins, Paul F. ^{[1
]}

Rosenberg, Steven A. ^{[1
]}

机构：

[1] NCI, Surg Branch, Ctr Canc Res, Bethesda, MD 20892 USA

来源：

JOURNAL FOR IMMUNOTHERAPY OF CANCER | 2024年 / 12卷 / 05期

关键词：

Adoptive cell therapy - ACT; Tumor infiltrating lymphocyte - TIL; T cell Receptor - TCR; REACTIVE T-CELLS; PERIPHERAL-BLOOD; TRANSFER THERAPY; IMMUNOTHERAPY; BLOCKADE; PATIENT; IDENTIFICATION; ACTIVATION; SIGNATURES; ANTIGENS;

D O I：

10.1136/jitc-2023-008645

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background Tumor-infiltrating lymphocytes (TILs) targeting neoantigens can effectively treat a selected set of metastatic solid cancers. However, harnessing TILs for cancer treatments remains challenging because neoantigen-reactive T cells are often rare and exhausted, and ex vivo expansion can further reduce their frequencies. This complicates the identification of neoantigen-reactive T-cell receptors (TCRs) and the development of TIL products with high reactivity for patient treatment.Methods We tested whether TILs could be in vitro stimulated against neoantigens to achieve selective expansion of neoantigen-reactive TILs. Given their prevalence, mutant p53 or RAS were studied as models of human neoantigens. An in vitro stimulation method, termed "NeoExpand", was developed to provide neoantigen-specific stimulation to TILs. 25 consecutive patient TILs from tumors harboring p53 or RAS mutations were subjected to NeoExpand.Results We show that neoantigenic stimulation achieved selective expansion of neoantigen-reactive TILs and broadened the neoantigen-reactive CD4+ and CD8+ TIL clonal repertoire. This allowed the effective isolation of novel neoantigen-reactive TCRs. Out of the 25 consecutive TIL samples, neoantigenic stimulation enabled the identification of 16 unique reactivities and 42 TCRs, while conventional TIL expansion identified 9 reactivities and 14 TCRs. Single-cell transcriptome analysis revealed that neoantigenic stimulation increased neoantigen-reactive TILs with stem-like memory phenotypes expressing IL-7R, CD62L, and KLF2. Furthermore, neoantigenic stimulation improved the in vivo antitumor efficacy of TILs relative to the conventional OKT3-induced rapid TIL expansion in p53-mutated or KRAS-mutated xenograft mouse models.Conclusions Taken together, neoantigenic stimulation of TILs selectively expands neoantigen-reactive TILs by frequencies and by their clonal repertoire. NeoExpand led to improved phenotypes and functions of neoantigen-reactive TILs. Our data warrant its clinical evaluation.Trial registration number NCT00068003, NCT01174121, and NCT03412877.

引用

页数：17

共 2 条

[1] A CLONING AND EXPRESSION SYSTEM OF THE NEOANTIGEN-SPECIFIC TCRS FROM TUMOR-INFILTRATING LYMPHOCYTES BY SINGLE-CELL SEQUENCING OF PAIRED TCRα AND TCRβ CHAINS
Kobayashi, Yukari
Nagaoka, Koji
Kubo, Kaori
Nishie, Toshikazu
Okamoto, Sachiko
Enoki, Tatsuji
Mineno, Junichi
Sato, Yasuyoshi
Takahashi, Shunji
Nakajima, Jun
Kakimi, Kazuhiro
JOURNAL FOR IMMUNOTHERAPY OF CANCER, 2021, 9 : A71 - A71
[2] Effect of a novel expansion process on tumor-infiltrating lymphocyte (TIL) polyfunctionality, cytotoxicity, and expansion, while preserving cells in a less differentiated and more stem-like phenotype
Yuhas, Andrew
Dean, Joe
Erickson, Tim
Machin, Marcus
Alkhouli, Mohammed
Yglesias, Joe
Cubas, Rafael
JOURNAL OF CLINICAL ONCOLOGY, 2023, 41 (16)

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