Enabling next-generation engineered TCR-T therapies based on high-throughput TCR discovery from diagnostic tumor biopsies

被引：0

作者：

Kuilman, Thomas ^{[1
,2
]}

Schrikkema, Deborah S. ^{[1
,2
]}

Gadiot, Jules ^{[1
,2
]}

Gomez-Eerland, Raquel ^{[1
,2
]}

Bies, Laura ^{[1
,2
]}

Walker, Julia ^{[1
,2
]}

Spaapen, Robbert M. ^{[1
,2
]}

Kok, Hanna ^{[1
,2
]}

Houg, Demi ^{[1
,2
]}

Viyacheva, Milena ^{[1
,2
]}

Claassen, Yvonne B. ^{[1
,2
]}

Saornil, Manuel ^{[1
,2
]}

Krijgsman, Oscar ^{[1
,2
]}

Stringer, Bas ^{[1
,2
]}

Ding, Huiwen ^{[1
,2
]}

Geleijnse, Anou ^{[1
,2
]}

Meinema, Anne C. ^{[1
,2
]}

Weissbrich, Bianca ^{[1
,2
]}

Lancee, Melissa ^{[1
,2
]}

Engele, Carmen G. ^{[1
,2
]}

Sabatino, Marianna ^{[1
,2
]}

Chen, Pei-Ling ^{[3
,4
]}

Tsai, Kenneth Y. ^{[3
,4
]}

Mule, James J. ^{[4
,5
,6
]}

Sondak, Vernon K. ^{[4
]}

van den Bulk, Jitske ^{[1
,7
]}

de Miranda, Noel F. ^{[7
]}

Jedema, Inge ^{[8
]}

Haanen, John G. ^{[8
,9
,10
]}

van Heijst, Jeroen W. J. ^{[1
,2
]}

Schumacher, Ton N. ^{[11
,12
]}

Linnemann, Carsten ^{[1
,2
]}

Bendle, Gavin M. ^{[1
,2
]}

机构：

[1] Neogene Therapeut, Amsterdam, Netherlands

[2] AstraZeneca Grp, Amsterdam, Netherlands

[3] H Lee Moffitt Canc Ctr & Res Inst, Dept Pathol, Tampa, FL USA

[4] H Lee Moffitt Canc Ctr & Res Inst, Dept Cutaneous Oncol, Tampa, FL USA

[5] H Lee Moffitt Canc Ctr & Res Inst, Dept Immunol, Tampa, FL USA

[6] H Lee Moffitt Canc Ctr & Res Inst, Radiat Oncol Program, Tampa, FL USA

[7] Leiden Univ, Med Ctr, Dept Pathol, Leiden, Netherlands

[8] Netherlands Canc Inst, Div Mol Oncol & Immunol, Amsterdam, Netherlands

[9] Netherlands Canc Inst, Div Med Oncol, Amsterdam, Netherlands

[10] Leiden Univ, Med Ctr, Dept Clin Oncol, Leiden, Netherlands

[11] Netherlands Canc Inst, Oncode Inst, Div Mol Oncol & Immunol, Amsterdam, Netherlands

[12] Leiden Univ, Med Ctr, Dept Hematol, Leiden, Netherlands

来源：

NATURE COMMUNICATIONS | 2025年 / 16卷 / 01期

基金：

欧盟地平线“2020”; 欧洲研究理事会;

关键词：

CELL THERAPY; METASTATIC MELANOMA; MEMORY; IDENTIFICATION; IMMUNOTHERAPY; LYMPHOCYTES; MYELOMA; PROTEIN;

D O I：

10.1038/s41467-024-55420-6

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL) can mediate tumor regression, including complete and durable responses, in a range of solid cancers, most notably in melanoma. However, its wider application and efficacy has been restricted by the limited accessibility, proliferative capacity and effector function of tumor-specific TIL. Here, we develop a platform for the efficient identification of tumor-specific TCR genes from diagnostic tumor biopsies, including core-needle biopsies frozen in a non-viable format, to enable engineered T cell therapy. Using a genetic screening approach that detects antigen-reactive TCRs with high sensitivity and specificity based on T cell activation, we show that high complexity TCR libraries can be efficiently screened against multiplexed antigen libraries to identify both HLA class I and II restricted TCRs. Through the identification of neoantigen-specific TCRs directly from melanoma as well as low tumor mutational burden microsatellite-stable colorectal carcinoma samples, we demonstrate the pan-cancer potential of this platform.

引用

页数：14