Pooled CAR-T screening in nonhuman primates identifies designs with enhanced proliferation, trafficking, and persistence

持久性(不连续性) 生物 经济地理学 计算生物学 地理 工程类 岩土工程
作者
Lucy H. Maynard,Eric J Cavanaugh,Haiying Zhu,Carly E. Starke,Sally Doherty,Teresa Einhaus,Ailyn Perez,Laurence Stensland,Michelle Hoffman,Veronica Nelson,Sarah Herrin,Chad Littlewood,Kaycee Camou,Erica Wilson,Christopher Wessel,Keith R. Jerome,Hans‐Peter Kiem,Christopher W. Peterson
标识
DOI:10.1101/2025.03.05.640197
摘要

Chimeric antigen receptor T (CAR-T) cell therapy has revolutionized treatment for B-cell malignancies, yet over 60% of patients relapse within one year, often due to insufficient CAR-T persistence. While mouse and primary cell models have been instrumental in advancing CAR-T therapy, they frequently fail to predict clinical outcomes, underscoring the need for more translationally relevant models. To address this limitation, we conducted the first systematic evaluation of CAR structure-function relationships in an immunocompetent nonhuman primate (NHP) model. We engineered an array of 20 CD20-targeted CARs with distinct combinations of hinge, transmembrane, and costimulatory domains. Following ex vivo characterization, we administered pooled autologous CAR-T arrays to three NHPs and tracked CAR abundance longitudinally using a novel digital droplet PCR assay. Ex vivo, CAR-T cells incorporating the MyD88-CD40 costimulatory domain exhibited markedly distinct functional profiles, including increased activation, unique cytokine secretion, tonic signaling, and resistance to exhaustion. In vivo, MyD88 CD40 CARs expanded dramatically, comprising up to 100% of peripheral T cells and significantly outperforming canonical CD28- and 4-1BB-based CARs. This expansion was associated with robust B-cell depletion across all animals. MyD88-CD40 CARs, particularly those with a CD28 hinge and transmembrane domain, demonstrated superior trafficking to secondary lymphoid tissues and persistence through study endpoint, unlike other CARs which waned by day 28. Our findings highlight the value of NHP models for screening CAR designs and identify MyD88-CD40 CARs as candidates with unmatched potency. The unique functional attributes conferred by this domain may provide key insights into features that drive enhanced CAR-T cell activity.

科研通智能强力驱动
Strongly Powered by AbleSci AI
科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
刚刚
悲伤西米露完成签到,获得积分10
刚刚
刚刚
123456发布了新的文献求助30
刚刚
刚刚
1秒前
天天完成签到 ,获得积分10
1秒前
圈圈黄发布了新的文献求助10
2秒前
1233330发布了新的文献求助10
2秒前
Akim应助超级大猩猩采纳,获得10
2秒前
2秒前
深情安青应助zxj采纳,获得10
3秒前
谷安完成签到,获得积分10
3秒前
Buxi完成签到,获得积分10
4秒前
Owen应助JusLovin采纳,获得10
4秒前
NexusExplorer应助科研通管家采纳,获得10
4秒前
毛豆应助科研通管家采纳,获得10
4秒前
萤火虫应助科研通管家采纳,获得30
5秒前
小星星bulingbuling完成签到,获得积分10
5秒前
我是老大应助科研通管家采纳,获得10
5秒前
传奇3应助科研通管家采纳,获得10
5秒前
星辰大海应助科研通管家采纳,获得10
5秒前
5秒前
5秒前
dty发布了新的文献求助10
6秒前
隐形的蓝天完成签到 ,获得积分20
6秒前
陆个核桃发布了新的文献求助10
6秒前
TAKERA发布了新的文献求助30
6秒前
7秒前
AoAoo发布了新的文献求助10
7秒前
xiaoxiao完成签到,获得积分10
7秒前
研究者发布了新的文献求助10
7秒前
乐乐应助怡然问晴采纳,获得10
8秒前
夏天来了发布了新的文献求助10
8秒前
开朗的手套应助Silence采纳,获得10
9秒前
Jasper应助炎晨采纳,获得10
10秒前
无花果应助dawei采纳,获得10
10秒前
10秒前
小新完成签到,获得积分10
11秒前
11秒前
高分求助中
Production Logging: Theoretical and Interpretive Elements 2700
Les Mantodea de Guyane Insecta, Polyneoptera 1000
Structural Load Modelling and Combination for Performance and Safety Evaluation 1000
Conference Record, IAS Annual Meeting 1977 820
England and the Discovery of America, 1481-1620 600
電気学会論文誌D(産業応用部門誌), 141 巻, 11 号 510
Exploring the effects of an evidenced-based professional development programme on teaching and learning in Chinese kindergartens 500
热门求助领域 (近24小时)
化学 材料科学 生物 医学 工程类 有机化学 生物化学 物理 纳米技术 计算机科学 内科学 化学工程 复合材料 基因 遗传学 物理化学 催化作用 量子力学 光电子学 冶金
热门帖子
关注 科研通微信公众号,转发送积分 3577193
求助须知:如何正确求助?哪些是违规求助? 3147019
关于积分的说明 9467405
捐赠科研通 2848511
什么是DOI,文献DOI怎么找? 1565765
邀请新用户注册赠送积分活动 733133
科研通“疑难数据库(出版商)”最低求助积分说明 719760