Inducible expression of interleukin-12 augments the efficacy of affinity-tuned chimeric antigen receptors in murine solid tumor models.
Inducible expression of interleukin-12 augments the efficacy of affinity-tuned chimeric antigen receptors in murine solid tumor models.
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DOI：
10.1038/s41467-023-37646-y
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发表时间：
2023-04-12
影响因子：
16.6
通讯作者：
Jin, Moonsoo M. M.
中科院分区：
文献类型：
--
作者：
Yang, Yanping;Yang, Huan;Alcaina, Yago;Puc, Janusz;Birt, Alyssa;Vedvyas, Yogindra;Gallagher, Michael;Alla, Srinija;Riascos, Maria Cristina;McCloskey, Jaclyn E.;Du, Karrie;Gonzalez-Valdivieso, Juan;Min, Irene M. M.;de Stanchina, Elisa;Britz, Matt;von Hofe, Eric;Jin, Moonsoo M. M.
有限数量的可靶向肿瘤特异性抗原和实体恶性肿瘤内微环境的免疫抑制性质代表了嵌合抗原受体（CAR）-T细胞疗法成功的主要障碍。在这里，使用上皮细胞粘附分子（EpCAM）作为模型抗原，我们使用丙氨酸扫描互补决定区来微调CAR亲和力。这使我们能够鉴定出可以保留原代上皮细胞同时仍然有效靶向EpCAM高肿瘤的汽车。虽然亲和力调节的汽车在体内显示出次优的抗肿瘤活性，但我们发现在NFAT启动子的控制下，白细胞介素-12（IL-12）的诱导性分泌可以将CAR活性恢复到接近亲本CAR的水平。该策略进一步用另一种特异于细胞间粘附分子-1（ICAM-1）的亲和力调节的CAR进行验证。仅在亲和力调节的CAR-T细胞中，NFAT活性受到严格控制，并限于高水平表达目标抗原的肿瘤。我们的研究证明了通过结合诱导型IL-12表达和亲和力调节的CAR来特异性地使CAR-T细胞识别实体瘤的可行性。嵌合抗原受体（CAR）T疗法的临床益处受到“靶向，脱瘤”效应的限制。在这项研究中，作者描述了一种策略，通过结合亲和力调节和诱导型白细胞介素-12表达，促进肿瘤细胞而不是正常细胞上抗原的识别。
The limited number of targetable tumor-specific antigens and the immunosuppressive nature of the microenvironment within solid malignancies represent major barriers to the success of chimeric antigen receptor (CAR)-T cell therapies. Here, using epithelial cell adhesion molecule (EpCAM) as a model antigen, we used alanine scanning of the complementarity-determining region to fine-tune CAR affinity. This allowed us to identify CARs that could spare primary epithelial cells while still effectively targeting EpCAMhigh tumors. Although affinity-tuned CARs showed suboptimal antitumor activity in vivo, we found that inducible secretion of interleukin-12 (IL-12), under the control of the NFAT promoter, can restore CAR activity to levels close to that of the parental CAR. This strategy was further validated with another affinity-tuned CAR specific for intercellular adhesion molecule-1 (ICAM-1). Only in affinity-tuned CAR-T cells was NFAT activity stringently controlled and restricted to tumors expressing the antigen of interest at high levels. Our study demonstrates the feasibility of specifically gearing CAR-T cells towards recognition of solid tumors by combining inducible IL-12 expression and affinity-tuned CAR. The clinical benefits of chimaeric antigen receptor (CAR) T therapy are limited by ‘on-target, off-tumour’ effects. In this study, the authors describe a strategy that promotes the recognition of antigen on tumour, but not normal, cells by combining affinity tuning with inducible interleukin-12 expression.
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影响因子：
5.4
作者：
Heufler, C;Koch, F;Schuler, G
通讯作者：
Schuler, G
影响因子：
2.7
作者：
Lacy, Martha Q.;Jacobus, Susanna;Greipp, Philip R.
通讯作者：
Greipp, Philip R.
影响因子：
4.6
作者：
Park S;Shevlin E;Vedvyas Y;Zaman M;Park S;Hsu YS;Min IM;Jin MM
通讯作者：
Jin MM
DOI：
10.1016/j.omto.2020.08.009
发表时间：
2020-09-25
期刊：
Molecular therapy oncolytics
影响因子：
--
作者：
Jung M;Yang Y;McCloskey JE;Zaman M;Vedvyas Y;Zhang X;Stefanova D;Gray KD;Min IM;Zarnegar R;Choi YY;Cheong JH;Noh SH;Rha SY;Chung HC;Jin MM
通讯作者：
Jin MM
影响因子：
82.9
作者：
Narayan, Vivek;Barber-Rotenberg, Julie S.;Jung, In-Young;Lacey, Simon F.;Rech, Andrew J.;Davis, Megan M.;Hwang, Wei-Ting;Lal, Priti;Carpenter, Erica L.;Maude, Shannon L.;Plesa, Gabriela;Vapiwala, Neha;Chew, Anne;Moniak, Michael;Sebro, Ronnie A.;Farwell, Michael D.;Marshall, Amy;Gilmore, Joan;Lledo, Lester;Dengel, Karen;Church, Sarah E.;Hether, Tyler D.;Xu, Jun;Gohil, Mercy;Buckingham, Thomas H.;Yee, Stephanie S.;Gonzalez, Vanessa E.;Kulikovskaya, Irina;Chen, Fang;Tian, Lifeng;Tien, Kyle;Gladney, Whitney;Nobles, Christopher L.;Raymond, Hayley E.;Hexner, Elizabeth O.;Siegel, Donald L.;Bushman, Frederic D.;June, Carl H.;Fraietta, Joseph A.;Haas, Naomi B.
通讯作者：
Haas, Naomi B.