Article
Biochemistry & Molecular Biology
Haiyong Peng, Thomas Nerreter, Katrin Mestermann, Jakob Wachter, Jing Chang, Michael Hudecek, Christoph Rader
Summary: The success of CAR-T therapy in treating hematologic malignancies has led to the development of sCAR-T systems. This study investigates the therapeutic potential of sCAR-Ts targeting ROR1 and identifies a switch with low affinity but potent antitumor activity. By converting the same antibody to a conventional CAR-T, it outperforms a clinically tested CAR-T with higher affinity. Therefore, sCAR-Ts have therapeutic utility and can aid in screening conventional CAR-T candidates.
Article
Immunology
Rui Zheng, Yuankun Chen, Yiting Zhang, Sixin Liang, Xiaojuan Zhao, Yiyi Wang, Pengju Wang, Ruotong Meng, Angang Yang, Bo Yan
Summary: Our study explores the effect of low-affinity CARs using humanized scFvs on the function of CAR-T cells. We find that moderately reducing the affinity of CARs can maintain anti-tumor efficacy and improve the safety of CAR therapy both in vitro and in vivo. In addition, T cells expressing the VL domain only antibody show long-lasting tumor elimination capability and lower cytokine levels.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Oncology
Jatuporn Sujjitjoon, Elias Sayour, Shih-Ting Tsao, Mongkol Uiprasertkul, Kleebsabai Sanpakit, Jassada Buaboonnam, Pa-thai Yenchitsomanus, La-ongsri Atchaneeyasakul, Lung-Ji Chang
Summary: GD2-specific CAR T cells showed promising therapeutic potential against retinoblastoma by recognizing and effectively killing cells with high GD2 antigen expression in vitro. However, prolonged exposure to the tumor resulted in a diminished killing activity of GD2-CAR T cells, suggesting the potential benefit of combination therapy with immune checkpoint inhibitors.
TRANSLATIONAL ONCOLOGY
(2021)
Article
Oncology
Nattaporn Phanthaphol, Chalermchai Somboonpatarakun, Kwanpirom Suwanchiwasiri, Thaweesak Chieochansin, Jatuporn Sujjitjoon, Sopit Wongkham, John Maher, Mutita Junking, Pa-thai Yenchitsomanus
Summary: CAR T cell therapy has shown efficacy in hematologic malignancies, but further investigation is needed for its application in solid tumors. The selection of target antigens highly expressed in cancer cells but not normal cells is crucial for successful immunotherapy.
FRONTIERS IN ONCOLOGY
(2021)
Article
Oncology
Jinrong Yang, Weilin Zhou, Dan Li, Ting Niu, Wei Wang
Summary: This article summarizes the application and research progress of BCMA-targeting CAR T cell therapy in the treatment of multiple myeloma, as well as measures to improve efficacy and safety.
Article
Immunology
Chengcheng Zhang, Linling Wang, Qianzhen Zhang, Junjie Shen, Xia Huang, Meiling Wang, Yi Huang, Jun Chen, Yanmin Xu, Wenxu Zhao, Yanan Qi, Yunyan Li, Yanjiao Ou, Zhi Yang, Cheng Qian
Summary: This study aimed to identify the optimal single-chain variable fragment (scFv) to optimize the therapeutic potential of CAR-T cells targeting CEA-positive carcinoma. The study tested four different antibody-derived scFvs (M5A, hMN-14, BW431/26, and C2-45) and found that M5A had the best cell proliferation and cytokine secretion levels, as well as better antitumor efficacy in a mouse xenograft model.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Oncology
Xiaochen Zhai, Fengtao You, Shufen Xiang, Licui Jiang, Dan Chen, Yafen Li, Shuangshuang Fan, Zhichao Han, Tingting Zhang, Gangli An, Bozhen Zhang, Yusheng Chen, Huimin Meng, Lin Yang
Summary: The study found that CAR-modified Vγ9Vδ2 T cells have anti-tumor activity against the MUC1-Tn antigen, with even stronger effects than CAR-alpha beta T cells. While CAR-Vγ9Vδ2 T cells have shorter persistence, their function can be improved with continuous stimulation.
AMERICAN JOURNAL OF CANCER RESEARCH
(2021)
Article
Pharmacology & Pharmacy
Wei Jiang, Guosheng Gu, Yumin Zhang, Yushuai Song, Ming Shi, Gang Wang, Huizhong Li, Tingting Tao, Jianhua Qin, Xianliang Li, Hongtao Jia, Feng Jiao, Weidong Xu, Xiaoyi Huang
Summary: A new treatment strategy for solid tumors using a natural killer-like T cell line (UNKT) with modified chimeric antigen receptors (CAR) has been reported, showing strong antitumor activity and increased expression of effector cytokines. The CAR-UNKT cells demonstrated migration and infiltration into the tumor.
PHARMACOLOGICAL RESEARCH
(2023)
Article
Biotechnology & Applied Microbiology
Christina Amatya, Melissa A. Pegues, Norris Lam, Danielle Vanasse, Claudia Geldres, Stephanie Choi, Stephen M. Hewitt, Steven A. Feldman, James N. Kochenderfer
Summary: CARs targeting SLAMF7 show promise for MM therapy due to specific expression on MM cells, and CD28-containing CARs exhibit superior anti-tumor activity compared to 4-1BB-containing CARs. Inclusion of a suicide gene in SLAMF7-targeting CAR T cells is prudent to eliminate cells expressing SLAMF7 on normal leukocytes when necessary.
Article
Oncology
Ernesto Lopez, Sofia Hidalgo, Eduardo Roa, Javiera Gomez, Carlos Hermansen Truan, Evy Sanders, Cristian Carrasco, Rodrigo Pacheco, Flavio Salazar-Onfray, Manuel Varas-Godoy, Vincenzo Borgna, Alvaro Lladser
Summary: Gallbladder cancer (GBC) is often diagnosed at late stages and lacks effective treatments. This study investigates the potential of using CAR-T cells targeting CEA as a potential immunotherapy for GBC. Results show that CEA is expressed in a high percentage of GBC tumors, and CAR-T cells can recognize and kill GBC cells expressing CEA. The findings support the further development of CEA-specific CAR-T cells for GBC immunotherapy.
Article
Oncology
Xiaorui Li, Yaru Feng, Fengqin Shang, Zhuoying Yu, Tieshan Wang, Jing Zhang, Zhiru Song, Ping Wang, Bingjie Shi, Jianxun Wang
Summary: Second-generation CAR-T cells targeting CD38 show efficient and specific antitumor activity in vitro and in vivo, indicating their potential as a novel therapy for clinical treatment of multiple myeloma.
FRONTIERS IN ONCOLOGY
(2021)
Review
Immunology
Ilse Gille, Frans H. J. Claas, Geert W. Haasnoot, Mirjam H. M. Heemskerk, Sebastiaan Heidt
Summary: Solid organ transplantation is an effective treatment for end-stage diseases, but the need for immunosuppression can lead to serious side effects. CAR Treg therapy, specifically with HLA-A2 CAR Tregs, shows potential in promoting transplantation tolerance and improving graft survival.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Haiyong Peng, Thomas Nerreter, Katrin Mestermann, Jakob Wachter, Jing Chang, Michael Hudecek, Christoph Rader
Summary: The development of switchable CAR-T (sCAR-T) systems, combining a universal CAR-T with bispecific adapter proteins, has gained considerable attention due to their controllability and versatility. In this study, the therapeutic utility of sCAR-Ts targeting the receptor tyrosine kinase ROR1 was explored, and bispecific adaptor proteins that effectively mediate universal CAR-T engagement were identified. Switches based on ROR1-targeting Fabs with different epitopes and affinities were compared in vitro and in vivo models, and a switch targeting a unique epitope with low affinity was found to have potent and selective antitumor activity. Conversion of the same anti-ROR1 mAb to a conventional CAR-T outperformed a clinically investigated conventional CAR-T with higher affinity. This study highlights the therapeutic potential of sCAR-Ts and their role in identifying conventional CAR-T candidates for further studies.
Article
Oncology
Ang Zhang, Shenyu Wang, Yao Sun, Yikun Zhang, Long Zhao, Yang Yang, Yijian Zhang, Lei Xu, Yangyang Lei, Jie Du, Hu Chen, Lian Duan, Mingyi He, Lintao Shi, Lei Liu, Quanjun Wang, Liangding Hu, Bin Zhang
Summary: By grafting the PD1 domain onto a conventional second-generation CAR, the research team successfully designed a novel CAR structure that demonstrates enhanced cytotoxicity and lower cytokine release specifically towards tumor cells overexpressing CD19 and PDL1, without PD1-related off-target toxicity.
EXPERIMENTAL HEMATOLOGY & ONCOLOGY
(2023)
Review
Medicine, Research & Experimental
Li Yin, Gui-lai Chen, Zhuo Xiang, Yu-lin Liu, Xing-yu Li, Jing-wang Bi, Qiang Wang
Summary: Breast cancer is the most common cancer in women, and a significant percentage of patients experience invasion or metastasis despite surgical resection. Current treatments, such as chemotherapy and targeted therapy, are not effective in all cases. CAR-T cell therapy has shown promise in tumor immunotherapy, but its effectiveness in solid tumors, including breast cancer, is limited due to various factors. This article discusses the prospects and challenges of CAR-T cell therapy in metastatic breast cancer and reviews the clinical targets for this therapy. Solutions and ideas for improving the efficacy of CAR-T cell therapy in breast cancer are also proposed.
BIOMEDICINE & PHARMACOTHERAPY
(2023)
Article
Chemistry, Multidisciplinary
Junpeng Qi, Kohei Tsuji, David Hymel, Terrence R. Burke, Michael Hudecek, Christoph Rader, Haiyong Peng
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2020)
Article
Biochemistry & Molecular Biology
Rebecca S. Goydel, Justus Weber, Haiyong Peng, Junpeng Qi, Jo Soden, Jim Freeth, HaJeung Park, Christoph Rader
JOURNAL OF BIOLOGICAL CHEMISTRY
(2020)
Article
Biochemistry & Molecular Biology
Alex R. Nanna, Alexander Kel'in, Christopher Theile, Justin M. Pierson, Zhi Xiang Voo, Ashish Garg, Jayaprakash K. Nair, Martin A. Maier, Kevin Fitzgerald, Christoph Rader
NUCLEIC ACIDS RESEARCH
(2020)
Article
Biochemistry & Molecular Biology
Dobeen Hwang, Christoph Rader
Article
Chemistry, Medicinal
Ajeeth Adhikari, Christiana N. Teijaro, Xiaohui Yan, Chin-Yuan Chang, Chun Gui, Yu-Chen Liu, Ivana Crnovcic, Dong Yang, Thibault Annaval, Christoph Rader, Ben Shen
JOURNAL OF MEDICINAL CHEMISTRY
(2020)
Article
Oncology
Shivani Srivastava, Scott N. Furlan, Carla A. Jaeger-Ruckstuhl, Megha Sarvothama, Carolina Berger, Kimberly S. Smythe, Sarah M. Garrison, Jennifer M. Specht, Sylvia M. Lee, Robert A. Amezquita, Valentin Voillet, Vishaka Muhunthan, Sushma Yechan-Gunja, Smitha P. S. Pillai, Christoph Rader, A. McGarry Houghton, Robert H. Pierce, Raphael Gottardo, David G. Maloney, Stanley R. Riddell
Summary: CAR-T therapy shows limited efficacy in lung adenocarcinoma, but combining oxaliplatin, cyclophosphamide, and anti-PD-L1 can improve CAR-T cell infiltration into tumors and enhance efficacy.
Article
Oncology
Damian Kovalovsky, Jeong Heon Yoon, Matthew G. Cyr, Samantha Simon, Elisaveta Voynova, Christoph Rader, Adrian Wiestner, Julie Alejo, Stefania Pittaluga, Ronald E. Gress
Summary: A novel CAR-T cell therapy targeting Siglec-6 for chronic lymphocytic leukemia was developed and shown to specifically target CLL cells. Additionally, Siglec-6 was identified as a potential target for immunotherapy based on the findings of this study.
Article
Biochemistry & Molecular Biology
Napon Nilchan, James M. Alburger, William R. Roush, Christoph Rader
Summary: h38C2 is a humanized catalytic antibody that can be site-selectively conjugated with molecules by rational mutation of its internal lysine residue, showing promise for new conjugation applications.
Article
Biotechnology & Applied Microbiology
Jun Luo, Dong Yang, Hindra, Ajeeth Adhikari, Liao-Bin Dong, Fei Ye, Xiaohui Yan, Christoph Rader, Ben Shen
Summary: The discovery of a new sub-family of AMM congeners, named AMEs, with different chemical features and modest cytotoxicity against cancer cells, expands the understanding of structure-activity relationship for pyrroloquinoline alkaloids. Comparative analysis of the gene clusters of AMEs and AMMs supports the use of a scaffold peptide for biosynthesis of the pyrroloquinoline family of natural products, providing insights for future efforts in mimicking Nature's combinatorial biosynthetic strategies for natural product structural diversity.
JOURNAL OF INDUSTRIAL MICROBIOLOGY & BIOTECHNOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Rebecca S. Goydel, Christoph Rader
Summary: Over the past 25 years, antibody therapeutics have become successful pharmaceuticals, particularly in the field of oncology. These therapies work through natural properties, engagement of cytotoxic T cells, and delivery of cytotoxic payloads. The success of antibody-based cancer therapy is built on both natural and engineered properties of the antibody molecule.
Article
Chemistry, Organic
Dong Yang, Fei Ye, Christiana N. Teijaro, Dobeen Hwang, Thibault Annaval, Ajeeth Adhikari, Gengnan Li, Xiaohui Yan, Chun Gui, Christoph Rader, Ben Shen
Summary: Comparative analysis of four anthraquinone-fused enediyne biosynthetic gene clusters revealed YpmL as a unique cytochrome P450 enzyme in the yangpumicin BGC. In vitro characterization confirmed YpmL as a hydroxylase that catalyzes C-6 hydroxylation in YPM A biosynthesis. In vivo application of YpmL enabled the engineered production of four novel tiancimycin analogues and provided insight into their cytotoxicity against human cancer cell lines.
Article
Biochemical Research Methods
Dobeen Hwang, Napon Nilchan, HaJeung Park, Raktim N. Roy, William R. Roush, Christoph Rader
Summary: In this study, the assembly strategy of antibody-drug conjugates (ADCs) was expanded by mutating the reactive lysine of the catalytic antibody h38C2 to a cysteine. Using a dibromomaleimide derivative as the electrophile, precise, fast, efficient, and stable assembly of ADCs with the h38C2_K99C module was achieved.
BIOCONJUGATE CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Haiyong Peng, Thomas Nerreter, Katrin Mestermann, Jakob Wachter, Jing Chang, Michael Hudecek, Christoph Rader
Summary: The success of CAR-T therapy in treating hematologic malignancies has led to the development of sCAR-T systems. This study investigates the therapeutic potential of sCAR-Ts targeting ROR1 and identifies a switch with low affinity but potent antitumor activity. By converting the same antibody to a conventional CAR-T, it outperforms a clinically tested CAR-T with higher affinity. Therefore, sCAR-Ts have therapeutic utility and can aid in screening conventional CAR-T candidates.
Article
Chemistry, Medicinal
Andrew D. Steele, Alexander F. Kiefer, Dobeen Hwang, Dong Yang, Christiana N. Teijaro, Ajeeth Adhikari, Christoph Rader, Ben Shen
Summary: Antibody-drug conjugates (ADCs) are cancer chemotherapeutics that combine an antibody-based delivery system, cytotoxic payload, and a chemical linker. Functionalization of the payload must be carefully designed to maintain the potency needed for ADC efficacy. In this study, we successfully translated biocatalytically functionalized TNMs into ADCs using a dual-variable domain (DVD)-mAb platform. We evaluated different linker chemistries and found a trade-off between potency and antigen selectivity. This work represents a novel approach in the development of ADCs for various cancer types.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Matthew G. Cyr, Henry D. Wilson, Anna-Lena Spierling, Jing Chang, Haiyong Peng, Peter Steinberger, Christoph Rader
Summary: This article introduces an unbiased approach to antibody discovery, which relies on generating monoclonal antibodies (mAbs) against native target cell surfaces via phage display. The authors demonstrated that this method efficiently identifies mAbs with the desired target cell reactivity and identified and validated three cell surface antigens in multiple myeloma. This study highlights the utility of optimized whole-cell phage display selection methods and their potential in target-unbiased antibody discovery workflows.
JOURNAL OF MOLECULAR BIOLOGY
(2023)