Article
Immunology
Markus Barden, Astrid Holzinger, Lukas Velas, Marianna Mezosi-Csaplar, Arpad Szoeor, Gyoergy Vereb, Gerhard J. Schuetz, Andreas A. Hombach, Hinrich Abken
Summary: In engineered T cells, CAR and physiological TCR/CD3 complex co-exist and utilize the same downstream signaling pathway for T cell activation. It is still unclear whether CAR-mediated T cell activation depends on the presence of TCR and whether CAR and TCR can activate each other upon engaging their respective antigens. Our study shows that CD3 zeta CAR is independent of TCR-associated CD3 zeta and cannot replace CD3 zeta to rescue the TCR complex in CD3 zeta knockout T cells. Additionally, CAR and TCR do not cross-activate each other and form separate synapses upon antigen engagement.
FRONTIERS IN IMMUNOLOGY
(2023)
Review
Oncology
Hongtao Liu, Chongxian Pan, Wenru Song, Delong Liu, Zihai Li, Lei Zheng
Summary: Cell therapy has advanced rapidly in recent years, with applications expanding beyond hematologic malignancies to solid tumors, targeting personalized tumor-specific neoantigens and enhancing T cell trafficking. Despite challenges, the maturation of technologies in T cell engineering is expected to lead a revolution in cancer immunotherapy in the near future.
BIOMARKER RESEARCH
(2021)
Review
Medicine, General & Internal
Aditi Mulgaonkar, Durga Udayakumar, Yaxing Yang, Shelby Harris, Orhan K. Oz, Praveen Ramakrishnan Geethakumari, Xiankai Sun
Summary: Chimeric antigen receptor (CAR) T-cell therapies have shown promise in treating hematological malignancies, but relapses and toxicities remain challenges. The use of immuno-PET/-SPECT imaging strategies can help identify resistance mechanisms, toxic events, and assess treatment efficacy of CAR-T cell therapies. This review discusses the current status and potential opportunities of using immuno-PET/-SPECT imaging in CAR-T cell therapies.
FRONTIERS IN MEDICINE
(2023)
Editorial Material
Oncology
Qi Cai, Sarah Warren, Violena Pietrobon, Markus Maeurer, Lei S. Qi, Timothy K. Lu, Marc J. Lajoie, David Barrett, David F. Stroncek, Francesco M. Marincola
Summary: Successful implementation of adoptive cell therapy (ACT) of cancer requires addressing biological and practical challenges comprehensively. However, this approach has been neglected, leading to a gap between the potential and effectiveness of ACT. In this article, we summarize the most promising technical strategies, especially focusing on CAR-engineered cells, in creating an ideal ACT product. As many requirements for effective ACT are common to most cancers, the outlined strategies might have a broader impact.
Review
Clinical Neurology
Kun-Wei Song, Brian J. Scott, Eudocia Q. Lee
Summary: This article outlines the spectrum of neurotoxicity associated with approved immunotherapies and clinical trials. It highlights the advances made in understanding and managing neurotoxicity as the use of cancer immunotherapies becomes more widespread. The expanding indications for immunotherapy have also presented new challenges, such as distinguishing neurotoxicity from disease progression.
CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS
(2023)
Review
Immunology
Frederik Holm Rothemejer, Nanna Pi Lauritsen, Ole Schmeltz Sogaard, Martin Tolstrup
Summary: This article reviews the challenges and potential strategies in designing CAR T cells against HIV and other chronic viral infections. It emphasizes the importance of CAR T cell persistence and efficacy, which is dependent on antigen density and target cell abundance.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Multidisciplinary Sciences
Ellis L. Reinherz, Wonmuk Hwang, Matthew J. Lang
Summary: T cell receptors (TCR) on cytolytic T lymphocytes (CTLs) recognize foreign antigens bound in the groove of major histocompatibility complex (MHC) molecules (H-2 in mouse and HLA in human) displayed on altered cells. Mechanobiology optimizes TCR specificity and sensitivity by applying mechanical load to the bond formed between TCR and pMHC ligand. Applying TCR mechanobiology to T cell monitoring and treatment can improve cancer vaccine development and immunotherapy paradigms.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Oncology
Chirag H. Patel, Jonathan D. Powell
Summary: Immunotherapy has become a well-established treatment for cancer, but metabolic reprogramming by cancer cells creates an immunosuppressive tumor microenvironment. This article discusses the metabolic programs of cancer cells and immune cells, as well as the role of metabolic checkpoints in immune evasion and tumor growth. Strategies targeting metabolism have the potential to enhance antitumor immune responses.
ANNUAL REVIEW OF CANCER BIOLOGY
(2023)
Article
Medicine, Research & Experimental
Haixia Li, Dani Zhong, Huiguan Luo, Wei Shi, Shenxia Xie, Hangbiao Qiang, Lichen Zhu, Li Gao, Jun Liu, Shuyang Sun, Ziqiang Ding, Xiaomei Yang, Xiaoling Lu
Summary: Chimeric antigen receptor (CAR) T-cell immunotherapy is a research hotspot in the field of malignant tumor treatment. This study investigates whether nanobody-based T cell receptor-like CAR T cells can target intracellular antigens and effectively kill tumor cells. By developing HLA-A2/GPC3 and HLA-A2/WT1-specific nanobodies and incorporating them into TCR-like CARs, the researchers found that these CAR-redirected T cells could selectively recognize and kill MHC/peptide complex-expressing tumor cells both in vitro and in mouse tumor models. This study offers a potential strategy to target intracellular antigens and expand the application of CAR T-cell therapy.
BIOMEDICINE & PHARMACOTHERAPY
(2022)
Article
Immunology
Rubi M. -H. Velasco Cardenas, Simon M. Brandl, Ana Valeria Melendez, Alexandra Emilia Schlaak, Annabelle Buschky, Timo Peters, Fabian Beier, Bryan Serrels, Sanaz Taromi, Katrin Raute, Simon Hauri, Matthias Gstaiger, Silke Lassmann, Johannes B. Huppa, Melanie Boerries, Geoffroy Andrieux, Bertram Bengsch, Wolfgang W. Schamel, Susana Minguet
Summary: Minguet and colleagues systematically examine how individual CD3 chains of the TCR-CD3 complex can improve chimeric antigen receptor (CAR) T cell performance. They found that CARs containing CD3 delta, CD3 epsilon, or CD3 gamma cytoplasmic tails outperformed traditional zeta CAR T cells in vivo. Transcriptomic and proteomic analysis reveals differences in activation potential, metabolism, and stimulation-induced T cell dysfunctionality that explain the enhanced anti-tumor performance. Dimerization of the CARs also improved their overall functionality. The study also identifies SHP-1 as a new interaction partner of CD3 delta, which attenuates activation signals and might prevent exhaustion and dysfunction.
Review
Medicine, General & Internal
Michael Boettcher, Alexander Joechner, Ziduo Li, Sile Fiona Yang, Patrick Schlegel
Summary: CAR-T cell therapy has revolutionized the treatment of relapsed and refractory leukemia and lymphoma in pediatric and young adult patients. Efforts should be made to develop CAR therapeutics and introduce new technologies to address the urgent need for more potent and specific therapies in childhood malignancies. This article discusses the basic aspects, evolution, and drawbacks of childhood CAR-T cell therapy, along with the latest clinically relevant information.
JOURNAL OF CLINICAL MEDICINE
(2022)
Editorial Material
Hematology
Rawan G. Faram, Marco L. Davila
Summary: The CAR-HEMATOTOX predictive model by Rejeski et al in this issue of Blood can identify patients at highest risk of hematologic toxicity following CD19-directed chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory large B-cell lymphoma.
Review
Biochemistry & Molecular Biology
Qiaofei Liu, Jiayi Li, Huaijin Zheng, Sen Yang, Yuze Hua, Nan Huang, Jorg Kleeff, Quan Liao, Wenming Wu
Summary: In recent decades, immune checkpoint blockade and CAR-T therapy have made significant contributions to clinical immunotherapy. However, their efficacy is limited in most solid neoplasms, leading to the exploration of new immunotherapeutic modalities. Adoptive cell therapies like TCR-T, CAR-NK, and CAR-M have emerged as potential treatments for solid neoplasms and have certain advantages over CAR-T. This review summarizes the evolution of adoptive cell therapies and discusses the advancements and potential clinical applications of TCR-T, CAR-NK, and CAR-M in solid neoplasms.
Editorial Material
Hematology
Rory McCulloch
Summary: In a large retrospective analysis, outcomes of post-BTKi mantle cell lymphoma patients were described, providing a benchmark for future studies and highlighting the challenges in managing this patient cohort.
BRITISH JOURNAL OF HAEMATOLOGY
(2023)
Article
Biotechnology & Applied Microbiology
Daniel C. C. Kirouac, Cole Zmurchok, Avisek Deyati, Jordan Sicherman, Chris Bond, Peter W. W. Zandstra
Summary: In this study, a mathematical model of T cell responses was developed to understand the mechanisms underlying clinical outcomes and patient variability in CAR-T cell therapy. Utilizing machine learning, the study demonstrated that pre-infusion transcriptomes can accurately predict patient outcomes, and additional pharmacological variance arises from cellular interactions with patient tumors. This research enables a new phase of predictive CAR-T product development.
NATURE BIOTECHNOLOGY
(2023)
Article
Biotechnology & Applied Microbiology
Liliana Wroblewska, Tasuku Kitada, Kei Endo, Velia Siciliano, Breanna Stillo, Hirohide Saito, Ron Weiss
NATURE BIOTECHNOLOGY
(2015)
Review
Multidisciplinary Sciences
Tasuku Kitada, Breanna DiAndreth, Brian Teague, Ron Weiss
Article
Multidisciplinary Sciences
Velia Siciliano, Breanna DiAndreth, Blandine Monel, Jacob Beal, Jin Huh, Kiera L. Clayton, Liliana Wroblewska, AnneMarie McKeon, Bruce D. Walker, Ron Weiss
NATURE COMMUNICATIONS
(2018)
Article
Biochemistry & Molecular Biology
Jeremy J. Gam, Breanna DiAndreth, Ross D. Jones, Jin Huh, Ron Weiss
NUCLEIC ACIDS RESEARCH
(2019)
Article
Biochemistry & Molecular Biology
Han Xu, Agnes E. Hamburger, Jee-Young Mock, Xueyin Wang, Aaron D. Martin, Talar Tokatlian, Julyun Oh, Mark E. Daris, Kathleen R. Negri, Grant B. Gabrelow, Ming Lun Wu, Daniel P. Nampe, Grace E. Asuelime, Michele E. McElvain, Mark L. Sandberg, Alexander Kamb
MOLECULAR IMMUNOLOGY
(2020)
Article
Oncology
Talar Tokatlian, Grace E. Asuelime, Jee-Young Mock, Breanna DiAndreth, Shruti Sharma, Dora Toledo Warshaviak, Mark E. Daris, Kristian Bolanos, Breanna L. Luna, Martin S. Naradikian, Kiran Deshmukh, Agnes E. Hamburger, Alexander Kamb
Summary: This study developed a dual-receptor system that can target mesothelin expressed in both tumor and normal tissues, reducing the risk of serious inflammation caused by the treatment.
JOURNAL FOR IMMUNOTHERAPY OF CANCER
(2022)
Review
Immunology
Breanna DiAndreth, Agnes E. Hamburger, Han Xu, Alexander Kamb
Summary: Immune cells engineered with receptors to integrate signals from multiple antigens provide a promising approach for achieving therapeutic selectivity in cancer patients. The Tmod system, a NOT-gated signal integrator, is being developed for patients with solid tumors. By selecting patients with defined lesions in their tumor genomes, the Tmod approach presents an opportunity to create truly selective therapies for certain cancer patients.
CLINICAL IMMUNOLOGY
(2022)
Article
Multidisciplinary Sciences
Breanna DiAndreth, Noreen Wauford, Eileen Hu, Sebastian Palacios, Ron Weiss
Summary: The authors developed an RNA-level regulation platform called PERSIST using CRISPR endoRNases, which is modular, scalable, and more stable than traditional transcriptional regulation. The platform exhibits strong ON and OFF responses, resists epigenetic silencing, and can be used for constructing robust and predictable gene circuits in various gene and cell therapies.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Ross D. Jones, Yili Qian, Velia Siciliano, Breanna DiAndreth, Jin Huh, Ron Weiss, Domitilla Del Vecchio
NATURE COMMUNICATIONS
(2020)