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)
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)
Article
Oncology
Corinna Grunert, Gerald Willimsky, Caroline Anna Peuker, Simone Rhein, Leo Hansmann, Thomas Blankenstein, Eric Blanc, Dieter Beule, Ulrich Keller, Antonio Pezzutto, Antonia Busse
Summary: T cell-based immunotherapy has shown remarkable clinical responses in cancer patients. However, isolating neoepitope-specific T cell receptors (TCRs) from the patients' own repertoire has limited success. This study suggests that using T cell repertoires from healthy donors and transgenic mice may be a viable strategy for isolating TCRs with known specificity against neoantigens.
Review
Immunology
Paul Shafer, Lauren M. Kelly, Valentina Hoyos
Summary: This article presents a review of the use of engineered T cells for cancer therapy. The mechanisms of T cell antigen recognition and signal transduction mediated through CARs and TCRs are discussed, along with the current classes of cancer antigens recognized by TCR T therapies and pre-clinical strategies for TCR discovery and enhancement. The current landscape of clinical trials for TCR T therapy is also reviewed, providing insights into the development of future engineered TCR approaches.
FRONTIERS IN IMMUNOLOGY
(2022)
Review
Oncology
Kinan Alhallak, Jennifer Sun, Amanda Jeske, Chaelee Park, Jessica Yavner, Hannah Bash, Berit Lubben, Ola Adebayo, Ayah Khaskiah, Abdel Kareem Azab
Summary: The use of BTCEs for MM treatment offers multiple targets and shows promise as a treatment modality, although challenges remain. While the advent of novel agents has altered the therapeutic landscape of MM, further research and development are needed as MM remains incurable.
Article
Biochemical Research Methods
Yiming Fang, Xuejun Liu, Hui Liu
Summary: This paper proposes an attention-aware contrastive learning model (ATMTCR) to infer the binding specificity of TCR-pMHC. The model utilizes attention weights to selectively mask key amino acids in TCR sequences, leading to improved prediction performance. Comparison experiments validate the effectiveness of the proposed method, and attention weights are used to identify important amino acids and their positional preference.
BRIEFINGS IN BIOINFORMATICS
(2022)
Article
Hematology
Christian Augsberger, Gerulf Hanel, Wei Xu, Vesna Pulko, Lydia Jasmin Hanisch, Angelique Augustin, John Challier, Katharina Hunt, Binje Vick, Pier Eduardo Rovatti, Christina Krupka, Maurine Rothe, Anne Schonle, Johannes Sam, Emmanuelle Lezan, Axel Ducret, Daniela Ortiz-Franyuti, Antje-Christine Walz, Jorg Benz, Alexander Bujotzek, Felix S. Lichtenegger, Christian Gassner, Alejandro Carpy, Victor Lyamichev, Jigar Patel, Nikola Konstandin, Antje Tunger, Marc Schmitz, Michael Von Bergwelt-Baildon, Karsten Spiekermann, Luca Vago, Irmela Jeremias, Estelle Marrer-Berger, Pablo Umana, Christian Klein, Marion Subklewe
Summary: The novel T-cell bispecific (TCB) antibody targets intracellular antigens, recognizing multiple leukemia-associated targets. WT1-TCB demonstrates potent killing of AML cells through various methods, with enhanced cytotoxicity when combined with immunomodulatory drugs.
Review
Cell Biology
Yimo Sun, Fenge Li, Heather Sonnemann, Kyle R. Jackson, Amjad H. Talukder, Arjun S. Katailiha, Gregory Lizee
Summary: Engineered TCR-T cell therapy has revolutionized the treatment of human cancer by targeting tumor antigen-specific adaptable cellular products. However, challenges such as low TCR avidity, off-target toxicities, and target antigen loss have limited the efficacy of TCR-T therapy for solid tumors. Further research is needed to address these limitations and improve the safety and efficacy of TCR-T therapies.
Article
Biochemistry & Molecular Biology
Dandan Yang, Zhihui Duan, Ping Yuan, Chengming Ding, Xiaoming Dai, Guodong Chen, Daichao Wu
Summary: TCR-engineered T cells have made significant progress in solid tumor therapy, with potential for further improvement in antigen selection and therapy strategies.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2023)
Article
Hematology
Meera Mohan, Rajshekhar Chakraborty, Susan Bal, Anoma Nellore, Muhamed Baljevic, Anita D'Souza, Peter G. Pappas, Jesus G. Berdeja, Natalie Callander, Luciano J. Costa
Summary: CAR T-cell and bispecific antibody therapies have shown remarkable efficacy in multiple myeloma patients, but they come with a significant risk of severe infections due to various factors. As these therapies have been recently approved, it is crucial to establish practical guidelines for infection monitoring and prevention until robust data from clinical trials become available. A panel of experienced investigators from COMMIT developed consensus recommendations for mitigating infections associated with CAR T-cell and bispecific antibody therapies in multiple myeloma patients.
BRITISH JOURNAL OF HAEMATOLOGY
(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
Oncology
Heng Mei, Chenggong Li, Huiwen Jiang, Xinying Zhao, Zhiping Huang, Dan Jin, Tao Guo, Haiming Kou, Lin Liu, Lu Tang, Ping Yin, Zhihui Wang, Lisha Ai, Sha Ke, Yimeng Xia, Jun Deng, Lei Chen, Li Cai, Chunyan Sun, Linghui Xia, Gaoquan Hua, Yu Hu
Summary: Bispecific BM38 CAR-T cells showed strong efficacy in patients with refractory or relapsed multiple myeloma (RRMM), with good clinical responses and manageable toxicities.
JOURNAL OF HEMATOLOGY & ONCOLOGY
(2021)
Article
Oncology
Jessica C. Hassel, Carola Berking, Andrea Forschner, Christoffer Gebhardt, Lucie Heinzerling, Friedegund Meier, Sebastian Ochsenreither, Jens Siveke, Axel Hauschild, Dirk Schadendorf
Summary: Tebentafusp is the first approved treatment option for HLA-A*02:01 metastatic uveal melanoma and has a new adverse event profile. Recommendations for its treatment, including AE management, were discussed by a national expert group. Patients in good clinical condition and with a low tumor burden are good candidates for Tebentafusp treatment.
EUROPEAN JOURNAL OF CANCER
(2023)
Article
Biochemistry & Molecular Biology
Vita Golubovskaya, Hua Zhou, Feng Li, Robert Berahovich, Jinying Sun, Michael Valentine, Shirley Xu, Hizkia Harto, John Sienkiewicz, Yanwei Huang, Lijun Wu
Summary: This study focused on developing novel CS1 CAR-T cells and bispecific CS1-BCMA CAR-T cells for targeting multiple myeloma. The experimental results demonstrated that these cells effectively killed multiple myeloma cells, showing promise for future clinical trials.
Article
Immunology
Eline van Diest, Mara J. T. Nicolasen, Lovro Kramer, Jiali Zheng, Patricia Hernandez-Lopez, Dennis X. Beringer, Jurgen Kuball
Summary: In this study, we developed a novel T cell engager concept called GAB by utilizing γδTCR as a tumor targeting domain. The γδ ECTO-alpha CD3-dimer design was found to be superior in function compared to monomers and does not induce T cell activation without simultaneous tumor engagement.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Immunology
Bruce J. MacLachlan, Georgina H. Mason, Alexander Greenshields-Watson, Frederic Triebel, Awen Gallimore, David K. Cole, Andrew Godkin
Summary: Immune checkpoint inhibitors have revolutionized the treatment of certain cancers, with combination approaches targeting multiple pathways showing increased efficacy. The newly identified immune checkpoint inhibitor LAG-3 interacts specifically with intact human leukocyte antigen class II heterodimers, providing insights into its function in initiating T cell inhibition.
EUROPEAN JOURNAL OF IMMUNOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Ross A. Robinson, Catriona McMurran, Michelle L. McCully, David K. Cole
Summary: Immunotherapy targeting pHLA complexes has gained attention for its broad potential, however, natural TCRs face stability and affinity challenges as soluble drugs. Protein engineering solutions have been applied to enhance TCR stability and affinity while maintaining target specificity, with a focus on developing next-generation soluble TCR-based therapies.
Review
Chemistry, Multidisciplinary
Edward Weaver, Shahid Uddin, David K. Cole, Andrew Hooker, Dimitrios A. Lamprou
Summary: Peptide-based therapy holds vast potential in the medical field, but faces challenges in delivery. The application of microfluidics could potentially propel this process, yet research in this area remains limited. Peptides play multifunctional roles in therapeutic formulations, and microfluidics offer a promising platform for diagnostics in the field of peptides.
APPLIED SCIENCES-BASEL
(2021)
Article
Immunology
Stephen Man, James E. Redman, Deborah L. Cross, David K. Cole, Ilona Can, Bethan Davies, Shaikh Shimaz Hashimdeen, Reiss Reid, Sian Llewellyn-Lacey, Kelly L. Miners, Kristin Ladell, Anya Lissina, Paul E. Brown, Linda Wooldridge, David A. Price, Pierre J. Rizkallah
Summary: The study identified a nonnatural epitope created as a by-product of protective group peptide synthesis, showing that chemical modifications directly altered the immunogenicity of a synthetic peptide. The structural studies highlighted the importance of the P4 residue for T cell recognition and demonstrated similar overall peptide conformations in complex with HLA-A*02:01.
JOURNAL OF IMMUNOLOGY
(2021)
Article
Multidisciplinary Sciences
Mathew Clement, Lea Knezevic, Tamsin Dockree, James E. McLaren, Kristin Ladell, Kelly L. Miners, Sian Llewellyn-Lacey, Anzelika Rubina, Ore Francis, David K. Cole, Andrew K. Sewell, John S. Bridgeman, David A. Price, Hugo A. van den Berg, Linda Wooldridge
Summary: This study investigates how CD8(+) T cells modulate antigen sensitivity through interactions with MHCI and CD8, showing that this interaction can reorder the agonist hierarchy of peptide ligands with different affinities for the TCR.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Cell Biology
Anna-Lisa Lanz, Giulia Masi, Nicla Porciello, Andre Cohnen, Deborah Cipria, Dheeraj Prakaash, Stefan Balint, Roberto Raggiaschi, Donatella Galgano, David K. Cole, Marco Lepore, Omer Dushek, Michael L. Dustin, Mark S. P. Sansom, Antreas C. Kalli, Oreste Acuto
Summary: The mechanism of T cell antigen receptor signaling is still not well understood. Mutations in TCR beta or CD3 zeta have been found to enhance pMHC-induced signaling, with pMHC binding reducing the cohesion between TCR alpha beta and CD3 zeta. These findings suggest that pMHC binding alone is sufficient to activate allosteric changes propagating from TCR alpha beta to CD3 zeta.
Article
Immunology
Claire Barber, Victoria Arena De Souza, Rachel L. Paterson, Magdalena Martin-Urdiroz, Nitha Charles Mulakkal, Velupillai Srikannathasan, Mary Connolly, Gwilym Phillips, Tein Foong-Leong, Robert Pengelly, Vijaykumar Karuppiah, Tressan Grant, Marcin Dembek, Anil Verma, Dawn Gibbs-Howe, Thomas H. Blicher, Andrew Knox, Ross A. Robinson, David K. Cole, Sarah Leonard
Summary: This study investigates the interaction between HLA-E molecules and peptides from different sources through structural analysis, and discovers a new method to stabilize pHLA-E complexes for the isolation of specific T cells, with significant implications for studying and identifying potential therapeutic TCRs.
EUROPEAN JOURNAL OF IMMUNOLOGY
(2022)
Article
Pharmacology & Pharmacy
Edward Weaver, Edward O'Connor, David K. Cole, Andrew Hooker, Shahid Uddin, Dimitrios A. Lamprou
Summary: The encapsulation of biologic molecules using a microfluidic platform shows great promise for the manufacturing of protein loaded lipid nanoparticles. This study investigates the encapsulation of bovine serum albumin (BSA) and trypsin using various phospholipids, and demonstrates the eligibility of the system to other biological medications. The results indicate that liposomes containing 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) show good stability and improved loading capacity for BSA compared to conventional methods, while maintaining controlled release of the active pharmaceutical ingredient.
INTERNATIONAL JOURNAL OF PHARMACEUTICS
(2022)
Article
Chemistry, Medicinal
Rory M. Crean, Christopher R. Pudney, David K. Cole, Marc W. van der Kamp
Summary: The study proposes a reliable protocol for evaluating the binding of T-cell receptor variants to target proteins, which can be efficiently applied to protein design with applications in biological therapeutics.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Oncology
Emily A. Bates, James A. Davies, Jana Vanova, Davor Nestic, Valerie S. Meniel, Sarah Koushyar, Tabitha G. Cunliffe, Rosie M. Mundy, Elise Moses, Hanni K. Uusi-Kerttula, Alexander T. Baker, David K. Cole, Dragomira Majhen, Pierre J. Rizkallah, Toby Phesse, John D. Chester, Alan L. Parker
Summary: Oncolytic virotherapies based on human adenoviruses show great clinical potential. Incorporating a peptide that selectively targets alpha v beta 6 integrin, the HAdV-D10 serotype vector can effectively target alpha v beta 6-positive tumor cells. Structural and biological studies show that HAdV-D10 has weak interactions with adenoviral receptors and does not engage blood coagulation factor X, reducing off-target hepatice sequestration. In vitro and in vivo experiments demonstrate that HAdV-D10.A20 selectively kills cancer cells and has significant potential for clinical translation.
MOLECULAR THERAPY-ONCOLYTICS
(2022)
Article
Multidisciplinary Sciences
Andrew Poole, Vijaykumar Karuppiah, Annabelle Hartt, Jaafar N. Haidar, Sylvie Moureau, Tomasz Dobrzycki, Conor Hayes, Christopher Rowley, Jorge Dias, Stephen Harper, Keir Barnbrook, Miriam Hock, Charlotte Coles, Wei Yang, Milos Aleksic, Aimee Bence Lin, Ross Robinson, Joe D. Dukes, Nathaniel Liddy, Marc Van der Kamp, Gregory D. Plowman, Annelise Vuidepot, David K. Cole, Andrew D. Whale, Chandramouli Chillakuri
Summary: This study presents the identification and development of an affinity-enhanced T cell receptor (TCR) and a bispecific protein targeting cancer cells with a high-frequency mutation in the KRAS oncogene.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Garry Dolton, Cristina Rius, Aaron Wall, Barbara Szomolay, Valentina Bianchi, Sarah A. E. Galloway, Md Samiul Hasan, Theo Morin, Marine E. Caillaud, Hannah L. Thomas, Sarah Theaker, Li Rong Tan, Anna Fuller, Katie Topley, Mateusz Legut, Meriem Attaf, Jade R. Hopkins, Enas Behiry, Joanna Zabkiewicz, Caroline Alvares, Angharad Lloyd, Amber Rogers, Peter Henley, Christopher Fegan, Oliver Ottmann, Stephen Man, Michael D. Crowther, Marco Donia, Inge Marie Svane, David K. Cole, Paul E. Brown, Pierre Rizkallah, Andrew K. Sewell
Summary: Tumor-infiltrating lymphocyte therapy can activate T cells of the immune system to target and eliminate solid cancers. Through the use of combinatorial peptide libraries and a proteomic database, the antigen specificities of persistent cancer-specific T cell receptors (TCRs) were identified after successful therapy for stage IV malignant melanoma. These TCRs were capable of targeting multiple tumor types through specific epitopes, and the atomic structures revealed the importance of a shared recognition motif. The ability of these multi-epitope targeting T cells to recognize cancer cells surpasses the recognition of individual epitopes, making them promising candidates for future immunotherapies.
Article
Immunology
Andrew Chancellor, Robert Alan Simmons, Rahul C. Khanolkar, Vladimir Nosi, Aisha Beshirova, Giuliano Berloffa, Rodrigo Colombo, Vijaykumar Karuppiah, Johanne M. Pentier, Vanessa Tubb, Hemza Ghadbane, Richard J. Suckling, Keith Page, Rory M. Crean, Alessandro Vacchini, Corinne De Gregorio, Verena Schaefer, Daniel Constantin, Thomas Gligoris, Angharad Lloyd, Miriam Hock, Velupillai Srikannathasan, Ross A. Robinson, Gurdyal S. Besra, Marc W. Van der Kamp, Lucia Mori, Raffaele Calogero, David K. Cole, Gennaro De Libero, Marco Lepore
Summary: Canonical MAIT TCRs with dual reactivity to microbial and self-antigens can recognize MR1 promiscuously, allowing MAIT cell responses in the absence of microbial infection. MAIT TCRs can also crossreact with self-antigens and perform T-helper-like functions in vitro. The promiscuity of MR1 recognition by a canonical MAIT TCR is associated with unique TCR β-chain features enriched in self-reactive MAIT cells of healthy individuals. These findings suggest a broader role of MAIT cells in immune homeostasis and diseases beyond microbial immunosurveillance.
JOURNAL OF EXPERIMENTAL MEDICINE
(2023)
Article
Chemistry, Multidisciplinary
William J. McDaid, Nikolai Lissin, Ellen Pollheimer, Michelle Greene, Adam Leach, Peter Smyth, Giovanna Bossi, Daniel Longley, David K. Cole, Christopher J. Scott
Summary: In this study, docetaxel-loaded polymeric nanoparticles were successfully conjugated with recombinant high affinity T cell receptors (TCRs) to target breast cancer cells. This approach enabled enhanced delivery of docetaxel and induced cell death through targeting tumour-specific peptide-HLA complexes. Overall, the study demonstrates the potential of using TCR-conjugated nanoparticles to target tumour-restricted peptide-HLA epitopes as a novel treatment strategy for delivering therapeutic drugs specifically to cancer cells.
Article
Biology
Mairene Coto-Llerena, Marco Lepore, Julian Spagnuolo, Daniela Di Blasi, Diego Calabrese, Aleksei Suslov, Glenn Bantug, Francois Ht Duong, Luigi M. Terracciano, Gennaro De Libero, Markus H. Heim
Summary: IFNλ plays a crucial role in innate pathogen defense in the lung and intestine, with IFNλ4 inhibiting spontaneous clearance of HCV and affecting T-cell responses. However, the mechanism by which IFNλ4 promotes CD8(+) T-cell responses and inhibits host immunity to HCV infections remains unclear.
LIFE SCIENCE ALLIANCE
(2021)