المؤلفون: Mathieu Ferrari, Matteo Righi, Vania Baldan, Patrycja Wawrzyniecka, Anna Bulek, Alexander Kinna, Biao Ma, Reyisa Bughda, Zulaikha Akbar, Saket Srivastava, Isaac Gannon, Mathew Robson, James Sillibourne, Ram Jha, Mohamed El-Kholy, Oliver Muhammad Amin, Evangelia Kokalaki, Mohammed Amin Banani, Rehan Hussain, William Day, Wen Chean Lim, Priyanka Ghongane, Jade R. Hopkins, Dennis Jungherz, Marco Herling, Martin Welin, Sachin Surade, Michael Dyson, John McCafferty, Derek Logan, Shaun Cordoba, Simon Thomas, Andrew Sewell, Paul Maciocia, Shimobi Onuoha, Martin Pule

المصدر: Nature Communications, Vol 15, Iss 1, Pp 1-16 (2024)

مصطلحات موضوعية: Science

الوصف: Abstract Peripheral T cell lymphomas are typically aggressive with a poor prognosis. Unlike other hematologic malignancies, the lack of target antigens to discriminate healthy from malignant cells limits the efficacy of immunotherapeutic approaches. The T cell receptor expresses one of two highly homologous chains [T cell receptor β-chain constant (TRBC) domains 1 and 2] in a mutually exclusive manner, making it a promising target. Here we demonstrate specificity redirection by rational design using structure-guided computational biology to generate a TRBC2-specific antibody (KFN), complementing the antibody previously described by our laboratory with unique TRBC1 specificity (Jovi-1) in targeting broader spectrum of T cell malignancies clonally expressing either of the two chains. This permits generation of paired reagents (chimeric antigen receptor-T cells) specific for TRBC1 and TRBC2, with preclinical evidence to support their efficacy in T cell malignancies.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-1723Test

الوصول الحر: https://doaj.org/article/0a0cba1c19b24f4e8e75069f7a2b0924Test

المؤلفون: Julia Taylor, Anna Bulek, Isaac Gannon, Mathew Robson, Evangelia Kokalaki, Thomas Grothier, Callum McKenzie, Mohamed El-Kholy, Maria Stavrou, Charlotte Traynor-White, Wen Chean Lim, Panagiota Panagiotou, Saket Srivastava, Vania Baldan, James Sillibourne, Mathieu Ferrari, Martin Pule, Simon Thomas

المصدر: Frontiers in Immunology, Vol 14 (2023)

مصطلحات موضوعية: chimeric antigen receptor, immunotherapy, immunosuppression, cancer, cell engineering, Immunologic diseases. Allergy, RC581-607

الوصف: SHP1 and SHP2 are SH2 domain-containing proteins which have inhibitory phosphatase activity when recruited to phosphorylated ITIMs and ITSMs on inhibitory immune receptors. Consequently, SHP1 and SHP2 are key proteins in the transmission of inhibitory signals within T cells, constituting an important point of convergence for diverse inhibitory receptors. Therefore, SHP1 and SHP2 inhibition may represent a strategy for preventing immunosuppression of T cells mediated by cancers hence improving immunotherapies directed against these malignancies. Both SHP1 and SHP2 contain dual SH2 domains responsible for localization to the endodomain of inhibitory receptors and a protein tyrosine phosphatase domain which dephosphorylates and thus inhibits key mediators of T cell activation. We explored the interaction of the isolated SH2 domains of SHP1 and SHP2 to inhibitory motifs from PD1 and identified strong binding of both SH2 domains from SHP2 and more moderate binding in the case of SHP1. We next explored whether a truncated form of SHP1/2 comprising only of SH2 domains (dSHP1/2) could act in a dominant negative fashion by preventing docking of the wild type proteins. When co-expressed with CARs we found that dSHP2 but not dSHP1 could alleviate immunosuppression mediated by PD1. We next explored the capacity of dSHP2 to bind with other inhibitory receptors and observed several potential interactions. In vivo we observed that the expression of PDL1 on tumor cells impaired the ability of CAR T cells to mediate tumor rejection and this effect was partially reversed by the co-expression of dSHP2 albeit at the cost of reduced CAR T cell proliferation. Modulation of SHP1 and SHP2 activity in engineered T cells through the expression of these truncated variants may enhance T cell activity and hence efficacy in the context of cancer immunotherapy.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fimmu.2023.1119350/fullTest; https://doaj.org/toc/1664-3224Test

الوصول الحر: https://doaj.org/article/e38d52e6c99944609c3459b7f08fd187Test

المؤلفون: Evangelia Kokalaki, Biao Ma, Mathieu Ferrari, Thomas Grothier, Warren Hazelton, Somayya Manzoor, Eren Costu, Julia Taylor, Anna Bulek, Saket Srivastava, Isaac Gannon, Ram Jha, Rosalind Gealy, Lukas Stanczuk, Tatiana Rizou, Mathew Robson, Mohamed El-Kholy, Vania Baldan, Matteo Righi, James Sillibourne, Simon Thomas, Shimobi Onuoha, Shaun Cordoba, Martin Pule

المصدر: Molecular Therapy.

مصطلحات موضوعية: Pharmacology, Drug Discovery, Genetics, Molecular Medicine, Molecular Biology

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::7569568c73a33662c465b418886f9290Test
https://doi.org/10.1016/j.ymthe.2023.03.020Test

المؤلفون: Nushmia Z. Khokhar, Denise Bonney, Paul Virgo, Saket Srivastava, Simon Thomas, Ram Jha, Jan Chu, Shaun Cordoba, Robert Chiesa, Persis Amrolia, Yiyun Zhang, Jeremy Hancock, Rachael Hough, Carlotta Peticone, Shimobi Onuoha, Kanchan Rao, Vania Baldan, Kevin Duffy, Paul Veys, Lucy Wheeler, Robert Wynn, William Day, Daniela Soriano Pignataro, Sara Ghorashian, Giovanna Lucchini, Koval Smith, Martin Pule, Liz Clark, Vijay G R Peddareddigari, Mathieu Ferrari, Sabine Domning, Ajay Vora, Frederick Arce Vargas, Muhammad Al-Hajj, Mei Mei Fung, Farzin Farzaneh

المصدر: Nature Medicine

مصطلحات موضوعية: Oncology, Adult, Male, medicine.medical_specialty, Antigen Targeting, Adolescent, Sialic Acid Binding Ig-like Lectin 2, Antigens, CD19, Cancer immunotherapy, Immunotherapy, Adoptive, Pediatrics, General Biochemistry, Genetics and Molecular Biology, Article, Paediatric cancer, Young Adult, Phase I trials, hemic and lymphatic diseases, Internal medicine, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, medicine, Clinical endpoint, Humans, Young adult, Adverse effect, Child, Acute lymphocytic leukaemia, Receptors, Chimeric Antigen, business.industry, Infant, General Medicine, medicine.disease, Chimeric antigen receptor, Progression-Free Survival, Cytokine release syndrome, medicine.anatomical_structure, Child, Preschool, Toxicity, Female, Bone marrow, Immunotherapy, business

الوصف: Chimeric antigen receptor (CAR) T cells targeting CD19 or CD22 have shown remarkable activity in B cell acute lymphoblastic leukemia (B-ALL). The major cause of treatment failure is antigen downregulation or loss. Dual antigen targeting could potentially prevent this, but the clinical safety and efficacy of CAR T cells targeting both CD19 and CD22 remain unclear. We conducted a phase 1 trial in pediatric and young adult patients with relapsed or refractory B-ALL (n = 15) to test AUTO3, autologous transduced T cells expressing both anti-CD19 and anti-CD22 CARs (AMELIA trial, EUDRA CT 2016-004680-39). The primary endpoints were the incidence of grade 3–5 toxicity in the dose-limiting toxicity period and the frequency of dose-limiting toxicities. Secondary endpoints included the rate of morphological remission (complete response or complete response with incomplete bone marrow recovery) with minimal residual disease-negative response, as well as the frequency and severity of adverse events, expansion and persistence of AUTO3, duration of B cell aplasia, and overall and event-free survival. The study endpoints were met. AUTO3 showed a favorable safety profile, with no dose-limiting toxicities or cases of AUTO3-related severe cytokine release syndrome or neurotoxicity reported. At 1 month after treatment the remission rate (that is, complete response or complete response with incomplete bone marrow recovery) was 86% (13 of 15 patients). The 1 year overall and event-free survival rates were 60% and 32%, respectively. Relapses were probably due to limited long-term AUTO3 persistence. Strategies to improve CAR T cell persistence are needed to fully realize the potential of dual targeting CAR T cell therapy in B-ALL.
Bicistronic CAR T cells targeting CD19 and CD22 exhibit clinical activity and low toxicity in pediatric and young adult patients with B cell acute lymphoblastic leukemia, with relapses associated with limited CAR T cell persistence.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2d1ab3822b837412315045c67a4edff5Test
http://europepmc.org/articles/PMC8516648Test

المؤلفون: Mathieu Ferrari, Vania Baldan, Patrycja Wawrzyniecka, Anna Bulek, Alex Kinna, Biao Ma, Reyisa Bugda, Zulaikha Akbar, Saket Srivast, Priyankha Ghongane, Isaac Gannon, Matthew Robson, James Sillibourne, Ram Jha, Wen Chean Lim, Jade Hopkins, Martin Welin, Sachin Surade, Michael Dyson, John McCafferty, Shaun Cordoba, Simon Thomas, Derek Logan, Andy Sewell, Paul Maciocia, Shimobi Onuoha, Martin Pule

الوصف: Peripheral T cell lymphomas are typically aggressive with a poor prognosis. Unlike other hematologic malignancies, the lack of target antigens to discriminate healthy from malignant cells has limited the efficacy of immunotherapeutic approaches. The T cell receptor expresses one of two highly homologous chains [T cell receptor β-chain constant (TRBC) domains 1 and 2] in a mutually exclusive manner, making it a promising target. We previously described an antibody with unique TRBC1 specificity (Jovi-1). Here we demonstrate specificity redirection by rational design using structure-guided computational biology to generate a TRBC2-specific antibody (KFN). This permitted the generation of paired reagents (chimeric antigen receptor-T cell) specific for TRBC1 and TRBC2, with preclinical evidence to support their efficacy in T cell malignancies.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::1bb26831952ccaeec228571bdbf82da9Test
https://doi.org/10.21203/rs.3.rs-1475171/v1Test

المؤلفون: Alexander Kinna, Rajeev Karattil, Zulaikha Akbar, Giada Mattiuzzo, Vania Baldan, James Sillibourne, Mathieu Ferrari, Yasuhiro Takeuchi, Christopher D.C. Allen, Katarzyna Ward, Katarina Lamb, Martin Pule, Shimobi Onuoha, Reyisa Bughda, Leila Mekkaoui, Emma M. Bentley, Philip Wu, F. Tudor Ilca, Farhaan Parekh, Preeta Datta

المصدر: Journal of Virology

مصطلحات موضوعية: Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Immunology, coronavirus, B.1.351, Plasma protein binding, Computational biology, Biology, Antibodies, Viral, medicine.disease_cause, Microbiology, Neutralization, P.1, spike affinity, Protein Domains, Virology, Vaccines and Antiviral Agents, medicine, Humans, Coronaviridae, Protein Interaction Domains and Motifs, Antibody-dependent enhancement, B.1.1.7, receptor decoy, skin and connective tissue diseases, Receptor, Coronavirus, Infectivity, Mutation, Chemistry, SARS-CoV-2, HEK 293 cells, Treatment options, COVID-19, biology.organism_classification, ACE2-Fc, Antibodies, Neutralizing, Antibody-Dependent Enhancement, Kinetics, HEK293 Cells, Insect Science, Spike Glycoprotein, Coronavirus, Angiotensin-Converting Enzyme 2, Decoy, Protein Binding

الوصف: The human angiotensin-converting enzyme 2 acts as the host cell receptor for SARS-CoV-2 and the other members of the Coronaviridae family SARS-CoV-1 and HCoV-NL63. Here, we report the biophysical properties of the SARS-CoV-2 spike variants D614G, B.1.1.7, B.1.351, and P.1 with affinities to the ACE2 receptor and infectivity capacity, revealing weaknesses in the developed neutralizing antibody approaches. Furthermore, we report a preclinical characterization package for a soluble receptor decoy engineered to be catalytically inactive and immunologically inert, with broad neutralization capacity, that represents an attractive therapeutic alternative in light of the mutational landscape of COVID-19. This construct efficiently neutralized four SARS-CoV-2 variants of concern. The decoy also displays antibody-like biophysical properties and manufacturability, strengthening its suitability as a first-line treatment option in prophylaxis or therapeutic regimens for COVID-19 and related viral infections. IMPORTANCE Mutational drift of SARS-CoV-2 risks rendering both therapeutics and vaccines less effective. Receptor decoy strategies utilizing soluble human ACE2 may overcome the risk of viral mutational escape since mutations disrupting viral interaction with the ACE2 decoy will by necessity decrease virulence, thereby preventing meaningful escape. The solution described here of a soluble ACE2 receptor decoy is significant for the following reasons: while previous ACE2-based therapeutics have been described, ours has novel features, including (i) mutations within ACE2 to remove catalytical activity and systemic interference with the renin/angiotensin system, (ii) abrogated FcγR engagement, reduced risk of antibody-dependent enhancement of infection, and reduced risk of hyperinflammation, and (iii) streamlined antibody-like purification process and scale-up manufacturability indicating that this receptor decoy could be produced quickly and easily at scale. Finally, we demonstrate that ACE2-based therapeutics confer a broad-spectrum neutralization potency for ACE2-tropic viruses, including SARS-CoV-2 variants of concern in contrast to therapeutic MAb.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9c04af08f3b7537dc264e8a926d82d11Test
https://doi.org/10.1128/jvi.00685-21Test

المؤلفون: Patrycja Wawrzyniecka, Paul Maciocia, Alex Nicholson, Shimobi Onuoha, Martin Pule, Reyisa Bughda, Mathieu Ferrari, Zulaikha Akbar, Priyanka Ghongane, Shaun Cordoba, Simon Thomas, Vania Baldan

المصدر: Cancer Research. 80:2183-2183

مصطلحات موضوعية: Cancer Research, education.field_of_study, biology, Chemistry, T cell, T-cell receptor, Population, medicine.disease, Chimeric antigen receptor, Lymphoma, medicine.anatomical_structure, Oncology, Antigen, medicine, Cancer research, biology.protein, Cytotoxic T cell, Antibody, education

الوصف: Background: Mature T cell lymphomas are aggressive, treatment resistant cancers that are associated with poor prognosis. Clinical application of immunotherapeutic approaches has been limited by a lack of target antigens that discriminate malignant from healthy T cells. Unlike B cell depletion, pan T cell aplasia is prohibitively toxic. The mutually exclusive expression of TCR β chains (TRBC) 1 or 2 allows targeting the malignant T cell population while preserving T cell function. Notably, a two amino acid inversion is the only exposed and antibody-accessible feature differentiating the two isoforms, making the development of therapeutics targeting TRBC1 and TRBC2 challenging. We have previously described a TRBC1 specific antibody which has been incorporated into a Chimeric Antigen Receptor (CAR) (Maciocia et al, Nat Med, 2017). Here we describe the derivation and characterization of a TRBC2 specific binder and CAR. In addition, we investigate use of these selective binders as Antibody Drug Conjugates (ADCs) for the treatment of HTLV-1 associated leukemia/lymphoma for which CAR T cell therapy may not be well suited. Methods: Anti TRBC2 antibodies were derived through crystallography and structural engineering of the previously described TRBC1 specific antibody. Briefly, TRBC2 binders were obtained by screening of small libraries of the TRBC1 binder with randomizations in key residues identified by crystallographic data and in silico design. TRBC2 binder candidates were first optimized for CAR function. Subsequently, TRBC2 specific CAR T cells were evaluated in vitro and in vivo for anti-tumor activity and selectivity. TRBC1/TRBC2 targeting antibodies, were further characterized as ADCs for biophysical properties, antibody internalization and cytotoxic function. Results: In vitro testing of TRBC2 CARs showed comparable efficacy to the previously described TRBC1 CAR. TRBC2 CAR T cells were effective at killing TRBC2 target cells while sparing TRBC1 positive cells. In vivo mouse models demonstrated that both TRBC1 and TRBC2 directed CARs could target their respective antigens with a high degree of specificity. TRBC1 and TRBC2 specific antibodies were used to generate ADC molecules as a proof of concept. Anti-TRBC1/TRBC2 antibodies were internalized and showed potential as ADCs. Interestingly, we demonstrate that an optimal affinity window facilitates improved antibody uptake and have further engineered both our TRBC1 and TRBC2 antibodies to take advantage of this particularity. Conclusions: Following on from structural and library-based approaches to generate CAR T cells capable of specifically targeting TRBC2, we have further characterized TRBC2 specific CAR T cells in vitro and in vivo. We have shown that highly specific antibodies, engineered as targeting moieties for TRBC1 and TRBC2 CAR T cells, show promising characteristics for utility potentially also as ADCs, offering another modality through which this targeting paradigm can be exploited for the treatment of peripheral T cell lymphomas. Citation Format: Mathieu Ferrari, Vania Baldan, Priyanka Ghongane, Alex Nicholson, Reyisa Bughda, Zulaikha Akbar, Patrycja Wawrzyniecka, Paul Maciocia, Shaun Cordoba, Simon Thomas, Shimobi Onuoha, Martin Pule. Targeting TRBC1 and 2 for the treatment of T cell lymphomas [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2183.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::4b8db6ca50afea64186bec3b47163fbfTest
https://doi.org/10.1158/1538-7445.am2020-2183Test

المؤلفون: Paul Maciocia, Kwee Yong, Manuel Rodriguez-Justo, Dominic Patel, Shimobi Onuoha, Simon Thomas, Martin Pule, Reyisa Bughda, Daria Galas-Filipowicz, Margarida Neves, Melody Chin, Brian Philip, Eva Kokalaki, Lydia Lee, Vania Baldan, James Francis, Benjamin Draper, Neil Chaplin

مصطلحات موضوعية: 0301 basic medicine, Cytotoxicity, Immunologic, Transmembrane Activator and CAML Interactor Protein, Immunology, Tumor Necrosis Factor Ligand Superfamily Member 13, Ligands, Biochemistry, 03 medical and health sciences, Mice, 0302 clinical medicine, Antineoplastic Agents, Immunological, Antigen, Cell Line, Tumor, medicine, Animals, Humans, Molecular Targeted Therapy, B-Cell Maturation Antigen, Receptor, Peptidylprolyl isomerase, Lymphoid Neoplasia, Receptors, Chimeric Antigen, biology, Chemistry, Cell Biology, Hematology, medicine.disease, Primary tumor, Chimeric antigen receptor, Cytolysis, 030104 developmental biology, Cell culture, 030220 oncology & carcinogenesis, biology.protein, Cancer research, Antibody, Multiple Myeloma

الوصف: B-cell maturation antigen (BCMA) is a promising therapeutic target for multiple myeloma (MM), but expression is variable, and early reports of BCMA targeting chimeric antigen receptors (CARs) suggest antigen downregulation at relapse. Dual-antigen targeting increases targetable tumor antigens and reduces the risk of antigen-negative disease escape. "A proliferation-inducing ligand" (APRIL) is a natural high-affinity ligand for BCMA and transmembrane activator and calcium-modulator and cyclophilin ligand (TACI). We quantified surface tumor expression of BCMA and TACI on primary MM cells (n = 50). All cases tested expressed BCMA, and 39 (78%) of them also expressed TACI. We engineered a third-generation APRIL-based CAR (ACAR), which killed targets expressing either BCMA or TACI (P < .01 and P < .05, respectively, cf. control, effector-to-target [E:T] ratio 16:1). We confirmed cytolysis at antigen levels similar to those on primary MM, at low E:T ratios (56.2% ± 3.9% killing of MM.1s at 48 h, E:T ratio 1:32; P < .01) and of primary MM cells (72.9% ± 12.2% killing at 3 days, E:T ratio 1:1; P < .05, n = 5). Demonstrating tumor control in the absence of BCMA, we maintained cytolysis of primary tumor expressing both BCMA and TACI in the presence of a BCMA-targeting antibody. Furthermore, using an intramedullary myeloma model, ACAR T cells caused regression of an established tumor within 2 days. Finally, in an in vivo model of tumor escape, there was complete ACAR-mediated tumor clearance of BCMA+TACI- and BCMA-TACI+ cells, and a single-chain variable fragment CAR targeting BCMA alone resulted in outgrowth of a BCMA-negative tumor. These results support the clinical potential of this approach.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e5369fc571019d2d8485611c849aa118Test
https://europepmc.org/articles/PMC5922275Test/

المؤلفون: Richard Griffiths, Robert E. Hawkins, David E. Gilham, Vania Baldan

المصدر: British Journal of Cancer

مصطلحات موضوعية: Cytotoxicity, Immunologic, Male, renal cell carcinoma, Cancer Research, Pathology, medicine.medical_specialty, T-Lymphocytes, Lymphocyte, Population, Cell, chemical and pharmacologic phenomena, Lymphocytes, Tumor-Infiltrating, T-cell, Renal cell carcinoma, lymphocyte, culture, Tumor Cells, Cultured, medicine, Carcinoma, Humans, education, Cytotoxicity, Carcinoma, Renal Cell, Molecular Diagnostics, Aged, education.field_of_study, tumour, business.industry, Melanoma, adoptive cell therapy, hemic and immune systems, TIL, Middle Aged, Prognosis, mitogen, medicine.disease, Kidney Neoplasms, In vitro, medicine.anatomical_structure, Oncology, disaggregation, Female, business, Follow-Up Studies

الوصف: Background: Tumour-infiltrating lymphocyte (TIL) therapy is showing great promise in the treatment of patients with advanced malignant melanoma. However, the translation of TIL therapy to non-melanoma tumours such as renal cell carcinoma has been less successful with a major constraint being the inability to reproducibly generate TILs from primary and metastatic tumour tissue. Methods: Primary and metastatic renal cell carcinoma biopsies were subjected to differential tumour disaggregation methods and procedures that stimulate the specific expansion of TILs tested to determine which reliably generated TIL maintained antitumour specificity. Results: Enzymatic or combined enzymatic/mechanical disaggregation resulted in equivalent numbers of TILs being liberated from renal cell carcinoma biopsies. Following mitogenic activation of the isolated TILs with anti-CD3/anti-CD28-coated paramagnetic beads, successful TIL expansion was achieved in 90% of initiated cultures. The frequency of T-cell recognition of autologous tumours was enhanced when tumours were disaggregated using the GentleMACS enzymatic/mechanical system. Conclusion: TILs can be consistently produced from renal cell carcinoma biopsies maintaining autologous tumour recognition after expansion in vitro. While the method of disaggregation has little impact on the success of TIL growth, methods that preserve the cell surface architecture facilitate TIL recognition of an autologous tumour, which is important in terms of characterising the functionality of the expanded TIL population.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::25fe291fe5bb87ccb8bc1958c83faab7Test
https://doi.org/10.1038/bjc.2015.96Test

المؤلفون: Robert E. Hawkins, Vivien Hanson, Eleanor J. Cheadle, David E. Gilham, Vania Baldan, Hannah Gornall

المصدر: Immunological Reviews. 257:91-106

مصطلحات موضوعية: Lymphoma, B-Cell, T cell, Chronic lymphocytic leukemia, Antigens, CD19, Immunology, Cell Culture Techniques, Receptors, Antigen, T-Cell, Cancer Vaccines, Immunotherapy, Adoptive, CD19, Immune system, Antigen, T-Lymphocyte Subsets, Leukemia, B-Cell, medicine, Animals, Humans, Immunology and Allergy, biology, Gene Transfer Techniques, Cancer, medicine.disease, Chimeric antigen receptor, medicine.anatomical_structure, biology.protein, Antibody, Genetic Engineering, Neuroscience

الوصف: Blockbuster antibody therapies have catapulted immune-based approaches to treat cancer into the consciousness of mainstay clinical research. On the back of this, other emerging immune-based therapies are providing great promise. T-cell therapy is one such area where recent trials using T cells genetically modified to express an antibody-based chimeric antigen receptor (CAR) targeted against the CD19 antigen have demonstrated impressive responses when adoptively transferred to patients with advanced chronic lymphocytic leukemia. The general concept of the CAR T cell was devised some 20 years ago. In this relatively short period of time, the technology to redirect T-cell function has moved at pace facilitating clinical translation; however, many questions remain with respect to developing the approach to improve CAR T-cell therapeutic activity and also to broaden the range of tumors that can be effectively targeted by this approach. This review highlights some of the underlying principles and compromises of CAR T-cell technology using the CD19-targeted CAR as a paradigm and discusses some of the issues that relate to targeting solid tumors with CAR T cells.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bcf4a52b5bfbd4366daf0cd58b521ab3Test
https://doi.org/10.1111/imr.12126Test