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CAR immune therapy

Reza Elahi, Elnaz Khosh, Safa Tahmasebi, Abdolreza Esmaeilzadeh
T cells equipped with chimeric antigen receptors (CAR T cells) have recently provided promising advances as a novel immunotherapeutic approach for cancer treatment. CAR T cell therapy has shown stunning results especially in B-cell malignancies; however, it has shown less success against solid tumors, which is more supposed to be related to the specific characteristics of the tumor microenvironment. In this review, we discuss the structure of the CAR, current clinical advantages from finished and ongoing trials, adverse effects, challenges and controversies, new engineering methods of CAR, and clinical considerations that are associated with CAR T cell therapy both in hematological malignancies and solid tumors...
2018: Frontiers in Immunology
Hua Wang, David J Mooney
The past decade has witnessed the accelerating development of immunotherapies for cancer treatment. Immune checkpoint blockade therapies and chimeric antigen receptor (CAR)-T cell therapies have demonstrated clinical efficacy against a variety of cancers. However, issues including life-threatening off-target side effects, long processing times, limited patient responses and high cost still limit the clinical utility of cancer immunotherapies. Biomaterial carriers of these therapies, though, enable one to troubleshoot the delivery issues, amplify immunomodulatory effects, integrate the synergistic effect of different molecules and, more importantly, home and manipulate immune cells in vivo...
August 13, 2018: Nature Materials
Anusha Thadi, Marian Khalili, William F Morano, Scott D Richard, Steven C Katz, Wilbur B Bowne
Peritoneal metastasis (PM) is an advanced stage malignancy largely refractory to modern therapy. Intraperitoneal (IP) immunotherapy offers a novel approach for the control of regional disease of the peritoneal cavity by breaking immune tolerance. These strategies include heightening T-cell response and vaccine induction of anti-cancer memory against tumor-associated antigens. Early investigations with chimeric antigen receptor T cells (CAR-T cells), vaccine-based therapies, dendritic cells (DCs) in combination with pro-inflammatory cytokines and natural killer cells (NKs), adoptive cell transfer, and immune checkpoint inhibitors represent significant advances in the treatment of PM...
August 10, 2018: Vaccines
Sarwish Rafiq, Oladapo O Yeku, Hollie J Jackson, Terence J Purdon, Dayenne G van Leeuwen, Dylan J Drakes, Mei Song, Matthew M Miele, Zhuoning Li, Pei Wang, Su Yan, Jingyi Xiang, Xiaojing Ma, Venkatraman E Seshan, Ronald C Hendrickson, Cheng Liu, Renier J Brentjens
The efficacy of chimeric antigen receptor (CAR) T cell therapy against poorly responding tumors can be enhanced by administering the cells in combination with immune checkpoint blockade inhibitors. Alternatively, the CAR construct has been engineered to coexpress factors that boost CAR-T cell function in the tumor microenvironment. We modified CAR-T cells to secrete PD-1-blocking single-chain variable fragments (scFv). These scFv-secreting CAR-T cells acted in both a paracrine and autocrine manner to improve the anti-tumor activity of CAR-T cells and bystander tumor-specific T cells in clinically relevant syngeneic and xenogeneic mouse models of PD-L1+ hematologic and solid tumors...
August 13, 2018: Nature Biotechnology
Gunilla Enblad, Hannah Karlsson, Gustav Gammelgard, Jessica Wenthe, Tanja Lovgren, Rose-Marie Amini, Kristina I Wikstrom, Magnus Essand, Barbara Savoldo, Helene Hallbook, Martin Höglund, Gianpietro Dotti, Malcolm K Brenner, Hans Hagberg, Angelica Loskog
PURPOSE: CAR T cell therapy has been effective for patients with CD19+ B cell malignancies. Most studies have investigated second generation CARs with either CD28 or 4-1BB co-stimulatory domains in the CAR receptor. Here we describe the first clinical phase I/IIa trial using third generation CAR T cells targeting CD19 to evaluate safety and efficacy. EXPERIMENTAL DESIGN: Fifteen patients with B cell lymphoma or leukemia were treated with CAR T cells. The lymphoma patients received chemotherapy during CAR manufacture and eleven of fifteen were given low dose cyclophosphamide and fludarabine conditioning prior to CAR infusion...
August 10, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Qi Hui Sam, Wen Shan Yew, Chaminda J Seneviratne, Matthew Wook Chang, Louis Yi Ann Chai
Invasive fungal disease (IFD) causes significant morbidity in immunocompromised patients due to their weakened immune system. Immunomodulatory therapy, in synergy with existing antifungal therapy, is an attractive option to enhance their immune system and aid clearance of these opportunistic pathogens. From a scientific and clinical perspective, we explore the immunotherapeutic options to augment standard antifungal drugs for patients with an IFD. We discuss the range of immunomodulatory therapies being considered in IFD - from cytokines, including G-CSF, GM-CSF, M-CSF, IFN-γ, and cytokine agonists, to cellular therapies, consisting of granulocyte transfusion, adoptive T-cell, CAR T-cell, natural killer cell therapies, and monoclonal antibodies...
2018: Frontiers in Microbiology
Andrew J Hou, ZeNan L Chang, Michael H Lorenzini, Eugenia Zah, Yvonne Y Chen
A chimeric antigen receptor (CAR) that responds to transforming growth factor beta (TGF-β) enables the engineering of T cells that convert this immunosuppressive cytokine into a potent T-cell stimulant. However, clinical translation of TGF-β CAR-T cells for cancer therapy requires the ability to productively combine TGF-β responsiveness with tumor-targeting specificity. Furthermore, the potential concern that contaminating, TGF-β?producing regulatory T (Treg) cells may preferentially expand during TGF-β CAR-T cell manufacturing and suppress effector T (Teff) cells demands careful evaluation...
May 2018: Bioengineering & Translational Medicine
DeGaulle I Chigbu, Bisant A Labib
Human adenovirus (HAdV) is a ubiquitous virus that infects the mucosa of the eye. It is the most common cause of infectious conjunctivitis worldwide, affecting people of all ages and demographics. Pharyngoconjunctival fever outbreak is due to HAdV types 3, 4, and 7, whereas outbreaks of epidemic keratoconjunctivitis are usually caused by HAdV types 8, 19, 37, and 54. Primary cellular receptors, such as CAR, CD46, and sialic acid interact with fiber-knob protein to mediate adenoviral attachment to the host cell, whereas adenoviral penton base-integrin interaction mediates internalization of adenovirus...
2018: Infection and Drug Resistance
Colby R Maldini, Gavin I Ellis, James L Riley
Chimeric antigen receptors (CARs) have shown remarkable ability to re-direct T cells to target CD19-expressing tumours, resulting in remission rates of up to 90% in individuals with paediatric acute lymphoblastic lymphoma. Lessons learned from these clinical trials of adoptive T cell therapy for cancer, as well as investments made in manufacturing T cells at commercial scale, have inspired researchers to develop CARs for additional applications. Here, we explore the challenges and opportunities of using this technology to target infectious diseases such as with HIV and undesired immune responses such as autoimmunity and transplant rejection...
July 25, 2018: Nature Reviews. Immunology
Giulia Escobar, Luigi Barbarossa, Giulia Barbiera, Margherita Norelli, Marco Genua, Anna Ranghetti, Tiziana Plati, Barbara Camisa, Chiara Brombin, Davide Cittaro, Andrea Annoni, Attilio Bondanza, Renato Ostuni, Bernhard Gentner, Luigi Naldini
Immunotherapy is emerging as a new pillar of cancer treatment with potential to cure. However, many patients still fail to respond to these therapies. Among the underlying factors, an immunosuppressive tumor microenvironment (TME) plays a major role. Here we show that monocyte-mediated gene delivery of IFNα inhibits leukemia in a mouse model. IFN gene therapy counteracts leukemia-induced expansion of immunosuppressive myeloid cells and imposes an immunostimulatory program to the TME, as shown by bulk and single-cell transcriptome analyses...
July 24, 2018: Nature Communications
Michelle H Townsend, Gajendra Shrestha, Richard A Robison, Kim L O'Neill
Biomarkers are an integral part of cancer management due to their use in risk assessment, screening, differential diagnosis, prognosis, prediction of response to treatment, and monitoring progress of disease. Recently, with the advent of Chimeric Antigen Receptor (CAR) T cell therapy, a new category of targetable biomarkers has emerged. These biomarkers are associated with the surface of malignant cells and serve as targets for directing cytotoxic T cells. The first biomarker target used for CAR T cell therapy was CD19, a B cell marker expressed highly on malignant B cells...
July 21, 2018: Journal of Experimental & Clinical Cancer Research: CR
Jian-Ping Zhang, Rui Zhang, Shih-Ting Tsao, Yu-Chen Liu, Xiaochuan Chen, Dao-Pei Lu, Paul Castillo, Lung-Ji Chang
No abstract text is available yet for this article.
July 24, 2018: Blood Advances
Zhen Zhang, Chaoqi Zhang, Feng Li, Bin Zhang, Yi Zhang
MicroRNAs (miRNAs) have emerged as crucial regulators of T lymphocyte survival, differentiation and function, all of which are key factors impacting the outcome of adoptive T cell-based immunotherapy. It has become increasingly clear that the adoptive transfer of memory CD8+ T cell subsets is highly correlated with objective clinical responses for patients with advanced cancer. However, it is unclear how to improve the long-term persistence of transferred CD8+ T cells using miRNAs. Here, we highlight the current advances in our understanding of the role of miRNAs in regulating the differentiation of memory CD8+ T cells...
2018: Cellular Physiology and Biochemistry
Uffe Klausen, Nicolai Grønne Dahlager Jørgensen, Jacob Handlos Grauslund, Morten Orebo Holmström, Mads Hald Andersen
Immunotherapy has played an important part in improving the life of patients with lymphoproliferative diseases especially since the addition of rituximab to chemotherapy in the CD20-positive neoplasms in the 1990s. While this field of passive immunotherapy is continuously evolving, several breakthroughs will expand the treatment modalities to include more active immunotherapy. With the approval of immune checkpoint-blocking antibodies for Hodgkin lymphoma and bispecific antibodies for acute lymphoblastic leukemia (ALL), activation of endogenous T cells already plays a role in several lymphoid malignancies...
July 13, 2018: Seminars in Immunopathology
Sadhak Sengupta, Steven C Katz, Sudarshana Sengupta, Prakash Sampath
Successful remission in hematological cancers by CAR-T cell immunotherapy has yet to be replicated in solid tumors like GBM. A significant impediment of CAR-T immunotherapy in solid tumors is poor exposure of T cells to tumor antigens resulting in suboptimal CAR-T cell activation, which ultimately fails to induce a robust anti-tumor immune response. Costimulatory moieties in advanced-generation CARs, along with additional IL2 therapy has been shown to be insufficient to overcome this hurdle and have its cytotoxic limitations...
October 1, 2018: Cancer Letters
Marcus P Watkins, Nancy L Bartlett
Ubiquitous expression of CD19 on B cell non-Hodgkin lymphoma identified it as a potential target for immune-based therapies. Areas covered: This article reviews the current literature on anti-CD19 therapies currently in clinical trials including monoclonal antibodies (mAb), antibody targeted cytotoxic drug conjugates (ADC), bispecific antibodies, and chimeric antigen receptor (CAR) modified T cells. Expert opinion: Naked anti-CD19 mAbs have shown little clinical benefit in B cell lymphomas. Despite unusual toxicity profiles with many anti-CD19 ADCs slowing development, durable remissions in a substantial minority of patients with refractory aggressive lymphomas should encourage continued efforts in this area...
July 2018: Expert Opinion on Investigational Drugs
C David Pauza, Mei-Ling Liou, Tyler Lahusen, Lingzhi Xiao, Rena G Lapidus, Cristiana Cairo, Haishan Li
Human gamma delta T cells have extraordinary properties including the capacity for tumor cell killing. The major gamma delta T cell subset in human beings is designated Vγ9Vδ2 and is activated by intermediates of isoprenoid biosynthesis or aminobisphosphonate inhibitors of farnesyldiphosphate synthase. Activated cells are potent for killing a broad range of tumor cells and demonstrated the capacity for tumor reduction in murine xenotransplant tumor models. Translating these findings to the clinic produced promising initial results but greater potency is needed...
2018: Frontiers in Immunology
Mariam Taha, Hesham Abdelbary, F Patrick Ross, Alberto V Carli
PURPOSE OF REVIEW: Periprosthetic joint infection (PJI) is a devastating complication after total joint replacement. A main source for antibiotic tolerance and treatment failure is bacterial production of biofilm-a resilient barrier against antibiotics, immune system, and mechanical debridement. The purpose of this review is to explore some novel approaches to treat PJI and biofilm-related infections. RECENT FINDINGS: Innovative treatment strategies of bacterial and biofilm infections revolve around (a) augmenting current therapies, such as improving the delivery and efficiency of conventional antibiotics and enhancing the efficacy of antiseptics and (b) administrating completely new therapeutic modalities, such as using immunotherapy, nanoparticles, lytic bacteriophages, photodynamic therapy, novel antibiotics, and antimicrobial peptides...
June 20, 2018: Current Reviews in Musculoskeletal Medicine
Robert D Leone, Leisha A Emens
Immune checkpoint antagonists (CTLA-4 and PD-1/PD-L1) and CAR T-cell therapies generate unparalleled durable responses in several cancers and have firmly established immunotherapy as a new pillar of cancer therapy. To extend the impact of immunotherapy to more patients and a broader range of cancers, targeting additional mechanisms of tumor immune evasion will be critical. Adenosine signaling has emerged as a key metabolic pathway that regulates tumor immunity. Adenosine is an immunosuppressive metabolite produced at high levels within the tumor microenvironment...
June 18, 2018: Journal for Immunotherapy of Cancer
Sophia Danhof, Michael Hudecek, Eric L Smith
Harnessing the endogenous immune system to eliminate malignant cells has long been an intriguing approach. After considerable success in the treatment of B-cell acute lymphoblastic leukemia, chimeric antigen receptor (CAR)-modified T cells have entered early clinical evaluation in the field of multiple myeloma (MM). The choice of suitable non-CD19 target antigens is challenging and a variety of myeloma-associated surface molecules have been under preclinical investigation. Most recent clinical protocols have focused on targeting B-cell maturation antigen (BCMA), and early results are promising...
June 2018: Best Practice & Research. Clinical Haematology
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