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chimeric t cell and lymphoma

Katherine C Pehlivan, Brynn B Duncan, Daniel W Lee
PURPOSE OF REVIEW: Genetically engineered T cells expressing a chimeric antigen receptor (CAR-T) targeting specific antigens present on acute lymphoblastic leukemia (ALL) blasts have generated promising results in children and adults with relapsed and refractory disease. We review the current evidence for CAR-T cell therapy in ALL, associated toxicities, and efforts to improve durable response to therapy. RECENT FINDINGS: CD19-directed CAR-T cells have recently been approved by the FDA for use in children and young adults with ALL and in adults with diffuse large B cell lymphoma (DLBCL) in the relapsed/refractory setting...
August 17, 2018: Current Hematologic Malignancy Reports
Ho Ngai, Gengwen Tian, Amy N Courtney, Soodeh B Ravari, Linjie Guo, Bin Liu, Jingling Jin, Elise T Shen, Erica J Di Pierro, Leonid S Metelitsa
T cells expressing CD19-specific chimeric Ag receptors (CARs) produce high remission rates in B cell lymphoma, but frequent disease recurrence and challenges in generating sufficient numbers of autologous CAR T cells necessitate the development of alternative therapeutic effectors. Vα24-invariant NKTs have intrinsic antitumor properties and are not alloreactive, allowing for off-the-shelf use of CAR-NKTs from healthy donors. We recently reported that CD62L+ NKTs persist longer and have more potent antilymphoma activity than CD62L- cells...
August 15, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Zijun Zhao, Yu Chen, Ngiambudulu M Francisco, Yuanqing Zhang, Minhao Wu
Chimeric antigen receptor T cell (CAR-T cell) therapy is a novel adoptive immunotherapy where T lymphocytes are engineered with synthetic receptors known as chimeric antigen receptors (CAR). The CAR-T cell is an effector T cell that recognizes and eliminates specific cancer cells, independent of major histocompatibility complex molecules. The whole procedure of CAR-T cell production is not well understood. The CAR-T cell has been used predominantly in the treatment of hematological malignancies, including acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphoma, and multiple myeloma...
July 2018: Acta Pharmaceutica Sinica. B
Irene Scarfò, Maria Ormhøj, Matthew J Frigault, Ana P Castano, Selena Lorrey, Amanda A Bouffard, Alexandria van Scoyk, Scott J Rodig, Alexandra J Shay, Jon C Aster, Frederic I Preffer, David M Weinstock, Marcela V Maus
Chimeric antigen receptor (CAR) T cells have emerged as a novel form of treatment for patients with B-cell malignancies. In particular, anti-CD19 CAR T-cell therapy has effected impressive clinical responses in B-cell acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL). However, not all patients respond, and relapse with antigen loss has been observed in all patient subsets. Here, we report on the design and optimization of a novel CAR directed to the surface antigen CD37, which is expressed in B-cell non-Hodgkin Lymphomas, in chronic lymphocytic leukemia (CLL) and in some cases of cutaneous and peripheral T-cell lymphomas (CTCL and PTCL, respectively)...
August 8, 2018: Blood
Julia Bluhm, Elisa Kieback, Stephen F Marino, Felix Oden, Jörg Westermann, Markus Chmielewski, Hinrich Abken, Wolfgang Uckert, Uta E Höpken, Armin Rehm
Autologous T cells genetically modified with a chimeric antigen receptor (CAR) redirected at CD19 have potent activity in the treatment of B cell leukemia and B cell non-Hodgkin's lymphoma (B-NHL). Immunotherapies to treat multiple myeloma (MM) targeted the B cell maturation antigen (BCMA), which is expressed in most cases of MM. We developed a humanized CAR with specificity for BCMA based on our previously generated anti-BCMA monoclonal antibody. The targeting single-chain variable fragment (scFv) domain exhibited a binding affinity in the low nanomolar range, conferring T cells with high functional avidity...
August 1, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Seong Hyun Jeong, Haa-Na Song, Joon Seong Park, Deok-Hwan Yang, Youngil Koh, Sung-Soo Yoon, Hye Won Lee, Hyeon Seok Eom, Jong-Ho Won, Won Seog Kim, Seok Jin Kim
BACKGROUND: Natural killer (NK)/T-cell lymphoid malignancy comprises extra-nodal NK/T-cell lymphoma (ENKTL) and aggressive NK-cell leukemia (ANKL), and the outcomes for advanced or relapsed/refractory ENKTL and ANKL remain poor. Allogeneic stem cell transplantation (SCT) can be used as a frontline consolidation treatment to prevent the relapse of advanced disease or as salvage treatment after chemotherapy for relapsed sensitive disease. METHODS: We retrospectively analyzed 36 patients (ENKTL, n = 26; ANKL, n = 10) who underwent upfront (n = 19) and salvage allogeneic SCT (n = 17) at six hospitals...
July 28, 2018: Biology of Blood and Marrow Transplantation
Viktória Golumba-Nagy, Johannes Kuehle, Andreas A Hombach, Hinrich Abken
Adoptive cell therapy with chimeric antigen receptor (CAR)-redirected T cells induced spectacular regressions of leukemia and lymphoma, however, failed so far in the treatment of solid tumors. A cause is thought to be T cell repression through TGF-β, which is massively accumulating in the tumor tissue. Here, we show that T cells with a CD28-ζ CAR, but not with a 4-1BB-ζ CAR, resist TGF-β-mediated repression. Mechanistically, LCK activation and consequently IL-2 release and autocrine IL-2 receptor signaling mediated TGF-β resistance; deleting the LCK-binding motif in the CD28 CAR abolished both IL-2 secretion and TGF-β resistance, while IL-2 add-back restored TGF-β resistance...
July 10, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
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
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
Sebastian Kobold, Angela Krackhardt, Hans Schlösser, Dominik Wolf
Pioneering work has unraveled the role of the immune system in the development and control of cancer. This knowledge has set the basis for the successful implementation of immunotherapy into the standard of care for a large number of cancer types. Based on response rates and prolongation of overall survival, immunotherapeutic approaches have been approved in a growing number of tumor diseases. Activation or therapeutic utilization of T cells represent the basis of these concepts. Checkpoint inhibitory antibodies inhibiting CTLA-4, PD1 and PD-L1 receptors and ligands induce long-term clinical tumor control in a significant number of cancer patients including metastatic melanoma and non-small cell lung cancer...
July 2018: Deutsche Medizinische Wochenschrift
Dimitri Kasakovski, Ling Xu, Yangqiu Li
T cell senescence has been recognized to play an immunosuppressive role in the aging population and cancer patients. Strategies dedicated to preventing or reversing replicative and premature T cell senescence are required to increase the lifespan of human beings and to reduce the morbidity from cancer. In addition, overcoming the T cell terminal differentiation or senescence from lymphoma and leukemia patients is a promising approach to enhance the effectiveness of adoptive cellular immunotherapy (ACT). Chimeric antigen receptor T (CAR-T) cell and T cell receptor-engineered T (TCR-T) cell therapy highly rely on functionally active T cells...
July 4, 2018: Journal of Hematology & Oncology
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
Lixun Guan, Xiaohong Li, Huaping Wei, Zhenyang Gu, Shasha Zhao, Chengying Zhu, Nan Yang, Feiyan Wang, Lan Luo, Zhe Gao, Wenrong Huang, Honghua Li, Quanshun Wang, Daihong Liu, Xiaoxiong Wu, Chunji Gao
BACKGROUND There is currently little information on haploidentical hematopoietic cell transplantation (haplo-HCT) for T-lymphoblastic lymphoma (T-LBL). Data about peripheral blood stem cells (PBSC) as a reliable graft source for T-LBL treatment are lacking. MATERIAL AND METHODS T-LBL patients who underwent T cell-replete haploidentical peripheral blood hematopoietic cell transplantation (haplo-PBHCT) from July 2007 to January 2017 were retrospectively evaluated. RESULTS A total of 25 patients (age ≥15 years) with median age of 24 (range 15-51) years were enrolled...
June 22, 2018: Annals of Transplantation: Quarterly of the Polish Transplantation Society
Alessandra Sacchi, Nicola Tumino, Andrea Sabatini, Eleonora Cimini, Rita Casetti, Veronica Bordoni, Germana Grassi, Chiara Agrati
γδ T cells represent less than 5% of circulating T cells; they exert a potent cytotoxic function against tumor or infected cells and secrete cytokines like conventional αβ T cells. As αβ T cells γδ T cells reside in the typical T cell compartments (the lymph nodes and spleen), but are more widely distributed in tissues throughout the body. For these reasons, some investigators are exploring the possibility of immunotherapies aimed to expand and activate Vδ2 T cells, or using them as Chimeric Antigen Receptor carriers...
2018: Frontiers in Immunology
Jakub Svoboda, Susan R Rheingold, Saar I Gill, Stephan A Grupp, Simon F Lacey, Irina Kulikovskaya, Megan M Suhoski, J Joseph Melenhorst, Brandon Loudon, Anthony R Mato, Sunita Dwivedy Nasta, Daniel J Landsburg, Matthew R Youngman, Bruce L Levine, David L Porter, Carl H June, Stephen J Schuster
Chimeric antigen receptor (CAR) modified T cells are being investigated in many settings including classical Hodgkin lymphoma (cHL). The unique biology of cHL, characterized by scant Hodgkin and Reed-Sternberg (HRS) cells within an immunosuppressive tumor microenvironment (TME), may pose challenges for cellular therapies directly targeting antigens expressed on HRS. We hypothesized that eradicating CD19 positive (+) B cells within the TME and the putative circulating CD19+ HRS clonotypic cells using anti-CD19 directed CAR modified T cells (CART19) may indirectly affect HRS cells, which do not express CD19...
June 20, 2018: Blood
Patricia A Young, Reiko E Yamada, Kham R Trinh, Alex Vasuthasawat, Satiro De Oliveira, Douglas H Yamada, Sherie L Morrison, John M Timmerman
An important emerging form of immunotherapy targeting B cell malignancies is chimeric antigen receptor (CAR) T cell therapy. Despite encouraging response rates of anti-CD19 CAR T cell therapy in B cell lymphomas, limited durability of response necessitates further study to potentiate CAR T cell efficacy. Antibody-targeted interferon (IFN) therapy is a novel approach in immunotherapy. Given the ability of IFNs to promote T cell activation and survival, target cell recognition, and cytotoxicity, we asked whether antibody-targeted IFN could enhance the antitumor effects of anti-CD19 CAR T cells...
June 2018: Journal of Interferon & Cytokine Research
Victor A Chow, Mazyar Shadman, Ajay K Gopal
Chimeric antigen receptor (CAR) T-cells demonstrate efficacy in B-cell malignancies, leading to FDA approval of axicaptagene ciloleucel in October 2017 and tisagenlecleucel in May 2018 for large B-cell lymphomas after two prior lines of therapy. Durable remissions are seen in 30-40% of study-treated patients, but unique toxicities of cytokine release syndrome and neurotoxicity require administration in specialized centers. This article reviews the data to-date within the context of current diffuse large B-cell lymphoma management, focusing on axicaptagene ciloleucel, tisagenlecleucel and lisocabtagene maraleucel...
June 18, 2018: Blood
Michael D Jain, Christina A Bachmeier, Vania H Phuoc, Julio C Chavez
Adoptive T-cell immunotherapy is a rapidly growing field and is shifting the paradigm of clinical cancer treatment. Axicabtagene ciloleucel (axi-cel) is an anti-CD19 chimeric antigen receptor T-cell therapy that was initially developed at the National Cancer Institute and has recently been commercially approved by the US Food and Drug Administration for relapsed or refractory aggressive non-Hodgkin's lymphomas including diffuse large B-cell lymphoma and its variants. The ZUMA-1 Phase I and II clinical trials formed the basis of the US Food and Drug Administration approval of this product, and we discuss the particulars of the clinical trials and the pharmacology of axi-cel...
2018: Therapeutics and Clinical Risk Management
Julio C Chavez, Frederick L Locke
B-cell non-Hodgkin's lymphoma (NHLs)is a very heterogonous malignancy with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) as the most common subtypes. Standard treatment with anti-CD20 based chemoimmunotherapy is usually very effective for disease control. However a significant proportion of patients with high-risk features (double hit lymphoma, transformed lymphomas or early relapses) will become refractory to standard therapies and will have limited alternatives for cure. Adoptive therapy with chimeric antigen receptor (CAR) T-cells is a new paradigm for effective treatment of poor prognosis lymphomas...
June 2018: Best Practice & Research. Clinical Haematology
Antoni Xavier Torres-Collado, Ali R Jazirehi
Patients with B-cell non-Hodgkin’s lymphoma (B-NHL) who fail to respond to first-line treatment regimens or develop resistance, exhibit poor prognosis. This signifies the need to develop alternative treatment strategies. CD19-chimeric antigen receptor (CAR) T cell-redirected immunotherapy is an attractive and novel option, which has shown encouraging outcomes in phase I clinical trials of relapsed/refractory NHL. However, the underlying mechanisms of, and approaches to overcome, acquired anti-CD19CAR CD8⁺ T cells (CTL)-resistance in NHL remain elusive...
June 14, 2018: Cancers
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