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Adoptive T-Cell Therapy

Christian S Hinrichs
As oncogenes drive carcinogenesis and promote cancer cell survival, they are highly attractive therapeutic targets, and oncogene-targeting small molecules have achieved some clinical success. While many oncogenes are presently considered to be "druggable," tumors often acquire treatment resistance, and patients are rarely cured in response to oncogene-specific treatment. In this issue of the JCI, Veatch and colleagues describe a patient with metastatic acral melanoma who experienced a complete tumor response following infusion of tumor-infiltrating T cells that targeted multiple tumor antigens, including a BRAFV600E driver mutation...
March 12, 2018: Journal of Clinical Investigation
Kendra C Foley, Michael I Nishimura, Tamson V Moore
Immunotherapy is a promising method of treatment for a number of cancers. Many of the curative results have been seen specifically in advanced-stage melanoma. Despite this, single-agent therapies are only successful in a small percentage of patients, and relapse is very common. As chemotherapy is becoming a thing of the past for treatment of melanoma, the combination of cellular therapies with immunotherapies appears to be on the rise in in-vivo models and in clinical trials. These forms of therapies include tumor-infiltrating lymphocytes, T-cell receptor, or chimeric antigen receptor-modified T cells, cytokines [interleukin (IL-2), IL-15, IL-12, granulocyte-macrophage colony stimulating factor, tumor necrosis factor-α, interferon-α, interferon-γ], antibodies (αPD-1, αPD-L1, αTIM-3, αOX40, αCTLA-4, αLAG-3), dendritic cell-based vaccines, and chemokines (CXCR2)...
March 8, 2018: Melanoma Research
Karolina Gołąb, Randall Grose, Veronica Placencia, Amittha Wickrema, Julia Solomina, Martin Tibudan, Evelyn Konsur, Kamil Ciepły, Natalia Marek-Trzonkowska, Piotr Trzonkowski, J Michael Millis, John Fung, Piotr Witkowski
The first clinical trials with adoptive Treg therapy have shown safety and potential efficacy. Feasibility of such therapy could be improved if cells are cryopreserved and stored until optimal timing for infusion. Herein, we report the evaluation of two cell-banking strategies for Treg therapy: 1) cryopreservation of CD4+ cells for subsequent Treg isolation/expansion and 2) cryopreservation of ex-vivo expanded Tregs (CD4+ CD25hi CD127lo/- cells). First, we checked how cryopreservation affects cell viability and Treg markers expression...
February 9, 2018: Oncotarget
Hisashi Yano, Shin Kaneko
Adoptive cell therapy using tumor-infiltrating T cells has shown durable responses in patients with melanoma, and immunotherapy using genetically engineered T cells (TCR-T or CAR-T) is rapidly emerging as a promising treatment, especially for hematological malignancies. However, the progress is limited because of the lack of readily available good-quality human T cells. Although the efficacy of adoptive cell therapy correlates with the quality of infusing T cells, most antigen-specific T cells in patients with cancer have been exhausted...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Shinichi Kageyama
Cancer immunotherapies using gene-engineered T cells comprise adoptive transfer of T-cell receptor (TCR) and chimeric antigen receptor (CAR) gene-transduced T cells. Although CD19-targeting CAR-T cell therapy is the most progressed, wherein B-cell malignancy is treated efficiently, it also induces cytokine release syndrome and neurotoxicity, which frequently leads to serious adverse events. Of note, TCR-T cell therapy has been primarily used to target melanoma, resulting in 30%-50% of tumor responses. In clinical trials that target NY-ESO-1-expressing synovial sarcoma, a high efficacy of 50%-60% has been obtained...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Sarah L Buchan, Mohannah Fallatah, Stephen M Thirdborough, Vadim Y Taraban, Anne Rogel, Lawrence J Thomas, Christine A Penfold, Li-Zhen He, Michael A Curran, Tibor Keler, Aymen Al-Shamkhani
PURPOSE: PD-1 checkpoint blockade has revolutionized the field of cancer immunotherapy, yet the frequency of responding patients is limited by inadequate T-cell priming secondary to a paucity of activatory dendritic cells (DCs). DC signals can be bypassed by CD27 agonists and we therefore investigated if the effectiveness of anti-PD-1/L1 could be improved by combining with agonist anti-CD27 monoclonal antibodies (mAb). EXPERIMENTAL DESIGN: The efficacy of PD-1/L1 blockade or agonist anti-CD27 mAb was compared with a dual-therapy approach in multiple tumor models...
March 7, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Qing Zhao Ruan, Jian Qian Fu, Xiao Xuan Wu, Li Ping Huang, Run Sheng Ruan
PURPOSE: It is now recognized that solid tumors encroach on the host's immune microenvironment to favor its own proliferation. Strategies to enhance the specificity of the endogenous T-cell population against tumors have been met with limited clinical success. We aimed to devise a two-tier protocol coupling in vivo whole antigen priming with ex vivo cellular expansion to clinically evaluate survival in patients following re-infusion of primed, autologous T cells, thereby determining treatment efficacy...
March 6, 2018: Cancer Immunology, Immunotherapy: CII
Dan Chen, Huanhuan Sha, Tianmu Hu, Shuchen Dong, Junying Zhang, Siwen Liu, Haixia Cao, Rong Ma, Yang Wu, Changwen Jing, Zhuo Wang, Jianzhong Wu, Jifeng Feng
Most of the patients with lung cancer are diagnosed at advanced stage, and they often lose the opportunity of surgical therapy, most of whom fail to reach good prognosis after chemotherapy. Recently, a few clinical studies have confirmed the role of adoptive T-cell transfer in the maintenance therapy of cancer patients. Here, we provided statistical insights into the role of CIKs in advanced lung cancer from three different levels, cell model (in vitro co-culture system), mice model (in situ lung cancer), and clinical research (in lung cancer patients of different progression stages)...
March 6, 2018: Cell Death & Disease
Ashley V Menk, Nicole E Scharping, Dayana B Rivadeneira, Michael J Calderon, McLane J Watson, Deanna Dunstane, Simon C Watkins, Greg M Delgoffe
Despite remarkable responses to cancer immunotherapy in a subset of patients, many patients remain resistant to these therapies. The tumor microenvironment can impose metabolic restrictions on T cell function, creating a resistance mechanism to immunotherapy. We have previously shown tumor-infiltrating T cells succumb to progressive loss of metabolic sufficiency, characterized by repression of mitochondrial activity that cannot be rescued by PD-1 blockade. 4-1BB, a costimulatory molecule highly expressed on exhausted T cells, has been shown to influence metabolic function...
March 6, 2018: Journal of Experimental Medicine
David P Funda, Jaroslav Goliáš, Tomáš Hudcovic, Hana Kozáková, Radek Špíšek, Lenka Palová-Jelínková
Tolerogenic DCs (tolDCs) are being researched as a promising intervention strategy also in autoimmune diseases including type 1 diabetes (T1D). T1D is a T-cell-mediated, organ-specific disease with several well-defined and rather specific autoantigens, i.e., proinsulin, insulin, glutamic acid decarboxylase 65 (GAD65), that have been used in animal as well as human intervention trials in attempts to achieve a more efficient, specific immunotherapy. In this study, we have tested tolerogenic DCs for their effectiveness to prevent adoptive transfer of diabetes by diabetogenic splenocytes into non-obese diabetes (NOD)-severe combined immunodeficiency (NOD-SCID) recipients...
2018: Frontiers in Immunology
Marina Gazdic, Bojana Simovic Markovic, Aleksandar Arsenijevic, Nemanja Jovicic, Aleksandar Acovic, C Randall Harrell, Crissy Fellabaum, Valentin Djonov, Nebojsa Arsenijevic, Miodrag L Lukic, Vladislav Volarevic
One of the therapeutic options for the treatment of fulminant hepatitis is re-population of intrahepatic regulatory cells since their pool is significantly reduced during acute liver failure. Although it is known that mesenchymal stem cells (MSCs), which have beneficent effects in the therapy of fulminant hepatitis, may promote expansion of T regulatory cells (Tregs) and B regulatory cells (Bregs), the role of these regulatory cells in MSC-mediated attenuation of acute liver injury is unknown. Herewith, we described the molecular mechanisms involved in the crosstalk between MSCs and liver regulatory cells and analyzed the potential of MSC-based therapy for the expansion of intrahepatic regulatory cells in mouse model of acute liver failure...
March 3, 2018: Liver Transplantation
C F Francisconi, A E Vieira, M C S Azevedo, A P Tabanez, A C Fonseca, A P F Trombone, A Letra, R M Silva, C S Sfeir, S R Little, G P Garlet
The chronic inflammatory immune response triggered by the infection of the tooth root canal system results in the local upregulation of RANKL, resulting in periapical bone loss. While RANKL has a well-characterized role in the control of bone homeostasis/pathology, it can play important roles in the regulation of the immune system, although its possible immunoregulatory role in infectious inflammatory osteolytic conditions remains largely unknown. Here, we used a mouse model of infectious inflammatory periapical lesions subjected to continuous or transitory anti-RANKL inhibition, followed by the analysis of lesion outcome and multiple host response parameters...
March 1, 2018: Journal of Dental Research
Rohtesh S Mehta, Katayoun Rezvani
Adoptive cell therapy has emerged as a powerful treatment for advanced cancers resistant to conventional agents. Most notable are the remarkable responses seen in patients receiving autologous CD19-redirected chimeric antigen receptor (CAR) T cells for the treatment of B lymphoid malignancies; however, the generation of autologous products for each patient is logistically cumbersome and has restricted widespread clinical use. A banked allogeneic product has the potential to overcome these limitations, yet allogeneic T-cells (even if human leukocyte antigen-matched) carry a major risk of graft-versus-host disease (GVHD)...
2018: Frontiers in Immunology
Jonathan T Sockolosky, Eleonora Trotta, Giulia Parisi, Lora Picton, Leon L Su, Alan C Le, Akanksha Chhabra, Stephanie L Silveria, Benson M George, Indigo C King, Matthew R Tiffany, Kevin Jude, Leah V Sibener, David Baker, Judith A Shizuru, Antoni Ribas, Jeffrey A Bluestone, K Christopher Garcia
Interleukin-2 (IL-2) is a cytokine required for effector T cell expansion, survival, and function, especially for engineered T cells in adoptive cell immunotherapy, but its pleiotropy leads to simultaneous stimulation and suppression of immune responses as well as systemic toxicity, limiting its therapeutic use. We engineered IL-2 cytokine-receptor orthogonal ( ortho ) pairs that interact with one another, transmitting native IL-2 signals, but do not interact with their natural cytokine and receptor counterparts...
March 2, 2018: Science
Angela R Elia, Matteo Grioni, Veronica Basso, Flavio Curnis, Massimo Freschi, Angelo Corti, Anna Mondino, Matteo Bellone
PURPOSE: Irregular blood flow and endothelial cell anergy, which characterize many solid tumors, hinder tumor infiltration by cytotoxic T lymphocytes (CTLs). This confers resistance to cancer immunotherapy with monoclonal antibodies directed against regulatory pathways in T lymphocytes (i.e., immune checkpoint blockade, ICB). We investigated whether NGR-TNF, a TNF derivative capable of targeting the tumor vasculature, and improving intra-tumor infiltration by activated CTLs, could sensitize tumors to ICB with antibodies specific for the PD-1 and CTLA-4 receptors...
February 28, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Fabian Schlott, Dominik Steubl, Stefanie Ameres, Andreas Moosmann, Stefan Dreher, Uwe Heemann, Volker Hösel, Dirk H Busch, Michael Neuenhahn
Human Cytomegalovirus (CMV) reactivation remains a major source of morbidity in patients after solid organ and hematopoietic stem cell transplantation (HSCT). Adoptive T cell therapy (ACT) with CMV-specific T cells is a promising therapeutic approach for HSCT recipients, but might be counteracted by CMV's immune evasion strategies. HLA-C*07:02 is less susceptible to viral immune evasion suggesting HLA-C*07:02-restricted viral epitopes as promising targets for ACT. For a better understanding of HLA-C*07:02-restricted CMV-specific T cells we used recently generated reversible HLA-C*07:02/IE-1 multimers (Streptamers) recognizing a CMV-derived Immediate-Early-1 (IE-1) epitope and analyzed phenotypic and functional T cell characteristics...
2018: PloS One
Alyssa K Kosmides, Kevin Necochea, John W Hickey, Jonathan P Schneck
T cell activation requires the coordination of a variety of signaling molecules including T cell receptor-specific signals and costimulatory signals. Altering the composition and distribution of costimulatory molecules during stimulation greatly affects T cell functionality for applications such as adoptive cell therapy (ACT), but the large diversity in these molecules complicates these studies. Here, we develop and validate a reductionist T cell activation platform that enables streamlined customization of stimulatory conditions...
February 28, 2018: Nano Letters
Pavlína Ptáčková, Jan Musil, Martin Štach, Petr Lesný, Šárka Němečková, Vlastimil Král, Milan Fábry, Pavel Otáhal
BACKGROUND AIMS: Clinical-grade chimeric antigenic receptor (CAR)19 T cells are routinely manufactured by lentiviral/retroviral (LV/RV) transduction of an anti-CD3/CD28 activated T cells, which are then propagated in a culture medium supplemented with interleukin (IL)-2. The use of LV/RVs for T-cell modification represents a manufacturing challenge due to the complexity of the transduction approach and the necessity of thorough quality control. METHODS: We present here a significantly improved protocol for CAR19 T-cell manufacture that is based on the electroporation of peripheral blood mononuclear cells with plasmid DNA encoding the piggyBac transposon/transposase vectors and their cultivation in the presence of cytokines IL-4, IL-7 and IL-21...
February 20, 2018: Cytotherapy
Myrna R Nahas, Jacalyn Rosenblatt, Hillard M Lazarus, David Avigan
The potential promise of therapeutic vaccination as effective therapy for hematologic malignancies is supported by the observation that allogeneic hematopoietic cell transplantation is curative for a subset of patients due to the graft-versus-tumor effect mediated by alloreactive lymphocytes. Tumor vaccines are being explored as a therapeutic strategy to re-educate host immunity to recognize and target malignant cells through the activation and expansion of effector cell populations. Via several mechanisms, tumor cells induce T cell dysfunction and senescence, amplifying and maintaining tumor cell immunosuppressive effects, resulting in failure of clinical trials of tumor vaccines and adoptive T cell therapies...
February 15, 2018: Blood Reviews
Fatemeh Safari, Safar Farajnia, Maryam Arya, Habib Zarredar, Ava Nasrolahi
INTRODUCTION: Rheumatoid arthritis (RA), as one of the most disabling autoimmune diseases, is a common health problem that progressively reduces the life quality of patients. Although various biologics have been introduced for RA, attempts to establish an efficient long-term therapies failed due to the heterogeneity of this disease. METHODS: In the last decade, immunomodulatory approaches such as T cell adoptive therapy have been developed for controlling autoimmunity...
February 23, 2018: Immunopharmacology and Immunotoxicology
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