scholarly journals CAR-T Cell Therapy—An Overview of Targets in Gastric Cancer

2020 ◽  
Vol 9 (6) ◽  
pp. 1894
Author(s):  
Dominika Bębnowska ◽  
Ewelina Grywalska ◽  
Paulina Niedźwiedzka-Rystwej ◽  
Barbara Sosnowska-Pasiarska ◽  
Jolanta Smok-Kalwat ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
Folate Receptor ◽  
Growth Factor Receptor ◽  
Genetically Engineered ◽  
Mucin 1 ◽  
Anion Exchanger 1 ◽  
T Cell Therapy ◽  
Neuropilin 1 ◽  
Car T

Gastric cancer (GC) is one of the most commonly diagnosed malignancies and, unfortunately, still has a high mortality rate. Recent research points to CAR-T immunotherapy as a promising treatment for this disease. Using genetically engineered T cells designed to target a previously selected antigen, researchers are able to harness the natural anti-tumor activity of T cells. For therapy to be successful, however, it is essential to choose antigens that are present on tumor cells but not on healthy cells. In this review, we present an overview of the most important targets for CAR-T therapy in the context of GC, including their biologic function and therapeutic application. A number of clinical studies point to the following as important markers in GC: human epidermal growth factor receptor 2, carcinoembryonic antigen, mucin 1, epithelial cell adhesion molecule, claudin 18.2, mesothelin, natural-killer receptor group 2 member D, and folate receptor 1. Although these markers have been met with some success, the search for new and improved targets continues. Key among these novel biomarkers are the B7H6 ligand, actin-related protein 2/3 (ARP 2/3), neuropilin-1 (NRP-1), desmocollin 2 (DSC2), anion exchanger 1 (AF1), and cancer-related antigens CA-72-4 and CA-19-9.

scholarly journals Strengthening the CAR-T Cell Therapeutic Application using CRISPR/Cas9 Technology

2021 ◽  
Author(s):  
Muhammad Sadeqi Nezhad ◽  
Mahboubeh Yazdanifar ◽  
Meghdad Abdollahpour-Alitappeh ◽  
Arash Sattari ◽  
Alexander seifalian ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Side Effects ◽  
Hematologic Malignancies ◽  
Genetically Engineered ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Promising Tool ◽  
Car T

Adoptive cell immunotherapy with chimeric antigen receptor (CAR) T cell has brought a revolutionary means of treatment for aggressive diseases such as hematologic malignancies and solid tumors. Over the last decade, FDA approved three types of CAR-T cells against CD19 hematologic malignancies, including Tisagenlecleucel (Kymriah), Axicabtagene ciloleucel (Yescarta), and Brexucabtagene autoleucel (Tecartus). Despite outstanding results gained from different clinical trials, CAR-T cell therapy is not free from side effects and toxicities, and needs careful investigations and improvements. Gene-editing technology, clustered regularly interspaced short palindromic repeats (CRISPR)/ CRISPR-associated protein 9 (Cas9) system has emerged as a promising tool to address some of the CAR-T therapy hurdles. Using CRISPR/Cas9 technology, CAR expression as well as other cellular pathways can be modified in various ways to enhance CAR-T cell’s anti-tumor function and persistence in immunosuppressive tumor microenvironment. CRISPR/Cas9 technology can also be utilized to reduce CAR-T cells toxicity and side effects. Hereby, we discuss the practical challenges and hurdles related to the accuracy, efficiency, efficacy, safety and delivery of CRISPR/Cas9 technology to the genetically engineered-T cells. Combining of these two state-of-the-art technologies, CRISPR/Cas9 and CAR-T cells, the field of oncology has an extraordinary opportunity to enter a new era of immunotherapy, which offers novel therapeutic options for different types of tumors.

scholarly journals Chimeric Antigen Receptor-T Cells: A Pharmaceutical Scope

2021 ◽  
Vol 12 ◽  
Author(s):  
Alejandrina Hernández-López ◽  
Mario A. Téllez-González ◽  
Paul Mondragón-Terán ◽  
Angélica Meneses-Acosta
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Adoptive Cell Therapy ◽  
Genetically Engineered ◽  
First Line ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Advanced Therapy ◽  
Car T

Cancer is among the leading causes of death worldwide. Therefore, improving cancer therapeutic strategies using novel alternatives is a top priority on the contemporary scientific agenda. An example of such strategies is immunotherapy, which is based on teaching the immune system to recognize, attack, and kill malignant cancer cells. Several types of immunotherapies are currently used to treat cancer, including adoptive cell therapy (ACT). Chimeric Antigen Receptors therapy (CAR therapy) is a kind of ATC where autologous T cells are genetically engineered to express CARs (CAR-T cells) to specifically kill the tumor cells. CAR-T cell therapy is an opportunity to treat patients that have not responded to other first-line cancer treatments. Nowadays, this type of therapy still has many challenges to overcome to be considered as a first-line clinical treatment. This emerging technology is still classified as an advanced therapy from the pharmaceutical point of view, hence, for it to be applied it must firstly meet certain requirements demanded by the authority. For this reason, the aim of this review is to present a global vision of different immunotherapies and focus on CAR-T cell technology analyzing its elements, its history, and its challenges. Furthermore, analyzing the opportunity areas for CAR-T technology to become an affordable treatment modality taking the basic, clinical, and practical aspects into consideration.

scholarly journals Folate receptor 1 (FOLR1) targeted chimeric antigen receptor (CAR) T cells for the treatment of gastric cancer

PLoS ONE ◽  
2018 ◽  
Vol 13 (6) ◽  
pp. e0198347 ◽  
Author(s):  
Minsung Kim ◽  
Suhkneung Pyo ◽  
Chung Hyo Kang ◽  
Chong Ock Lee ◽  
Heung Kyoung Lee ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
Chimeric Antigen Receptor ◽  
Folate Receptor ◽  
Antigen Receptor ◽  
Car T Cells ◽  
Car T

Chimeric antigen receptor (CAR) T cells genetically engineered to deliver IL-12 to the tumor microenvironment in ovarian cancer.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 141-141
Author(s):  
Oladapo O. Yeku ◽  
Terence Purdon ◽  
David R. Spriggs ◽  
Renier J. Brentjens
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Genetically Engineered ◽  
Ovarian Cancer Cells ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T

141 Background: Chimeric antigen receptor (CAR) T cell therapy for solid tumor malignancies has not shown the same degree of clinical efficacy observed in hematologic malignancies such as B-ALL. The presence of an immunosuppressive cellular and cytokine microenvironment has been hypothesized as one reason for the failure of adoptive immunotherapy for solid tumors. In ovarian cancer, myeloid derived suppressor cells (MDSC) and immunosuppressive cytokines in the ascitic microenvironment have been reported. IL-12 is a proinflammatory cytokine produced by macrophages, dendritic cells (DC), and NK cells, and it has been shown to increase proliferation of T cells, induce differentiation of type 1 T helper cells, inhibit regulatory T cells, promote maturation of DCs, and enhance antigen presentation by macrophages. We hypothesize that CAR T cells genetically modified to constitutively secrete IL-12 will overcome a hostile tumor microenvironment in a peritoneal carcinomatosis model of ovarian cancer. Methods: CAR T cells were generated from retroviral transduction of second generation and IL-12 modified CAR’s directed to either an irrelevant CD-19 antigen or Muc16ecto. C57BL/6 mice were inoculated i.p with syngeneic ovarian cancer cells and treated with various CAR T cells. Results: Here we report increased production of IL-12, improved proliferation and cytotoxic activity of 4H1128ζ-IL12 CAR T cells. Further, we show increased levels of inflammatory cytokines at 24 and 48hrs after treatment of tumor-bearing mice, leading to increased survival at advanced stages of disease. Animals treated with 4H1128ζ-IL12 CAR T cells had decreased levels of F4/80+ CD11b+MDSCs. Genetic analysis of recovered MDSCs from the ascites of treated animals showed skewing towards an M1-phenotype via upregulation of cytokines, chemokines, MHC-II, and downregulation of Arg1. Furthermore, clodronate-mediated depletion of TAM’s further enhanced survival in mice treated with 4H1128ζ-IL12 CAR T cells. Conclusions: These results demonstrate the mechanisms of efficacy of localized delivery of IL-12 to the tumor microenvironment by 4H1128ζ-IL12 CAR T cells.

scholarly journals Unexpected neurologic complications following a novel lymphoma treatment ‘expected’ to give rise to neurologic toxicity

2019 ◽  
Vol 12 (11) ◽  
pp. e229946 ◽  
Author(s):  
Marie José Kersten ◽  
Cornelis N van Ettekoven ◽  
Dianne M Heijink
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Sinus Thrombosis ◽  
Genetically Engineered ◽  
Cellular Immunotherapy ◽  
T Cell Therapy ◽  
Neurologic Symptoms ◽  
Car T Cell ◽  
Car T

Chimeric antigen receptor (CAR) T-cell therapy is a novel and promising form of cellular immunotherapy using genetically engineered, tumour-specific autologous T cells. CD19-specific CAR T-cells have been shown to be very effective as a treatment for relapsed/refractory B-cell acute lymphoblastic leukaemia and aggressive B-cell non-Hodgkin’s lymphoma. ICANS (immune effector cell-associated neurotoxicity syndrome) is one of the most frequently occurring toxicities of CAR T-cell treatment. We describe two cases of patients with neurologic symptoms following CAR T-cell infusion who were suspected to have ICANS, but in fact had cerebral toxoplasmosis and venous sinus thrombosis respectively. The focus on CRS and ICANS after CAR T-cell infusion may lead to less vigilance to the ‘normal’ threats faced by intensively pretreated patients with lymphoma such as infections and thrombosis. Both cases underscore the importance of a broad and thorough examination of patients if they experience neurologic symptoms after CAR T-cell treatment.

scholarly journals CAR T-cell therapy and critical care

2021 ◽  
Author(s):  
Anna S. Messmer ◽  
Yok-Ai Que ◽  
Christoph Schankin ◽  
Yara Banz ◽  
Ulrike Bacher ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Genetically Engineered ◽  
Therapeutic Interventions ◽  
Medical Emergency ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

SummaryChimeric antigen receptor (CAR) T‑cells are genetically engineered to give T‑cells the ability to attack specific cancer cells, and to improve outcome of patients with refractory/relapsed aggressive B‑cell malignancies. To date, several CAR T‑cell products are approved and additional products with similar indication or extended to other malignancies are currently being evaluated. Side effects of CAR T‑cell treatment are potentially severe or even life-threatening immune-related toxicities, specifically cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Consequently, medical emergency teams (MET) are increasingly involved in the assessment and management of CAR T‑cell recipients. This article describes the principles of CAR T‑cell therapy and summarizes the main complications and subsequent therapeutic interventions aiming to provide a survival guide for METs with a proposed management algorithm.

Chimeric antigen receptor (CAR) T cells genetically engineered to deliver IL-12 to the tumor microenvironment in ovarian cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3050-3050 ◽  
Author(s):  
Oladapo O. Yeku ◽  
Terence Purdon ◽  
David R. Spriggs ◽  
Renier J. Brentjens
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Genetically Engineered ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T ◽  
Fas L

3050 Background: Chimeric antigen receptor (CAR) T cell therapy for solid tumor malignancies has not shown the same degree of clinical efficacy observed in hematologic malignancies. The presence of an immunosuppressive cytokine and cellular microenvironment has been hypothesized as one reason for the failure of adoptive immunotherapy for solid tumors. In ovarian cancer, the presence of tumor associated macrophages (TAMs) and immunosuppressive cytokines in the ascitic microenvironment have been reported. IL-12 is a proinflammatory cytokine produced by macrophages, dendritic cells (DC) and NK cells, and has been shown to increase proliferation of T cells and enhance antigen presentation by macrophages. We hypothesized that CAR T cells genetically modified to constitutively secrete IL-12 would overcome a hostile tumor microenvironment in a peritoneal carcinomatosis model of ovarian cancer. Methods: CAR T cells were generated from retroviral transduction of second generation and IL-12 modified CAR’s directed to either an irrelevant CD-19 antigen or Muc16ecto. Results: Here we report increased production of IL-12, improved proliferation and cytotoxic activity of 4H1128-IL12 CAR T cells. We show increased levels of inflammatory cytokines at 24 and 48hrs after treatment of tumor-bearing mice, leading to increased survival at advanced stages of disease. Mice treated with 4H1128-IL12 CAR T cells had decreased levels of F4/80+ CD11b+TAM’s. Genetic analysis of recovered TAM’s from the ascites of treated animals showed skewing towards an M1-phenotype via upregulation of cytokines, chemokines, MHC-II and downregulation of Arg1. Recovered 4H1128-IL12 CAR T cells showed upregulation of FAS-L and recovered TAMs showed increased expression of FAS suggesting FAS/FAS-L engagement was responsible for decreased TAMs. Blocking the FAS/FAS-L pathway led to recovery of TAM populations in 4H1128-IL12 treated mice. Finally, clodronate-mediated depletion of TAM’s further enhanced survival in mice treated with 4H1128-IL12 CAR T cells. Conclusions: These results demonstrate the mechanisms of efficacy of localized delivery of IL-12 to the tumor microenvironment by 4H1128-IL12 CAR T cells.

scholarly journals Chimeric antigen receptor T-cell therapy in glioblastoma: charging the T cells to fight

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Craig A. Land ◽  
Phillip R. Musich ◽  
Dalia Haydar ◽  
Giedre Krenciute ◽  
Qian Xie
Keyword(s):  
Drug Delivery ◽  
T Cells ◽  
T Cell ◽  
Antigen Processing ◽  
High Specificity ◽  
Genetically Engineered ◽  
Normal Brain ◽  
T Cell Therapy ◽  
Additional Advantage ◽  
Car T

Abstract Glioblastoma multiforme (GBM) is the most common malignant brain cancer that invades normal brain tissue and impedes surgical eradication, resulting in early local recurrence and high mortality. In addition, most therapeutic agents lack permeability across the blood brain barrier (BBB), further reducing the efficacy of chemotherapy. Thus, effective treatment against GBM requires tumor specific targets and efficient intracranial drug delivery. With the most recent advances in immunotherapy, genetically engineered T cells with chimeric antigen receptors (CARs) are becoming a promising approach for treating cancer. By transducing T lymphocytes with CAR constructs containing a tumor-associated antigen (TAA) recognition domain linked to the constant regions of a signaling T cell receptor, CAR T cells may recognize a predefined TAA with high specificity in a non-MHC restricted manner, and is independent of antigen processing. Active T cells can travel across the BBB, providing additional advantage for drug delivery and tumor targeting. Here we review the CAR design and technical innovations, the major targets that are in pre-clinical and clinical development with a focus on GBM, and multiple strategies developed to improve CAR T cell efficacy.

scholarly journals Intratumoral IL-12 delivery empowers CAR-T cell immunotherapy in a pre-clinical model of glioblastoma

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Giulia Agliardi ◽  
Anna Rita Liuzzi ◽  
Alastair Hotblack ◽  
Donatella De Feo ◽  
Nicolás Núñez ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Growth Factor Receptor ◽  
T Cell Therapy ◽  
Clinical Model ◽  
Tumor Microenvironments ◽  
Car T Cells ◽  
Car T Cell ◽  
Promising Therapeutic Approach ◽  
Car T

AbstractGlioblastoma multiforme (GBM) is the most common and aggressive form of primary brain cancer, for which effective therapies are urgently needed. Chimeric antigen receptor (CAR)-based immunotherapy represents a promising therapeutic approach, but it is often impeded by highly immunosuppressive tumor microenvironments (TME). Here, in an immunocompetent, orthotopic GBM mouse model, we show that CAR-T cells targeting tumor-specific epidermal growth factor receptor variant III (EGFRvIII) alone fail to control fully established tumors but, when combined with a single, locally delivered dose of IL-12, achieve durable anti-tumor responses. IL-12 not only boosts cytotoxicity of CAR-T cells, but also reshapes the TME, driving increased infiltration of proinflammatory CD4+ T cells, decreased numbers of regulatory T cells (Treg), and activation of the myeloid compartment. Importantly, the immunotherapy-enabling benefits of IL-12 are achieved with minimal systemic effects. Our findings thus show that local delivery of IL-12 may be an effective adjuvant for CAR-T cell therapy for GBM.

The Other Side of CAR T-Cell Therapy: Cytokine Release Syndrome, Neurologic Toxicity, and Financial Burden

2019 ◽  
pp. 433-444 ◽  
Author(s):  
Bianca Santomasso ◽  
Carlos Bachier ◽  
Jason Westin ◽  
Katayoun Rezvani ◽  
Elizabeth J. Shpall
Keyword(s):  
T Cells ◽  
T Cell ◽  
Financial Burden ◽  
Hematologic Malignancies ◽  
Genetically Engineered ◽  
T Cell Therapy ◽  
Immune Effector ◽  
Effector Cells ◽  
Car T Cell ◽  
Car T

Immune effector cells, including T cells and natural killer cells, which are genetically engineered to express a chimeric antigen receptor (CAR), constitute a powerful new class of therapeutic agents to treat patients with hematologic malignancies. Several CAR T-cell trials have shown impressive remission rates in patients with relapsed/refractory hematologic cancers. Although the clinical responses of these agents in hematologic malignancies have been very encouraging, they have also produced substantial morbidity and occasionally mortality resulting from toxicity. With more experience and collaboration, hopefully the toxicities and the costs will come down, increasing the availability of CAR T cells to patients in need.

Sign in / Sign up

Export Citation Format

Share Document