scholarly journals CAR T Cells: Precision Cancer Immunotherapy

2018 ◽  
Vol 10 (3) ◽  
pp. 203-16
Author(s):  
Anna Meiliana ◽  
Nurrani Mustika Dewi ◽  
Andi Wijaya
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Cancer Immunotherapy ◽  
Tumor Cells ◽  
T Cell Receptor ◽  
Adoptive Cell Therapy ◽  
Cell Receptor ◽  
Car T Cells ◽  
Car T

BACKGROUND: Current cancer drugs and treatments are aiming at eradicating tumor cells, but often are more toxic then effective, killing also the normal cells and not selectively the tumor cells. There is good personalized cancer therapy that involves administration to the cancer-bearing host of immune cells with direct anticancer activity, which called adoptive cell therapy (ACT). A review of the unique biology of T cell therapy and of recent clinical experience compels a reassessment of target antigens that traditionally have been viewed from the perspective of weaker immunotherapeutic modalities.CONTENT: Chimeric antigen receptors (CAR) are recombinant receptors which provide both antigen-binding and T cell-activating functions. Many kind of CARs has been reported for the past few years, targeting an array of cell surface tumor antigens. Their biologic functions have extremely changed following the introduction of tripartite receptors comprising a costimulatory domain, termed second-generation CARs. The combination of CARs with costimulatory ligands, chimeric costimulatory receptors, or cytokines can be done to further enhance T cell potency, specificity and safety. CARs reflects a new class of drugs with exciting potential for cancer immunotherapy.SUMMARY: CAR-T cells have been arising as a new modality for cancer immunotherapy because of their potent efficacy against terminal cancers. They are known to exert higher efficacy than monoclonal antibodies and antibodydrug conjugates, and act via mechanisms distinct from T cell receptor-engineered T cells. These cells are constructed by transducing genes encoding fusion proteins of cancer antigen-recognizing single-chain Fv linked to intracellular signaling domains of T cell receptors.KEYWORDS: chimeric antigen receptor, CAR T cells, adoptive cell therapy, ACT, T cell receptor, TCR, cancer, immunotherapy

scholarly journals CRISPR/Cas9 revitalizes adoptive T-cell therapy for cancer immunotherapy

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Sasan Ghaffari ◽  
Nastaran Khalili ◽  
Nima Rezaei
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Cancer Immunotherapy ◽  
Cell Receptor ◽  
Adoptive T Cell Therapy ◽  
Therapeutic Modality ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T

AbstractCancer immunotherapy has gained attention as the supreme therapeutic modality for the treatment of various malignancies. Adoptive T-cell therapy (ACT) is one of the most distinctive modalities of this therapeutic approach, which seeks to harness the potential of combating cancer cells by using autologous or allogenic tumor-specific T-cells. However, a plethora of circumstances must be optimized to produce functional, durable, and efficient T-cells. Recently, the potential of ACT has been further realized by the introduction of novel gene-editing platforms such as the CRISPR/Cas9 system; this technique has been utilized to create T-cells furnished with recombinant T-cell receptor (TCR) or chimeric antigen receptor (CAR) that have precise tumor antigen recognition, minimal side effects and treatment-related toxicities, robust proliferation and cytotoxicity, and nominal exhaustion. Here, we aim to review and categorize the recent breakthroughs of genetically modified TCR/CAR T-cells through CRISPR/Cas9 technology and address the pearls and pitfalls of each method. In addition, we investigate the latest ongoing clinical trials that are applying CRISPR-associated TCR/CAR T-cells for the treatment of cancers.

scholarly journals Advances in Adoptive Cell Therapy Using Induced Pluripotent Stem Cell-Derived T Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Ratchapong Netsrithong ◽  
Methichit Wattanapanitch
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Cell Biology ◽  
Ex Vivo ◽  
Adoptive Cell Therapy ◽  
Basic Knowledge ◽  
Car T Cells ◽  
Car T ◽  
Induced Pluripotent

Adoptive cell therapy (ACT) using chimeric antigen receptor (CAR) T cells holds impressive clinical outcomes especially in patients who are refractory to other kinds of therapy. However, many challenges hinder its clinical applications. For example, patients who undergo chemotherapy usually have an insufficient number of autologous T cells due to lymphopenia. Long-term ex vivo expansion can result in T cell exhaustion, which reduces the effector function. There is also a batch-to-batch variation during the manufacturing process, making it difficult to standardize and validate the cell products. In addition, the process is labor-intensive and costly. Generation of universal off-the-shelf CAR T cells, which can be broadly given to any patient, prepared in advance and ready to use, would be ideal and more cost-effective. Human induced pluripotent stem cells (iPSCs) provide a renewable source of cells that can be genetically engineered and differentiated into immune cells with enhanced anti-tumor cytotoxicity. This review describes basic knowledge of T cell biology, applications in ACT, the use of iPSCs as a new source of T cells and current differentiation strategies used to generate T cells as well as recent advances in genome engineering to produce next-generation off-the-shelf T cells with improved effector functions. We also discuss challenges in the field and future perspectives toward the final universal off-the-shelf immunotherapeutic products.

scholarly journals Armored CAR T-cells: utilizing cytokines and pro-inflammatory ligands to enhance CAR T-cell anti-tumour efficacy

2016 ◽  
Vol 44 (2) ◽  
pp. 412-418 ◽  
Author(s):  
Oladapo O. Yeku ◽  
Renier J. Brentjens
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Second Generation ◽  
Cell Receptor ◽  
Tumour Microenvironment ◽  
Interleukin 12 ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Chimaeric antigen receptor (CAR) T-cells are T-cells that have been genetically modified to express an artificial construct consisting of a synthetic T-cell receptor (TCR) targeted to a predetermined antigen expressed on a tumour. Coupling the T-cell receptor to a CD3ζ signalling domain paved the way for first generation CAR T-cells that were efficacious against cluster of differentiation (CD)19-expressing B-cell malignancies. Optimization with additional signalling domains such as CD28 or 4-1BB in addition to CD3ζ provided T-cell activation signal 2 and further improved the efficacy and persistence of these second generation CAR T-cells. Third generation CAR T-cells which utilize two tandem costimulatory domains have also been reported. In this review, we discuss a different approach to optimization of CAR T-cells. Through additional genetic modifications, these resultant armored CAR T-cells are typically modified second generation CAR T-cells that have been further optimized to inducibly or constitutively secrete active cytokines or express ligands that further armor CAR T-cells to improve efficacy and persistence. The choice of the ‘armor’ agent is based on knowledge of the tumour microenvironment and the roles of other elements of the innate and adaptive immune system. Although there are several variants of armored CAR T-cells under investigation, here we focus on three unique approaches using interleukin-12 (IL-12), CD40L and 4-1BBL. These agents have been shown to further enhance CAR T-cell efficacy and persistence in the face of a hostile tumour microenvironment via different mechanisms.

Abstract A043: Anti-CD19 CAR T-cells with a CRISPR/Cas9-mediated T-cell receptor knockout show high functionality in the absence of alloreactivity in vitro

2019 ◽  
Author(s):  
Dana Stenger ◽  
Tanja Stief ◽  
Theresa Käuferle ◽  
Semjon Manuel Willier ◽  
Felicitas Rataj ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Car T Cells ◽  
Car T

Identification of HLA-A0201 restricted epitope of novel cancer/testis antigens VCX/Y and generation of antigen-specific T-cell receptor engineered T cells for treatment of solid tumor malignancies.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 160-160
Author(s):  
Ke Pan ◽  
Cassian Yee
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
High Activity ◽  
Tumor Cells ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Engineered T Cells ◽  
Restricted Epitope ◽  
Cancer Testis

160 Background: To identify HLA-A0201 restricted epitope of novel cancer/testis antigen VCX/Y, generate antigen specific T cells and T-cell receptor (TCR) engineered T cells for adoptive cell therapy (ACT) of solid cancer patients. Methods: Reverse-immunology method was used to identify HLA-A0201 restricted epitope of VCX/Y. The high binding score peptide or whole length of VCX3A mRNA were pulsed or transfected to mature dendritic cells (mDC) from HLA-A0201+ donor and then stimulated autologous naïve T cells. Tetramer guided sorting were performed to purify the epitope specific T cells and CTL clones were generated with limiting dilution. TCR were cloned out from high activity CTL clone and the recombinant of retrovirus vector were constructed to introduce the TCR to allogeneic PBMC to generate the TCR engineered T cells. Results: One peptide which its sequence was shared with all VCX/Y members was identified. Interesting, only CTL clone generated from simulation of VCX3A mRNA transfected DC can recognize naturally processed VCX/Y presented by HLA-A0201+ tumor cells. Cold target inhibition detection confirmed that this VCX/Y peptide was naturally processed and recognized by HLA-A0201+ CTL clone. After infection of retrovirus containing the TCR from high activity of CTL clone, the TCR engineered T cells can recognize HLA-A2+ tumor cells but not normal lung cells. Moreover, these TCR engineered T cells specifically secreted IFN-γ in response to T2 cells pulsed with peptide, as well as HLA-A0201+ and VCX/Y overexpressed tumor cells. Conclusions: VCX/Y peptide we identified is a novel candidate peptide antigen for vaccine or for endogenous adoptive T cell therapy. The correlated high activity TCR gene can generate TCR engineered T cells from patients with anti-tumor activity and offer an alternative adoptive T cell treatment for patients with VCX/Y expressing solid tumor malignancies.

scholarly journals New Generation Chimeric Antigen Receptor T-Cell Therapy (CoupledCAR) Induces High Rate Remissions in Solid Tumor

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4631-4631
Author(s):  
Lei Xiao
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
Thyroid Cancer ◽  
T Cell ◽  
Cell Therapy ◽  
Solid Tumors ◽  
Tumor Cells ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T

New Generation Chimeric Antigen Receptor T-Cell Therapy ( CoupledCAR ) Induces High Rate Remissions in Solid Tumor Yu Liu1,Song Li2,Youli Luo3,Haixia Song4,Chengfei Pu5, Zhiyuan Cao 5, Cheng Lu5,Yang Hang5,Xi Huang5,Xiaogang Shen5 ,Xiaojun Hu3 , Renbin Liu1,Xiuwen Wang2,Junjie Mao3,Shihong Wei4 ,Zhao Wu5and Lei Xiao5* 1.The Third Affiliated Hospital, SUN YAT-SEN University 2.Qilu Hospital of Shandong University 3.The Fifth Affiliated Hospital, SUN YAT-SEN University 4.Gansu Procincial Cancer Hospital 5.Innovative Cellular Therapeutics *Corresponding to: Lei Xiao, [email protected] Chimeric antigen receptor (CAR) T cell therapy made significant progress for treating blood cancer such as leukemia, lymphoma, and myeloma. However, the therapy faces many challenges, such as physical barrier, tumor microenvironment immunosuppression, tumor heterogeneity, target specificity, and cell expansion in vivo for treatment of solid tumors Conventional CAR T cell therapy showed weak CAR T expansion in patients and thus achieved no or little response for treating solid tumors. Here, we generated "CoupledCAR" T cells including an anti-TSHR CAR molecule. Compared with conventional CART cells,these "CoupledCAR" T cells successfully improved the expansion of CART cells more than 100 times and enhanced CAR T cells' migration ability, allowing the CAR T cells to resist and infiltrate the tumor microenvironment and killed tumor cells. To verify the effect of "CoupledCAR" T cells on solid tumors, we have completed several clinical trials for different solid tumors, including two patients with thyroid cancer. Immunohistochemistry (IHC) results showed that thyroid stimulating hormone receptors (TSHR) were highly expressed in thyroid cancer cells. In vitro co-culture experiments showed that TSHR CAR T cells specifically recognized and killed TSHR-positive tumor cells. Animal experiments showed that TSHR CAR T cells inhibited the proliferation of TSHR-positive tumor cells. Therefore, we designed "CoupledCAR" T cells expressing a binding domain against TSHR. Further,we did clinical trials of two group patients that were successfully treated using conventional TSHR CAR T cells and the "CoupledCAR" T cells, respectively. In the first group using conventional TSHR CAR T cells, patients showed weak cell expansion and less migration ability. In the group using TSHR "CoupledCAR" T cells, patients showed rapid expansion of CAR T cells and killing of tumor cells. One month after infusion (M1), the patient was evaluated as PR(Partial Response): the lymph node metastasis disappeared, and thoracic paratracheal tumors decreased significantly. Three months after infusion (M3), the patient was evaluated as a durable response, and the tumor tissue was substantially smaller than M1. Further, two patients with colonrectal cancer were enrolled in this trial and infused "CoupledCAR" T cells. One patient achieved PR and the other one achieved SD (Stable Disease). Therefore, "CoupledCAR" T cells can effectively promote expansion, migration and killing ability of CAR T cells in patients with thyroid cancer. "CoupledCAR" T cell technology is a technological platform, which may be used to treat other cancer types. Next, we are recruiting more patients with solid tumors in clinical trials using "CoupledCAR" T cells. Disclosures No relevant conflicts of interest to declare.

scholarly journals 200. Generation of CAR-T Cells Lacking T Cell Receptor and Human Leukocyte Antigen Using Engineered Meganucleases

2016 ◽  
Vol 24 ◽  
pp. S78 ◽  
Author(s):  
Christina Pham ◽  
Aaron Martin ◽  
Jeyaraj Antony ◽  
Daniel MacLeod ◽  
Audrey Brown ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Human Leukocyte Antigen ◽  
T Cell Receptor ◽  
Human Leukocyte ◽  
Cell Receptor ◽  
Leukocyte Antigen ◽  
Car T Cells ◽  
Car T

scholarly journals Engineered Removal of PD-1 From the Surface of CD19 CAR-T Cells Results in Increased Activation and Diminished Survival

2021 ◽  
Vol 8 ◽  
Author(s):  
R. S. Kalinin ◽  
V. M. Ukrainskaya ◽  
S. P. Chumakov ◽  
A. M. Moysenovich ◽  
V. M. Tereshchuk ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Tumor Cells ◽  
Functional Impairment ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

CAR-T cell therapy is the most advanced way to treat therapy resistant hematologic cancers, in particular B cell lymphomas and leukemias, with high efficiency. Donor T cells equipped ex vivo with chimeric receptor recognize target tumor cells and kill them using lytic granules. CAR-T cells that recognize CD19 marker of B cells (CD19 CAR-T) are considered the gold standard of CAR-T therapy and are approved by FDA. But in some cases, CD19 CAR-T cell therapy fails due to immune suppressive microenvironment. It is shown that tumor cells upregulate expression of PD-L1 surface molecule that binds and increases level and signal provided by PD-1 receptor on the surface of therapeutic CAR-T cells. Induction of this negative signaling results in functional impairment of cytotoxic program in CAR-T cells. Multiple attempts were made to block PD-1 signaling by reducing binding or surface level of PD-1 in CAR-T cells by various means. In this study we co-expressed CD19-CAR with PD-1-specific VHH domain of anti-PD-1 nanobody to block PD-1/PD-L1 signaling in CD19 CAR-T cells. Unexpectedly, despite increased activation of CAR-T cells with low level of PD-1, these T cells had reduced survival and diminished cytotoxicity. Functional impairment caused by disrupted PD-1 signaling was accompanied by faster maturation and upregulation of exhaustion marker TIGIT in CAR-T cells. We conclude that PD-1 in addition to its direct negative effect on CAR-induced signaling is required for attenuation of strong stimulation leading to cell death and functional exhaustion. These observations suggest that PD-1 downregulation should not be considered as the way to improve the quality of therapeutic CAR-T cells.

scholarly journals Proceedings From the First International Workshop at Sidra Medicine: “Engineered Immune Cells in Cancer Immunotherapy (EICCI): From Discovery to Off-the-Shelf Development”, 15th–16th February 2019, Doha, Qatar

2021 ◽  
Vol 11 ◽  
Author(s):  
Bella Guerrouahen ◽  
Muhammad Elnaggar ◽  
Anjud Al-Mohannadi ◽  
Dhanya Kizhakayil ◽  
Chiara Bonini ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Cancer Immunotherapy ◽  
Immune Cells ◽  
Adoptive Cell Therapy ◽  
Clinical Development ◽  
Clinical Activity ◽  
Isolation And Characterization ◽  
Car T

The progress in the isolation and characterization of tumor antigen (TA)-specific T lymphocytes and in the genetic modification of immune cells allowed the clinical development of adoptive cell therapy (ACT). Several clinical studies highlighted the striking clinical activity of T cells engineered to express either Chimeric Antigen (CAR) or T Cell (TCR) Receptors to target molecularly defined antigens expressed on tumor cells. The breakthrough of immunotherapy is represented by the approval of CAR-T cells specific for advanced or refractory CD19+ B cell malignancies by both the Food and Drug Administration (FDA) and the European Medicinal Agency (EMA). Moreover, advances in the manufacturing and gene editing of engineered immune cells contributed to the selection of drug products with desired phenotype, refined specificity and decreased toxicity. An important step toward the optimization of CAR-T cell therapy is the development of “off-the shelf” T cell products that allow to reduce the complexity and the costs of the manufacturing and to render these drugs available for a broad number of cancer patients. The Engineered Immune Cells in Cancer Immunotherapy (EICCI) workshop hosted in Doha, Qatar, renowned experts, from both academia and industry, to present and discuss the progress on both pre-clinical and clinical development of genetically modified immune cells, including advances in the “off-the-shelf” manufacturing. These experts have addressed also organizational needs and hurdles for the clinical grade production and application of these biological drugs.

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