Chimeric antigen receptor T-cells (CARs) in cancer treatment

2021 ◽  
Vol 14 ◽  
Author(s):  
Wissam Zam ◽  
Amany Assaad
Keyword(s):  
T Cells ◽  
Cancer Treatment ◽  
Solid Tumors ◽  
Hematologic Malignancies ◽  
Genetically Engineered ◽  
Great Success ◽  
Car T Cells ◽  
New Therapeutic Approaches ◽  
Limited Effectiveness ◽  
Car T

Background: Cancer is one of the leading causes of death worldwide. Chemotherapy, radiation therapy, and stem cell transplantation were the main cancer treatment approaches for several years but due to their limited effectiveness, there was a constant search for new therapeutic approaches. Cancer immunotherapy that utilizes and enhances the normal capacity of the patient's immune system was used to fight against cancer. Genetically engineered T-cells that express chimeric antigen receptors (CARs) showed remarkable anti-tumor activity against hematologic malignancies and is now being investigated in a variety of solid tumors. The use of this therapy in the last few years has been successful, achieving a great success in improving the quality of life and prolonging the survival time of patients with a reduction in remission rates. However, many challenges still need to be resolved in order for this technology to gain widespread adoption. Objective: This review summarizes various experimental approaches towards the use of CAR T-cells in hematologic malignancies and solid tumors. Conclusion: Finally, we address the challenges posed by CAR T-cells and discuss strategies for improving the performance of these T cells in fighting cancers.

scholarly journals CAR-T cells and BiTEs in solid tumors: challenges and perspectives

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Julien Edeline ◽  
Roch Houot ◽  
Aurélien Marabelle ◽  
Marion Alcantara
Keyword(s):  
T Cells ◽  
Solid Tumors ◽  
Specific Antigen ◽  
Hematologic Malignancies ◽  
Antibody Fragments ◽  
New Drugs ◽  
Car T Cells ◽  
Cell Specificity ◽  
Car T ◽  
Early Phase Clinical Trials

AbstractChimeric antigen receptor (CAR)-modified T cells and BiTEs are both immunotherapies which redirect T cell specificity against a tumor-specific antigen through the use of antibody fragments. They demonstrated remarkable efficacy in B cell hematologic malignancies, thus paving the way for their development in solid tumors. Nonetheless, the use of such new drugs to treat solid tumors is not straightforward. So far, the results from early phase clinical trials are not as impressive as expected but many improvements are under way. In this review we present an overview of the clinical development of CAR-T cells and BiTEs targeting the main antigens expressed by solid tumors. We emphasize the most frequent hurdles encountered by either CAR-T cells or BiTEs, or both, and summarize the strategies that have been proposed to overcome these obstacles.

scholarly journals CAR-T in Cancer Treatment: Develop in Self-Optimization, Win-Win in Cooperation

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1955
Author(s):  
Feifei Guo ◽  
Jiuwei Cui
Keyword(s):  
T Cells ◽  
Cancer Treatment ◽  
Unmet Needs ◽  
Hematologic Malignancies ◽  
Limiting Factors ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell Therapy ◽  
Car T ◽  
Application Prospects

Despite remarkable achievements in the treatment of hematologic malignancies, chimeric antigen receptor (CAR)-T cell therapy still faces many obstacles. The limited antitumor activity and persistence of infused CAR-T cells, especially in solid tumors, are the main limiting factors for CAR-T therapy. Moreover, clinical security and accessibility are important unmet needs for the application of CAR-T therapy. In view of these challenges, many potentially effective solutions have been proposed and confirmed. Both the independent and combined strategies of CAR-T therapy have exhibited good application prospects. Thus, in this review, we have discussed the cutting-edge breakthroughs in CAR-T therapy for cancer treatment, with the aim of providing a reference for addressing the current challenges.

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 Development of CAR-T Cell Persistence in Adoptive Immunotherapy of Solid Tumors

2021 ◽  
Vol 10 ◽  
Author(s):  
Jiaqiao Fan ◽  
Jugal Kishore Das ◽  
Xiaofang Xiong ◽  
Hailong Chen ◽  
Jianxun Song
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
T Cell ◽  
Solid Tumors ◽  
Adoptive Cell Transfer ◽  
Great Success ◽  
Cell Transfer ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Chimeric antigen receptor (CAR) T (CAR-T) cell transfer has made great success in hematological malignancies, but only shown a limited effect on solid tumors. One of the major hurdles is the poor persistence of infused cells derived from ex vivo activation/expansion and repeated antigen encounter after re-infusion. Bcl-xL has been demonstrated to play an important role on normal T cell survival and function as well as genetically engineered cells. In the current study, we developed a retroviral CAR construct containing a second-generation carcinoembryonic antigen (CEA)-targeting CAR with the Bcl-xL gene and tested the anti-CEA CAR-T cell immunotherapy for colorectal cancer. In vitro, the anti-CEA CAR-T cells destroyed CEA-expressing tumor cells and sustained survival. In vivo, adoptive cell transfer of anti-CEA CAR-T cells significantly enhanced the ability of the CAR-T cells to accumulate in tumor tissues, suppress tumor growth and increase the overall survival rate of tumor-bearing mice in a murine model of colorectal cancer. These results demonstrate a novel CAR-T platform that has the ability to increase the persistence of CAR-T cells in solid tumors through exogenous expression of persistent genes. The data provide a potentially novel approach to augment CAR-T immunotherapy for solid tumors.

scholarly journals Obstacles and Coping Strategies of CAR-T Cell Immunotherapy in Solid Tumors

2021 ◽  
Vol 12 ◽  
Author(s):  
Lele Miao ◽  
Zhengchao Zhang ◽  
Zhijian Ren ◽  
Futian Tang ◽  
Yumin Li
Keyword(s):  
T Cells ◽  
T Cell ◽  
Solid Tumors ◽  
Hematologic Malignancies ◽  
Car T Cells ◽  
Car T Cell ◽  
Cell Immunotherapy ◽  
Car T ◽  
And Coping ◽  
T Cell Immunotherapy

Chimeric antigen receptor (CAR) T-cell immunotherapy refers to an adoptive immunotherapy that has rapidly developed in recent years. It is a novel type of treatment that enables T cells to express specific CARs on their surface, then returns these T cells to tumor patients to kill the corresponding tumor cells. Significant strides in CAR-T cell immunotherapy against hematologic malignancies have elicited research interest among scholars in the treatment of solid tumors. Nonetheless, in contrast with the efficacy of CAR-T cell immunotherapy in the treatment of hematologic malignancies, its general efficacy against solid tumors is insignificant. This has been attributed to the complex biological characteristics of solid tumors. CAR-T cells play a better role in solid tumors, for instance by addressing obstacles including the lack of specific targets, inhibition of tumor microenvironment (TME), homing barriers of CAR-T cells, differentiation and depletion of CAR-T cells, inhibition of immune checkpoints, trogocytosis of CAR-T cells, tumor antigen heterogeneity, etc. This paper reviews the obstacles influencing the efficacy of CAR-T cell immunotherapy in solid tumors, their mechanism, and coping strategies, as well as economic restriction of CAR-T cell immunotherapy and its solutions. It aims to provide some references for researchers to better overcome the obstacles that affect the efficacy of CAR-T cells in solid tumors.

A chimeric antigen receptor with antigen-independent OX40 signaling mediates potent antitumor activity

2021 ◽  
Vol 13 (578) ◽  
pp. eaba7308
Author(s):  
Huihui Zhang ◽  
Fanlin Li ◽  
Jiang Cao ◽  
Xin Wang ◽  
Hai Cheng ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antitumor Activity ◽  
Solid Tumors ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Mouse Tumor ◽  
Great Success ◽  
Car T Cells ◽  
Car T

Although chimeric antigen receptor (CAR)–modified T cells have shown great success in the treatment of B cell malignancies, this approach has limited efficacy in patients with solid tumors. Various modifications in CAR structure have been explored to improve this efficacy, including the incorporation of two costimulatory domains. Because costimulatory signals are transduced together with T cell receptor signals during T cell activation, we engineered a type of CAR-T cells with a costimulatory signal that was activated independently from the tumor antigen to recapitulate physiological stimulation. We screened 12 costimulatory receptors to identify OX40 as the most effective CAR-T function enhancer. Our data indicated that these new CAR-T cells showed superior proliferation capability compared to current second-generation CAR-T cells. OX40 signaling reduced CAR-T cell apoptosis through up-regulation of genes encoding Bcl-2 family members and enhanced proliferation through increased activation of the NF-κB (nuclear factor κB), MAPK (mitogen-activated protein kinase), and PI3K-AKT (phosphoinositide 3-kinase to the kinase AKT) pathways. OX40 signaling not only enhanced the cytotoxicity of CAR-T cells but also reduced exhaustion markers, thereby maintaining their function in immunosuppressive tumor microenvironments. In mouse tumor models and in patients with metastatic lymphoma, these CAR-T cells exhibited robust amplification and antitumor activity. Our findings provide an alternative option for CAR-T optimization with the potential to overcome the challenge of treating solid tumors.

scholarly journals CAR-T cells leave the comfort zone: current and future applications beyond cancer

2020 ◽  
Author(s):  
Mariana Torres Mazzi ◽  
Karina Lôbo Hajdu ◽  
Priscila Rafaela Ribeiro ◽  
Martín Hernán Bonamino
Keyword(s):  
T Cells ◽  
Cardiac Fibrosis ◽  
Tumor Therapy ◽  
General Purpose ◽  
Great Success ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T ◽  
Potential Applications ◽  
Membrane Antigens

Abstract Chimeric antigen receptor (CAR)-T cell therapy represents a breakthrough in the immunotherapy field and has achieved great success following its approval in 2017 for the treatment of B cell malignancies. While CAR-T cells are mostly applied as anti-tumor therapy in the present, their initial concept was aimed at a more general purpose of targeting membrane antigens, thus translating in many potential applications. Since then, several studies have assessed the use of CAR-T cells towards non-malignant pathologies such as autoimmune diseases, infectious diseases and, more recently, cardiac fibrosis and cellular senescence. In this review, we present the main findings and implications of CAR-based therapies for non-malignant conditions.

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