Renaissance of armored immune effector cells, CAR-NK cells, brings the higher hope for successful cancer therapy

Marofi, Faroogh; Rahman, Heshu Sulaiman; Thangavelu, Lakshmi; Dorofeev, A.E.; Bayas-Morejón, Favian; Shirafkan, Naghmeh; Shomali, Navid; Chartrand, Max Stanley; Jarahian, Mostafa; Vahedi, Ghasem; Mohammed, Rebar N.; Shahrokh, Somayeh; Akbari, Morteza; Khiavi, Farhad Motavalli

doi:10.1186/s13287-021-02251-7

Cited by 32 publications

(26 citation statements)

References 195 publications

(257 reference statements)

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“…CARs are designed by using part of mAbs and can recognize only one specific antigen epitope. Therefore, CAR T cell engineering is implemented first by isolation of patients' T cells, next by incorporating the CARs into the T cells, expansion of newly generated CAR T cells, and then re-infusion of newly engineered cells into the patient's body [59,60].…”

Section: Car T Cell Therapymentioning

confidence: 99%

Novel CAR T therapy is a ray of hope in the treatment of seriously ill AML patients

et al. 2021

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Acute myeloid leukemia (AML) is a serious, life-threatening, and hardly curable hematological malignancy that affects the myeloid cell progenies and challenges patients of all ages but mostly occurs in adults. Although several therapies are available including chemotherapy, allogeneic hematopoietic stem cell transplantation (alloHSCT), and receptor-antagonist drugs, the 5-year survival of patients is quietly disappointing, less than 30%. alloHSCT is the major curative approach for AML with promising results but the treatment has severe adverse effects such as graft-versus-host disease (GVHD). Therefore, as an alternative, more efficient and less harmful immunotherapy-based approaches such as the adoptive transferring T cell therapy are in development for the treatment of AML. As such, chimeric antigen receptor (CAR) T cells are engineered T cells which have been developed in recent years as a breakthrough in cancer therapy. Interestingly, CAR T cells are effective against both solid tumors and hematological cancers such as AML. Gradually, CAR T cell therapy found its way into cancer therapy and was widely used for the treatment of hematologic malignancies with successful results particularly with somewhat better results in hematological cancer in comparison to solid tumors. The AML is generally fatal, therapy-resistant, and sometimes refractory disease with a disappointing low survival rate and weak prognosis. The 5-year survival rate for AML is only about 30%. However, the survival rate seems to be age-dependent. Novel CAR T cell therapy is a light at the end of the tunnel. The CD19 is an important target antigen in AML and lymphoma and the CAR T cells are engineered to target the CD19. In addition, a lot of research goes on the discovery of novel target antigens with therapeutic efficacy and utilizable for generating CAR T cells against various types of cancers. In recent years, many pieces of research on screening and identification of novel AML antigen targets with the goal of generation of effective anti-cancer CAR T cells have led to new therapies with strong cytotoxicity against cancerous cells and impressive clinical outcomes. Also, more recently, an improved version of CAR T cells which were called modified or smartly reprogrammed CAR T cells has been designed with less unwelcome effects, less toxicity against normal cells, more safety, more specificity, longer persistence, and proliferation capability. The purpose of this review is to discuss and explain the most recent advances in CAR T cell-based therapies targeting AML antigens and review the results of preclinical and clinical trials. Moreover, we will criticize the clinical challenges, side effects, and the different strategies for CAR T cell therapy.

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Section: Car T Cell Therapymentioning

confidence: 99%

Novel CAR T therapy is a ray of hope in the treatment of seriously ill AML patients

et al. 2021

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“…In recent years, CAR-T cell immunotherapy has revealed promising therapeutic manifestation in a series of hematologic malignancies, yet also with considerable drawbacks and limitations in metastatic solid tumor management as well (Fig. 4 , Table 2 ) [ 55 , 134 ]. Considering the intrinsic and advantaged properties, including substantially cytolytic ability, non-MHC-restricted recognition, natural infiltration in tumor tissues and convenience for their preparation as well as minimal untoward effects (e.g., CRS, GvHD and neurotoxicity), engineered CAR-NK cells are supposed as promising therapeutic option for solid tumor administration in clinical practice [ 54 , 134 , 135 ].…”

Section: Car-nks In Cancer Immunotherapymentioning

confidence: 99%

“…4 , Table 2 ) [ 55 , 134 ]. Considering the intrinsic and advantaged properties, including substantially cytolytic ability, non-MHC-restricted recognition, natural infiltration in tumor tissues and convenience for their preparation as well as minimal untoward effects (e.g., CRS, GvHD and neurotoxicity), engineered CAR-NK cells are supposed as promising therapeutic option for solid tumor administration in clinical practice [ 54 , 134 , 135 ]. Currently, CAR-NK cells have been preclinically tested in multiple solid tumors including breast cancer, ovarian cancer, pancreatic cancer, colon cancer, glioblastoma, hepatocellular carcinoma, head and neck squamous cell carcinoma (HNSCC) [ 90 , 117 , 136 , 137 ].…”

Section: Car-nks In Cancer Immunotherapymentioning

confidence: 99%

CAR-NK cells for cancer immunotherapy: from bench to bedside

et al. 2022

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Natural killer (NK) cells are unique innate immune cells and manifest rapid and potent cytotoxicity for cancer immunotherapy and pathogen removal without the requirement of prior sensitization or recognition of peptide antigens. Distinguish from the T lymphocyte-based cythotherapy with toxic side effects, chimeric antigen receptor-transduced NK (CAR-NK) cells are adequate to simultaneously improve efficacy and control adverse effects including acute cytokine release syndrome (CRS), neurotoxicity and graft-versus-host disease (GVHD). Moreover, considering the inherent properties of NK cells, the CAR-NK cells are “off-the-shelf” product satisfying the clinical demand for large-scale manufacture for cancer immunotherapy attribute to the cytotoxic effect via both NK cell receptor-dependent and CAR-dependent signaling cascades. In this review, we mainly focus on the latest updates of CAR-NK cell-based tactics, together with the opportunities and challenges for cancer immunotherapies, which represent the paradigm for boosting the immune system to enhance antitumor responses and ultimately eliminate malignancies. Collectively, we summarize and highlight the auspicious improvement in CAR-NK cells and will benefit the large-scale preclinical and clinical investigations in adoptive immunotherapy.

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“…For instance, the T-box transcription factors in NK cells have been shown to be key for NK cell function and development, and several reports thus far have suggested their expression levels to be dysregulated in exhausted NK cells. Given that significant progress has been made in developing drugs to target transcription factors ( 150 ), further study on how these transcription factors are precisely regulated by the TME may open up a new avenue of treatment to restore NK cells to their full cytotoxic capacity. To this end, whether and how transcriptional signals can be desensitized for ‘self-tolerance’ in response to persistent stimulation by cancer cells, could be addressed.…”

Section: Looking Beyond Targeting Nk Cell Receptors For Therapeutic Advancesmentioning

confidence: 99%

NK Cells in a Tug-of-War With Cancer: The Roles of Transcription Factors and Cytoskeleton

2021

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Natural killer (NK) cells are innate immune cells which play a key role in shaping the immune response against cancer. Initially hailed for their potential to recognise and eliminate tumour cells, their application has been greatly hindered by the immunosuppressive tumour microenvironment (TME) which suppresses NK functions (e.g., cytotoxicity). This dysfunctional state that is accompanied by phenotypic changes such as upregulation of inhibitory receptors and downregulation of activating receptors, forms the basis of what many researchers have referred to as ‘exhausted’ NK cells. However, there is no consensus on whether these phenotypes are sufficient to define an exhausted state of the NK cell. While recent advances in checkpoint inhibition appear to show promise in early-stage pre-clinical studies, much remains to be fully explored and understood in the context of the TME. The TME is where the NK cells are subjected to interaction with various cell types and soluble factors, which could exert an inhibitory effect on NK cytotoxicity. In this review, we provide an overview of the general markers of NK cell exhaustion viz, the surface activating and inhibitory receptors. We also highlight the potential role of T-box transcription factors in characterising such a dysfunctional state and discuss the often-overlooked mechanism of cell cytoskeletal dynamics in regulating NK cell function. These aspects may further contribute to NK exhaustion or NK revival in cancer and may open new avenues to explore cancer treatment strategies.

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Renaissance of armored immune effector cells, CAR-NK cells, brings the higher hope for successful cancer therapy

Cited by 32 publications

References 195 publications

Novel CAR T therapy is a ray of hope in the treatment of seriously ill AML patients

Novel CAR T therapy is a ray of hope in the treatment of seriously ill AML patients

CAR-NK cells for cancer immunotherapy: from bench to bedside

NK Cells in a Tug-of-War With Cancer: The Roles of Transcription Factors and Cytoskeleton

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