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1.
Article in Chinese | WPRIM | ID: wpr-880128

ABSTRACT

B-cell acute lymphoblastic leukemia (B-ALL) is a common malignant tumor in hematopoietic system. Although the remission rate of the patients with adult B-ALL is similar to those with childhood B-ALL, the rate of long-term disease-free survival (DFS) rate is significantly lower, once recurrence, the remission rate of routine chemotherapy is low and the prognosis is so poor. Based on the expression of tumor cell surface antigens(such as CD19, CD20 and CD22), the specific monoclonal antibodies, bispecific antibodies and chimeric antigen receptor T cells (CAR-T), and other targeted immunotherapy can greatly improve the efficacy of B-ALL patients, especially for patients with relapse and refractory. In this review, the progress of immunotherapy against B-ALL cell surface antigen is summarized briefly.


Subject(s)
Adult , Antigens, CD19 , Antigens, Surface , B-Lymphocytes , Burkitt Lymphoma , Child , Humans , Immunotherapy, Adoptive , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Receptors, Antigen, T-Cell
2.
Article in Chinese | WPRIM | ID: wpr-880069

ABSTRACT

T lymphoid malignancy is a group of highly heterogeneous hematological tumors. Disease recurrence and resistance to therapy are the common causes of failed treatment. Traditional therapy is radiotherapy and chemotherapy, although it has achieved great success. However, many patients still failed to survive following the treatment. With the introduction of monoclonal antibodies, immunotherapy and cellular therapy into clinical practice, the outcome of hematologic malignancies has been significantly improved. In particular, chimeric antigen receptor T cells (CAR-T) showed high efficacy in treating B-cell lymphoma and acute B lymphocytic leukemia and surpassed any previous therapeutic strategies. However, this treatment seldom succeeded in treating T cell malignancies. In this review, the history of CAR-T cells treating T cell malignancies, and the clinical trials, adverse events of previously reported were summarized briefly.


Subject(s)
Humans , Immunotherapy , Immunotherapy, Adoptive , Receptors, Antigen, T-Cell , Receptors, Chimeric Antigen , T-Lymphocytes
3.
Rev. méd. Minas Gerais ; 31: 31209, 2021.
Article in Portuguese | LILACS | ID: biblio-1292752

ABSTRACT

Introdução: O tratamento da leucemia linfoblástica aguda (LLA) atualmente baseia-se em quimioterapia e/ou transplante de células tronco hematopoiéticas; entretanto, uma nova terapia vem se tornando promissora: a imunoterapia com células T modificadas geneticamente que expressam um receptor de antígeno quimérico (CAR-T) visando antígenos específicos presente em blastos de LLA, gerando resultados promissores em crianças e adultos com doença recidivada e refratária (r/r). Objetivo: Discorrer sobre a LLA e descrever a imunoterapia com CAR-T, como inovação terapêutica no tratamento da LLA de linhagem B. Método: Foi realizada uma revisão bibliográfica por meio de publicações indexadas nas bases de dados Scielo e Pubmed, utilizando os descritores: leucemia linfoblástica aguda de células B; células CAR-T; receptores de antígeno quimérico, recidivados/refratários; imunoterapia. Resultados: As altas taxas de remissão completa (42% até 100%) e parcial (28,5%) da LLA (r/r) tratadas com CAR-T, possibilitam um aumento considerável da sobrevida geral comparado a outros tratamentos convencionais. Efeitos desfavoráveis, tais como síndrome da liberação de citocinas (CRS) (0 até 90%) e neurotoxicidade (NT) (0 até 29%) podem ser vistos, sendo manejáveis, não prejudicando o desfecho do tratamento. Conclusão: A LLA é uma doença grave, de difícil tratamento e prognóstico reservado. A imunoterapia vêm se mostrando promissora à essa enfermidade, principalmente em casos de doença r/r se mostrado uma ferramenta poderosa que permite o foco específico de células malignas por meio de engenharia de células T


Introduction: The treatment of acute lymphoblastic leukemia (ALL) is currently based on chemotherapy and/or hematopoietic stem cell transplantation; however, a new therapy is becoming promising: immunotherapy with genetically modified T cells that express a chimeric antigen receptor (CAR-T) targeting specific antigens present on ALL blasts, reaching promising results in children and adults with relapsed and refractory disease (r/r). Objective: To discuss ALL and describe immunotherapy with CAR-T as a therapeutic innovation in the treatment of B-lineage ALL. Method: A literature review was carried out through publications indexed in the Scielo and Pubmed databases, using the following descriptors: B-cell acute lymphoblastic leukemia; CAR-T cells; chimeric antigen receptors, relapsed/refractory; immunotherapy. Results: The high rates of complete (42% to 100%) and partial remission (28.5%) of ALL (r/r) treated with CAR-T allows a considerable increase in overall survival compared to other conventional treatments. Unfavorable effects such as cytokine release syndrome (CRS) (0 to 90%) and neurotoxicity (NT) (0 to 29%) can be seen, being manageable, not impairing the treatment outcome. Conclusion: ALL is a serious disease, with a difficult treatment and poor prognosis. Immunotherapy has shown benefits for this disease, especially in cases of r/r ALL, showing itself to be a powerful tool that allows the specific focus of malignant cells through T cell engineering.


Subject(s)
Humans , Child , Adult , Leukemia/therapy , Receptors, Chimeric Antigen , Immunotherapy , Neprilysin , Immunotherapy, Adoptive , Hematopoietic Stem Cell Transplantation , Cytokine Release Syndrome
4.
Frontiers of Medicine ; (4): 701-710, 2020.
Article in English | WPRIM | ID: wpr-880968

ABSTRACT

Chimeric antigen receptor T cell (CAR T) therapies have achieved unprecedented efficacy in B-cell tumors, prompting scientists and doctors to exploit this strategy to treat other tumor types. Acute myeloid leukemia (AML) is a group of heterogeneous myeloid malignancies. Relapse remains the main cause of treatment failure, especially for patients with intermediate or high risk stratification. Allogeneic hematopoietic stem cell transplantation could be an effective therapy because of the graft-versus-leukemia effect, which unfortunately puts the patient at risk of serious complications, such as graft-versus-host disease. Although the identification of an ideal target antigen for AML is challenging, CAR T therapy remains a highly promising strategy for AML patients, particularly for those who are ineligible to receive a transplantation or have positive minimal residual disease. In this review, we focus on the most recent and promising advances in CAR T therapies for AML.


Subject(s)
Hematopoietic Stem Cell Transplantation , Humans , Immunotherapy, Adoptive , Leukemia, Myeloid, Acute/therapy , Receptors, Chimeric Antigen , T-Lymphocytes
5.
Frontiers of Medicine ; (4): 711-725, 2020.
Article in English | WPRIM | ID: wpr-880967

ABSTRACT

The combination of the immunotherapy (i.e., the use of monoclonal antibodies) and the conventional chemotherapy increases the long-term survival of patients with lymphoma. However, for patients with relapsed or treatment-resistant lymphoma, a novel treatment approach is urgently needed. Chimeric antigen receptor T (CAR-T) cells were introduced as a treatment for these patients. Based on recent clinical data, approximately 50% of patients with relapsed or refractory B-cell lymphoma achieved complete remission after receiving the CD19 CAR-T cell therapy. Moreover, clinical data revealed that some patients remained in remission for more than two years after the CAR-T cell therapy. Other than the CD19-targeted CAR-T, the novel target antigens, such as CD20, CD22, CD30, and CD37, which were greatly expressed on lymphoma cells, were studied under preclinical and clinical evaluations for use in the treatment of lymphoma. Nonetheless, the CAR-T therapy was usually associated with potentially lethal adverse effects, such as the cytokine release syndrome and the neurotoxicity. Therefore, optimizing the structure of CAR, creating new drugs, and combining CAR-T cell therapy with stem cell transplantation are potential solutions to increase the effectiveness of treatment and reduce the toxicity in patients with lymphoma after the CAR-T cell therapy.


Subject(s)
Cell- and Tissue-Based Therapy , Humans , Immunotherapy, Adoptive , Lymphoma/therapy , Receptors, Antigen, T-Cell , Receptors, Chimeric Antigen
6.
Frontiers of Medicine ; (4): 726-745, 2020.
Article in English | WPRIM | ID: wpr-880949

ABSTRACT

Chimeric antigen receptor (CAR) T cells have been indicated effective in treating B cell acute lymphoblastic leukemia and non-Hodgkin lymphoma and have shown encouraging results in preclinical and clinical studies. However, CAR T cells have achieved minimal success against solid malignancies because of the additional obstacles of their insufficient migration into tumors and poor amplification and persistence, in addition to antigen-negative relapse and an immunosuppressive microenvironment. Various preclinical studies are exploring strategies to overcome the above challenges. Mobilization of endogenous immune cells is also necessary for CAR T cells to obtain their optimal therapeutic effect given the importance of the innate immune responses in the elimination of malignant tumors. In this review, we focus on the recent advances in the engineering of CAR T cell therapies to restore the immune response in solid malignancies, especially with CAR T cells acting as cellular carriers to deliver immunomodulators to tumors to mobilize the endogenous immune response. We also explored the sensitizing effects of conventional treatment approaches, such as chemotherapy and radiotherapy, on CAR T cell therapy. Finally, we discuss the combination of CAR T cells with biomaterials or oncolytic viruses to enhance the anti-tumor outcomes of CAR T cell therapies in solid tumors.


Subject(s)
Humans , Immunotherapy, Adoptive , Neoplasms/therapy , T-Lymphocytes , Tumor Microenvironment
7.
Frontiers of Medicine ; (4): 786-791, 2020.
Article in English | WPRIM | ID: wpr-880947

ABSTRACT

Factors associated with complete and durable remissions after anti-CD19 chimeric antigen receptor T (CAR-T) cell immunotherapy for relapsed or refractory non-Hodgkin lymphoma (r/r NHL) have not been well characterized. In this study, we found that the different sites of extranodal involvement may affect response, overall survival (OS), and progression-free survival (PFS) in patients with r/r NHL treated with anti-CD19 CAR-T cells. In a cohort of 32 treated patients, 12 (37.5%) and 8 (25%) patients exhibited soft tissue lymphoma and bone marrow (BM) infiltrations, respectively, and 13 (41%) patients exhibited infiltration at other sites. The factors that may affect prognosis were identified through multivariable analysis. As an independent risk factor, soft tissue infiltration was the only factor significantly correlated with adverse prognosis (P < 0.05), whereas other factors did not reach statistical significance. Furthermore, the site of extranodal tumor infiltration significantly and negatively affected OS and PFS in patients with r/r NHL treated with anti-CD19 CAR-T cell therapy. PFS and OS in patients with BM involvement were not significantly different from those of patients with lymph node involvement alone. Thus, anti-CD19 CAR-T cell therapy may improve the prognosis of patients with BM infiltration.


Subject(s)
Cell- and Tissue-Based Therapy , Humans , Immunotherapy, Adoptive , Lymphoma, Non-Hodgkin/therapy , Receptors, Antigen, T-Cell , Receptors, Chimeric Antigen
8.
Frontiers of Medicine ; (4): 811-815, 2020.
Article in English | WPRIM | ID: wpr-880944

ABSTRACT

Mantle cell lymphoma (MCL) is a distinct histological type of B-cell lymphoma with a poor prognosis. Several agents, such as proteasome inhibitors, immunomodulatory drugs, and inhibitors of B cell lymphoma-2 and Bruton's tyrosine kinase have shown efficacy for relapsed or refractory (r/r) MCL but often have short-term responses. Chimeric antigen receptor (CAR) T-cell therapy has emerged as a novel treatment modality for r/r non-Hodgkin's lymphoma. However, long-term safety and tolerability associated with CAR T-cell therapy are not defined well, especially in MCL. In this report, we described a 70-year-old patient with r/r MCL with 48-month duration of follow-up who achieved long-term remission after CAR T-cell therapy. CAR T-cell-related toxicities were also mild and tolerated well even in this elderly patient. This report suggested that CAR T-cell therapy is a promising treatment modality for patients with MCL, who are generally elderly and have comorbid conditions.


Subject(s)
Adult , Aged , Cell- and Tissue-Based Therapy , Humans , Immunotherapy, Adoptive , Lymphoma, Mantle-Cell/therapy , Neoplasm Recurrence, Local , Receptors, Chimeric Antigen
9.
Journal of Experimental Hematology ; (6): 2089-2092, 2020.
Article in Chinese | WPRIM | ID: wpr-880020

ABSTRACT

Acute myeloid leukemia (AML) is a malignant tumor with abnormal myelocyte differentiation. With the development of immunological technology, great importance has been attached to the immunotherapy of AML patients, which may become an effective treatment strategy for AML, and providing a new means for the prognosis and survival. In this review, the advanced research of immunotherapy for AML, such as antibody-dependent drugs, chimeric antigen receptor T cell therapy, and checkpoint inhibitors, the bastest reaserch advanves of clinical experiment for immunotherapy was summarized briefly.


Subject(s)
Humans , Immunologic Factors , Immunotherapy , Immunotherapy, Adoptive , Leukemia, Myeloid, Acute/therapy , T-Lymphocytes
10.
Journal of Experimental Hematology ; (6): 1069-1074, 2020.
Article in Chinese | WPRIM | ID: wpr-827159

ABSTRACT

Abstract  Acute myeloid leukemia (AML) is a malignant clonal proliferative hematological tumor that originates from hematopoietic stem progenitor cells. Traditional chemotherapy can achieve complete remission in most patients, but so far, only allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only way to cure AML. Recurrence, drug resistance, and transplant-related deaths remain a key issue for AML treatment. Therefore, finding new treatments to improve the prognosis of patients with AML is urgently needed. In recent years, the emergence of new immunotherapy has revolutionized the concept of cancer treatment in the past few decades. Cellular immunotherapy represented by chimeric-antigen receptor T cell (CAR-T) and immunological detection point inhibitor represented by PD-1 blockade have achieved remarkable effects in hematological malignancies. This article mainly reviews the recent research progress of CAR-T and PD-1 blockade in the clinical treatment of AML.


Subject(s)
Hematopoietic Stem Cell Transplantation , Humans , Immunotherapy, Adoptive , Leukemia, Myeloid, Acute , Programmed Cell Death 1 Receptor , Receptors, Chimeric Antigen
11.
Article in Chinese | WPRIM | ID: wpr-771907

ABSTRACT

Currently, the traditional chemotherapeutic drugs for acute myeloid leukemia (AML) showed significant curative efficacy, including the improving long-term prognosis and the life quality of the patients, however the traditional chemotherapeuatic drugs showed the some limitatious in the aspects of enhancing the complete remission rate of newly diagnosed AML patients, overcoming the relapse after remission,as well as the primary and secondary drug-resstance to chemotherapeutics. In order to improve the long-term prognisis of patients, the immuno therapy will the best choice for these patients. This review sammarizes the main current advance of immunotherapy of AML at home and abroad, such as antibody-drug conjugate(ADC), bispecific T cell engager (BiTE), chimeric type of antigen receptor T cell (CAR-T) therapy, checkpoint inhibitors; dendritic cell vaccination and peptide vaccines; natural killer cell (NK) therapy and so on.


Subject(s)
Cancer Vaccines , Humans , Immunotherapy , Immunotherapy, Adoptive , Leukemia, Myeloid, Acute , Therapeutics , T-Lymphocytes
12.
Article in Chinese | WPRIM | ID: wpr-771851

ABSTRACT

OBJECTIVE@#To investigate the safety and clinical efficacy of autologous DC-CIK cells combined with other immune cells for patients with hematological malignancies and analyze patient prognosis.@*METHODS@#50 patients with hematological malignancies who received cellular immunotherapy from September 2014 to April 2016 were retrospectively studied in the First Affiliated Hospital of Xi'an Jiaotong University, 115 cases times of cellular immunotherapy were performed. According to the selected treatment, the patients were divided into the dual cell group (DC-CIK cell treatment) and the multi-cell group (DC-CIK cell combined with other immune cells); According to the treatment course, the patients were divided into the single course group (completed by <3 times) and the multiple course group. The changes of T lymphocyte subsets, blood routine indicators and KPS scores as well as the overall survival time before and after treatment were compared and analyzed.@*RESULTS@#[WTB1]The difference of general conditions before treatment including the number of patients, sex, age, T lymphocyte subsets, blood routine indicators, KPS scores and so on in 2 groups divided according to 2 kinds of treatment methods were not statistically significant, indicating that the 2 groups were comparable. Grouped by selected treatment, the CD4/CD8 ratio, Hb and Plt levels decreased in the dual cell group, compared with those before treatment(P<0.05). The CD3CD4 ratio after treatment in multiple cell group decreased, compared with that before treatment (P<0.05). The 3-year survival rate of patients in dual cell and multiple cell groups was 61.3% vs 69.8%, the overall survival time of patients in 2 groups was 32.4 months vs 39.6 months, there were no statisticall differences between 2 groups(P>0.05). Grouped by treatment course, the CD3 ratio after treatment increased, while the Hb level after treatment decreased in single course group, compared with level before treatment(P<0.05). The CD3CD4 ratio, Plt level decreased, while the KPS scores increased after treatment in multiple course group, compared with those before treatment(P<0.05). The 3-year survival rate in single course and multiple course groups was 52% vs 76.4%, the overall survival time was 28.7 months vs 40.9 months respectively, statistically significant with difference (P<0.05).@*CONCLUSION@#Autologous DC-CIK cells combined with other immune cells in the treatment of hematological malignancies can change the immune function of the patients and improve the antitumor activity. The multi-course treatment can improve the quality of life, prolong the overall survival time, thus worthing clinical promotion.


Subject(s)
Cytokine-Induced Killer Cells , Dendritic Cells , Hematologic Neoplasms , Humans , Immunotherapy, Adoptive , Quality of Life , Retrospective Studies , Treatment Outcome
13.
Chinese Journal of Biotechnology ; (12): 2339-2349, 2019.
Article in Chinese | WPRIM | ID: wpr-781634

ABSTRACT

Chimeric antigen receptor T (CAR-T) cell therapy, which adoptively transfers engineered T cells expressing synthetic receptors to target specific antigens, has achieved great clinical success in treating hematological malignancies. Though FDA has approved two CAR-T products, CAR-T therapy can cause some side effects, such as cytokine release syndrome (CRS), neurotoxicity and B cell aplasia. Meanwhile, lacking tumor specific antigen and the suppressive tumor environment limit the efficacy of CAR-T therapy in solid tumor. This review focuses on the structural components, clinical applications and synthetic biology approaches on CAR-T cell design, and summarizes the challenges and perspectives of CAR-T therapy as a revolutionary cancer immunotherapy.


Subject(s)
Cell- and Tissue-Based Therapy , Child , Humans , Immunotherapy , Immunotherapy, Adoptive , Receptors, Antigen, T-Cell , Receptors, Chimeric Antigen , T-Lymphocytes
14.
Journal of Experimental Hematology ; (6): 1311-1315, 2019.
Article in Chinese | WPRIM | ID: wpr-775723

ABSTRACT

Abstract  Double-hit lymphoma (DHL) is a high-grade B-cell lymphoma with MYC and BCL-2/BCL-6 rearrangement, which is a invasive disease with a poor prognosis. FISH is the most important diagnostic method. There is no standard protocol for this disease yet. New therapeutic approaches including targeted therapy,checkpoint inhibitors and chimeric antigen receptor T-cell therapy are changing the paradigm of treatment for DHL. This review summarizes new developments in diagnosis and treatment of double-hit lymphoma.


Subject(s)
Genetic Predisposition to Disease , Humans , Immunotherapy, Adoptive , Lymphoma, B-Cell , Proto-Oncogene Proteins c-bcl-2 , Proto-Oncogene Proteins c-bcl-6 , Proto-Oncogene Proteins c-myc
15.
Journal of Experimental Hematology ; (6): 1316-1320, 2019.
Article in Chinese | WPRIM | ID: wpr-775722

ABSTRACT

Abstract  Chimeric antigen receptor-T cell(CAR-T) is a kind of genetically engineered T cells that can express tumor antigen-specific receptors on its surface, and the modified T cells can be used for cancer therapy through targeting malignant tumor cells with its specific receptor and killing tumor cells with its cytotoxicity. CAR-T has been successfully applied to treat various hematological malignancies, such as ALL, CLL, NHL and MM. It is a feasible treatment for relapsed and refractory multiple myeloma (RRMM). The achievements of CAR-T in clinical trials have been widely reported, which is expected to be a therapy to prolong patients survival. In this review, the clinical application of CAR-T in the treatment of RRMM from the following aspects:different types of CAR-T and its curative efficacy, adverse effects, opportunities and challenges are summarized beriefly.


Subject(s)
Humans , Immunotherapy, Adoptive , Multiple Myeloma , Receptors, Antigen, T-Cell , Receptors, Chimeric Antigen , T-Lymphocytes
16.
Article in English | WPRIM | ID: wpr-772941

ABSTRACT

Chimeric antigen receptor (CAR) T cell therapy has exhibited dramatic anti-tumor efficacy in clinical trials. In this study, we reported the transcriptome profiles of bone marrow cells in four B cell acute lymphoblastic leukemia (B-ALL) patients before and after CD19-specific CAR-T therapy. CD19-CAR-T therapy remarkably reduced the number of leukemia cells, and three patients achieved bone marrow remission (minimal residual disease negative). The efficacy of CD19-CAR-T therapy on B-ALL was positively correlated with the abundance of CAR and immune cell subpopulations, e.g., CD8 T cells and natural killer (NK) cells, in the bone marrow. Additionally, CD19-CAR-T therapy mainly influenced the expression of genes linked to cell cycle and immune response pathways, including the NK cell mediated cytotoxicity and NOD-like receptor signaling pathways. The regulatory network analyses revealed that microRNAs (e.g., miR-148a-3p and miR-375), acting as oncogenes or tumor suppressors, could regulate the crosstalk between the genes encoding transcription factors (TFs; e.g., JUN and FOS) and histones (e.g., HIST1H4A and HIST2H4A) involved in CD19-CAR-T therapy. Furthermore, many long non-coding RNAs showed a high degree of co-expression with TFs or histones (e.g., FOS and HIST1H4B) and were associated with immune processes. These transcriptome analyses provided important clues for further understanding the gene expression and related mechanisms underlying the efficacy of CAR-T immunotherapy.


Subject(s)
Adult , Antigens, CD19 , Metabolism , Bone Marrow , Metabolism , CD8-Positive T-Lymphocytes , Allergy and Immunology , Female , Gene Expression Regulation, Leukemic , Gene Regulatory Networks , Humans , Immunotherapy, Adoptive , Male , MicroRNAs , Genetics , Metabolism , Middle Aged , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Genetics , Allergy and Immunology , Therapeutics , RNA, Long Noncoding , Genetics , Metabolism , Receptors, Antigen, T-Cell , Transcription Factors , Metabolism , Transcriptome , Genetics
17.
Frontiers of Medicine ; (4): 3-11, 2019.
Article in English | WPRIM | ID: wpr-771266

ABSTRACT

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. This malignancy is associated with poor prognosis and high mortality. Novel approaches for prolonging the overall survival of patients with advanced HCC are urgently needed. The antitumor activities of adoptive cell transfer therapy (ACT), such as strategies based on tumor-infiltrating lymphocytes and cytokine-induced killer cells, are more effective than those of traditional strategies. Currently, chimeric antigen receptor T-cell (CAR-T) immunotherapy has achieved numerous breakthroughs in the treatment of hematological malignancies, including relapsed or refractory lymphoblastic leukemia and refractory large B-cell lymphoma. Nevertheless, this approach only provides a modest benefit in the treatment of solid tumors. The clinical results of CAR-T immunotherapy for HCC that could be obtained at present are limited. Some published studies have demonstrated that CAR-T could inhibit tumor growth and cause severe side effects. In this review, we summarized the current application of ACT, the challenges encountered by CAR-T technology in HCC treatment, and some possible strategies for the future direction of immunotherapeutic research.


Subject(s)
Adoptive Transfer , Methods , Carcinoma, Hepatocellular , Allergy and Immunology , Therapeutics , Humans , Immunotherapy, Adoptive , Methods , Liver Neoplasms , Allergy and Immunology , Therapeutics , Lymphocytes, Tumor-Infiltrating , Cell Biology , Randomized Controlled Trials as Topic , Receptors, Chimeric Antigen , T-Lymphocytes , Cell Biology
18.
Frontiers of Medicine ; (4): 57-68, 2019.
Article in English | WPRIM | ID: wpr-771260

ABSTRACT

Lung cancer is the most common incident cancer and the leading cause of cancer death. In recent years, the development of tumor immunotherapy especially chimeric antigen receptor T (CAR-T) cell has shown a promising future. Epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific mutation expressed in various types of tumors and has been detected in non-small cell lung cancer with a mutation rate of 10%. Thus, EGFRvIII is a potential antigen for targeted lung cancer therapy. In this study, CAR vectors were constructed and transfected into virus-packaging cells. Then, activated T cells were infected with retrovirus harvested from stable virus-producing single clone cell lines. CAR expression on the surfaces of the T cells was detected by flow cytometry and Western blot. The function of CAR-T targeting EGFRvIII was then evaluated. The EGFRvIII-CAR vector was successfully constructed and confirmed by DNA sequencing. A stable virus-producing cell line was produced from a single clone by limited dilution. The culture conditions for the cell line, including cell density, temperature, and culture medium were optimized. After infection with retrovirus, CAR was expressed on more than 90% of the T cells. The proliferation of CAR-T cells were induced by cytokine and specific antigen in vitro. More importantly, EGFRvIII-CART specifically and efficiently recognized and killed A549-EGFRvIII cells with an effector/target ratio of 10:1 by expressing and releasing cytokines, including perforin, granzyme B, IFN-γ, and TNF-α. The in vivo study indicated that the metastasis of A549-EGFRvIII cells in mice were inhibited by EGFRvIII-CART cells, and the survival of the mice was significantly prolonged with no serious side effects. EGFRvIII-CART showed significantly efficient antitumor activity against lung cancer cells expressing EGFRvIII in vivo and in vitro. Therefore, CAR-T targeting EGFRvIII is a potential therapeutic strategy in preventing recurrence and metastasis of lung cancer after surgery.


Subject(s)
Animals , Carcinoma, Non-Small-Cell Lung , Allergy and Immunology , Therapeutics , Cell Line, Tumor , ErbB Receptors , Allergy and Immunology , Metabolism , Female , Humans , Immunotherapy, Adoptive , Methods , Lung Neoplasms , Allergy and Immunology , Therapeutics , Mice , Mice, Inbred NOD , Receptors, Chimeric Antigen , Allergy and Immunology , T-Lymphocytes , Allergy and Immunology , Xenograft Model Antitumor Assays
19.
Frontiers of Medicine ; (4): 69-82, 2019.
Article in English | WPRIM | ID: wpr-771259

ABSTRACT

Cytokine-activated T cells (CATs) can be easily expanded and are widely applied to cancer immunotherapy. However, the good efficacy of CATs is rarely reported in clinical applications because CATs have no or very low antigen specificity. The low-efficacy problem can be resolved using T cell antigen receptor-engineered CAT (TCR-CAT). Herein, we demonstrate that NY-ESO-1 HLA-A*02:01-specific high-affinity TCR (HAT)-transduced CATs can specifically kill cancer cells with good efficacy. With low micromolar range dissociation equilibrium constants, HAT-transduced CATs showed good specificity with no off-target killing. Furthermore, the high-affinity TCR-CATs delivered significantly better activation and cytotoxicity than the equivalent TCR-engineered T cells (TCR-Ts) in terms of interferon-γ and granzyme B production and in vitro cancer cell killing ability. TCR-CAT may be a very good alternative to the expensive TCR-T, which is considered an effective personalized cyto-immunotherapy.


Subject(s)
Cell Line, Tumor , Cytokines , Metabolism , Cytotoxicity, Immunologic , Genetic Engineering , HLA-A2 Antigen , Metabolism , Humans , Immunotherapy, Adoptive , Methods , Lymphocyte Activation , Receptors, Antigen, T-Cell , Genetics , Allergy and Immunology , T-Lymphocytes , Allergy and Immunology
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