Objective: Cytokine release syndrome (CRS) and tumor lysis syndrome (TLS) that occur after chimeric antigen receptor T (CAR-T) cells are reinfused, which severely affect the survival and prognosis of patients. Althoug...Objective: Cytokine release syndrome (CRS) and tumor lysis syndrome (TLS) that occur after chimeric antigen receptor T (CAR-T) cells are reinfused, which severely affect the survival and prognosis of patients. Although several articles have reported on the care of CAR-T cell immunotherapy, the quality of the study and the effectiveness of holistic nursing interventions have not been systematically reviewed. The purpose of this study was to systematically evaluate the existing holistic nursing interventions of CAR-T cell immunotherapy. Methods: A literature search for keywords was performed in PubMed, EMBASE, the Cochrane Library, CNKI, CBM, and Wanfang Data from its inception until January 2018. Studies were deemed eligible if they comprised patients with tumor receiving CAR-T cell immunotherapy, described the holistic nursing process, and were published in Chinese and English. Results: A total of 6 articles on holistic nursing interventions of CAR-T cell immunotherapy are reported, and the nursing methods and results of each article are analyzed. The quality of the studies included was medium. All nursing measures were considered effective. Conclusions: Holistic nursing programs reduce the incidence of CRS and TLS and improve the quality of life of cancer patients.展开更多
Relapses remain a major concern in acute leukemia. It is well known that leukemia stem cells(LSCs) hide in hematopoietic niches and escape to the immune system surveillance through the outgrowth of poorly immunogenic ...Relapses remain a major concern in acute leukemia. It is well known that leukemia stem cells(LSCs) hide in hematopoietic niches and escape to the immune system surveillance through the outgrowth of poorly immunogenic tumor-cell variants and the suppression of the active immune response. Despitethe introduction of new reagents and new therapeutic approaches, no treatment strategies have been able to definitively eradicate LSCs. However, recent adoptive immunotherapy in cancer is expected to revolutionize our way to fight against this disease, by redirecting the immune system in order to eliminate relapse issues. Initially described at the onset of the 90's, chimeric antigen receptors(CARs) are recombinant receptors transferred in various T cell subsets, providing specific antigens binding in a non-major histocompatibility complex restricted manner, and effective on a large variety of human leukocyte antigen-divers cell populations. Once transferred, engineered T cells act like an expanding "living drug" specifically targeting the tumor-associated antigen, and ensure long-term antitumor memory. Over the last decades, substantial improvements have been made in CARs design. CAR T cells have finally reached the clinical practice and first clinical trials have shown promising results. In acute lymphoblastic leukemia, high rate of complete and prolonged clinical responses have been observed after anti-CD19 CAR T cell therapy, with specific but manageable adverse events. In this review, our goal was to describe CAR structures and functions, and to summarize recent data regarding pre-clinical studies and clinical trials in acute leukemia.展开更多
Background: Chimeric antigen receptor-engineered T-cell(CAR-T) therapy is a newly developed immunotherapy used in the treatment of cancers. Because CAR-T therapy has shown great success in treating CD19-positive hemat...Background: Chimeric antigen receptor-engineered T-cell(CAR-T) therapy is a newly developed immunotherapy used in the treatment of cancers. Because CAR-T therapy has shown great success in treating CD19-positive hematological malignancies, its application has been explored in the treatment of solid tumors, such as liver cancer. In this review, we discuss the immune characteristics of liver cancer, the obstacles encountered during the application of CAR-T therapy, and preclinical and clinical progress in the use of CAR-T therapy in patients with liver cancer.Data sources: The data on CAR-T therapy related to liver cancers were collected by searching Pub Med and the Web of Science databases prior to December 2017 with the keywords "chimeric antigen receptor","CAR-T", "liver cancer", "hepatocellular carcinoma", and "solid tumor". Additional articles were identified by manual search of references found in the primary articles. The data for clinical trials were collected by searching Clinical Trials.gov.Results: The liver has a tolerogenic nature in the intrahepatic milieu and its tumor microenvironment significantly affects tumor progression. The obstacles that reduce the efficacy of CAR-T therapy in solid tumors include a lack of specific tumor antigens, limited trafficking and penetration of CAR-T cells to tumor sites, and an immunosuppressive tumor microenvironment. To overcome these obstacles, several strategies have emerged. In addition, several strategies have been developed to manage the side effects of CAR-T, including enhancing the selectivity of CARs and controlling CAR-T activity. To date, no clinical trials of CAR-T therapy against HCC have been completed. However, preclinical studies in vitro and in vivo have shown potent antitumor efficacy. Glypican-3, mucin-1, epithelial cell adhesion molecule, carcinoembryonic antigen, and other targets are currently being studied.Conclusions: The application of CAR-T therapy for liver cancer is just beginning to be explored and more research is needed. However, we are optimistic that CAR-T therapy will offer a new approach for the treatment of liver cancers in the future.展开更多
With the advance of genome engineering technology,chimeric antigen receptors(CARs)-based immunotherapy has become an emerging therapeutic strategy for tumors.Although initially designed for T cells in tumor immunother...With the advance of genome engineering technology,chimeric antigen receptors(CARs)-based immunotherapy has become an emerging therapeutic strategy for tumors.Although initially designed for T cells in tumor immunotherapy,CARs have been exploited to modify the function of natural killer(NK)cells against a variety of tumors,including hepatocellular carcinoma(HCC).CAR-NK cells have the potential to sufficiently kill tumor antigen-expressing HCC cells,independent of major histocompatibility complex matching or prior priming.In this review,we summarize the recent advances in genetic engineering of CAR-NK cells against HCC and discuss the current challenges and prospects of CAR-NK cells as a revolutionary cellular immunotherapy against HCC.展开更多
The adoptive transfer of T cells is a promising approach to treat cancers. Primary human T cells can be modified using viral and non-viral vectors to promote the specific targeting of cancer cells via the introduction...The adoptive transfer of T cells is a promising approach to treat cancers. Primary human T cells can be modified using viral and non-viral vectors to promote the specific targeting of cancer cells via the introduction of exogenous T-cell receptors(TCRs) or chimeric antigen receptors(CARs). This gene transfer displays the potential to increase the specificity and potency of the anticancer response while decreasing the systemic adverse effects that arise from conventional treatments that target both cancerous and healthy cells. This review highlights the generation of clinical-grade T cells expressing CARs for immunotherapy, the use of these cells to target B-cell malignancies and, particularly, the first clinical trials deploying the Sleeping Beauty gene transfer system, which engineers T cells to target CD19+ leukemia and non-Hodgkin's lymphoma.展开更多
BACKGROUND Chimeric antigen receptor T-Cell(CAR-T)therapy is an effective new treatment for hematologic malignancies.Cytokine release syndrome(CRS)and neurologic toxicity are main toxicities.CRS-induced rhabdomyolysis...BACKGROUND Chimeric antigen receptor T-Cell(CAR-T)therapy is an effective new treatment for hematologic malignancies.Cytokine release syndrome(CRS)and neurologic toxicity are main toxicities.CRS-induced rhabdomyolysis(RM)followed by CART therapy treatment has not been previously reported.CASE SUMMARY We report a case of a 22-year-old woman with relapsed acute lymphoblastic leukemia obtained sequential cluster of differentiation(CD)19 and CD22 CAR-T infusion.This patient experienced grade 3 CRS with RM,mild hypotension requiring intravenous fluids,and mild hypoxia and was managed effectively with the IL-6 receptor antagonist tocilizumab.This patient had no signs of immune effector cell-associated neurologic syndrome.Restaging scans 30 d postCAR-T therapy demonstrated a complete remission,and the symptoms of muscle weakness improved through rehabilitation.CONCLUSION Myalgia is an easily overlooked symptom of severe CRS after CAR-T therapy.It is necessary to monitor myoglobin levels when a patient presents with symptoms of myalgia or acute renal insufficiency.展开更多
BACKGROUND Diffuse large B-cell lymphoma(DLBCL)is curable with first-line chemoimmunotherapy but patients with relapsed/refractory(R/R)DLBCL still face a poor prognosis.For patients with R/R DLBCL,the complete respons...BACKGROUND Diffuse large B-cell lymphoma(DLBCL)is curable with first-line chemoimmunotherapy but patients with relapsed/refractory(R/R)DLBCL still face a poor prognosis.For patients with R/R DLBCL,the complete response rate to traditional next-line therapy is only 7%and the median overall survival is 6.3 mo.Recently,CD19-targeting chimeric antigen receptor T cells(CAR-T)have shown promise in clinical trials.However,approximately 50%of patients treated with CAR-T cells ultimately progress and few salvage therapies are effective.CASE SUMMARY Here,we report on 7 patients with R/R DLBCL whose disease progressed after CAR-T infusion.They received a PD-1 inhibitor(sintilimab)and a histone deacetylase inhibitor(chidamide).Five of the 7 patients tolerated the treatment without any serious adverse events.Two patients discontinued the treatment due to lung infection and rash.At the 20-mo follow-up,the median overall survival of these 7 patients was 6 mo.Of note,there were 2 complete response rates(CRs)and 2 partial response rates(PRs)during this novel therapy,with an overall response rate(ORR)of 57.1%,and one patient had a durable CR that lasted at least 20 mo.CONCLUSION In conclusion,chidamide combined with sintilimab may be a choice for DLBCL patients progressing after CD19-targeting CAR-T therapy.展开更多
Chimeric antigen receptors (CARs) are fusion molecules that may be genetically delivered ex-vivo to T-cells and other immune cell populations, thereby conferring specifcity for native target antigens found on the s...Chimeric antigen receptors (CARs) are fusion molecules that may be genetically delivered ex-vivo to T-cells and other immune cell populations, thereby conferring specifcity for native target antigens found on the surface of tumour and other target cell types. Antigen recognition by CARs is neither restricted by nor dependent upon human leukocyte antigen antigen expression, favouring widespread use of this technology across transplantation barriers. Signalling is delivered by a designer endodomain that provides a tailored and target-dependent activation signal to polyclonal circulating T-cells. Recent clinical data emphasise the enormous promise of this emer-ging immunotherapeutic strategy for B-cell malignancy, notably acute lymphoblastic leukaemia. In that context, CARs are generally targeted against the ubiquitous B-cell antigen, CD19. However, CAR T-cell immunotherapy is limited by potential for severe ontarget toxicity, notably due to cytokine release syndrome. Furthermore, effcacy in the context of solid tumours remains unproven, owing in part to lack of availability of safe tumourspecific targets, inadequate CAR T-cell homing and hostility of the tumour microenvironment to immune effector deployment. Manufacture and commercial development encountered with more traditional drug products. Finally, there is increasing interest in the application of this technology to the treatment of non-malignant disease states, such as autoimmunity, chronic infection and in the suppression of allograft rejection. Here, we consider the background and direction of travel of this emerging and highly promising treatment for malignant and other disease types.展开更多
Natural killer (NK) cells are key innate immune cells that provide the first line of defense against viral infection and cancer. Although NK cells can discriminate between "self" and "non-self," re...Natural killer (NK) cells are key innate immune cells that provide the first line of defense against viral infection and cancer. Although NK cells can discriminate between "self" and "non-self," recognize abnormal cells, and eliminate transformed cells and malignancies in real time, tumors develop several strategies to escape from NK cell attack. These strategies include upregulating ligands for the inhibitory receptors of NK cells and producing soluble molecules or immunosuppressive factors. Various types of NK cells are currently being applied in clinical trials, including autologous or allogeneic NK cells, umbilical cord blood (UCB) or induced pluripotent stem cell (iPSC)-derived NK cells, memory-like NK cells, and NK cell line NK-92 cells, for the treatment of different types of tumors. Chimeric antigen receptors (CARs)-NK cells have recently shown great potential due to their redirect specificity and effective antitumor activity. In this review, we summarize the mechanisms of tumor escape from NK cell recognition, the current status and advanced progress of NK cell-based immunotherapy, ways of enhancing the antitumor capacity of NK cells in vivo, and major challenges for clinical practice in this field.展开更多
Neoantigen-targeted immunotherapy is a rapidly advancing field that holds great promise for treating cancer.The recognition of antigens by immune cells is a crucial step in tumor-specific killing,and neoantigens gener...Neoantigen-targeted immunotherapy is a rapidly advancing field that holds great promise for treating cancer.The recognition of antigens by immune cells is a crucial step in tumor-specific killing,and neoantigens generated by mutations in cancer cells possess high immunogenicity and are selectively expressed in tumor cells,making them an attractive therapeutic target.Currently,neoantigens find utility in various domains,primarily in the realm of neoantigen vaccines such as DC vaccines,nucleic acid vaccines,and synthetic long peptide vaccines.Additionally,they hold promise in adoptive cell therapy,encompassing tumor-infiltrating cells,T cell receptors,and chimeric antigen receptors which are expressed by genetically modified T cells.In this review,we summarized recent progress in the clinical use of tumor vaccines and adoptive cell therapy targeting neoantigens,discussed the potential of neoantigen burden as an immune checkpoint in clinical settings.With the aid of state-of-the-art sequencing and bioinformatics technologies,together with significant advancements in artificial intelligence,we anticipated that neoantigens will be fully exploited for personalized tumor immunotherapy,from screening to clinical application.展开更多
Hepatocellular carcinoma(HCC)is associated with high morbidity and mortality,and is prone to intra-and extrahepatic metastasis due to the anatomical and functional characteristics of the liver.Due to the complexity an...Hepatocellular carcinoma(HCC)is associated with high morbidity and mortality,and is prone to intra-and extrahepatic metastasis due to the anatomical and functional characteristics of the liver.Due to the complexity and high relapse rate associated with radical surgery or radiofrequency ablation,immune checkpoint inhibitors(ICIs)are increasingly being used to treat HCC.Several immunotherapeutic agents,along with their combinations,have been clinically approved to treat advanced or recurrent HCC.This review discusses the leading ICIs in practice and those currently undergoing randomized phase 1-3 trials as monotherapy or combination therapy.Furthermore,we summarize the rapidly developing alternative strategies such as chimeric antigen receptor-engineered T cell therapy and tumor vaccines.Combination therapy is a promising potential treatment option.These immunotherapies are also summarized in this review,which provides insights into the advantages,limitations,and novel angles for future research in establishing viable and alternative therapies against HCC.展开更多
The discovery of CAR T cell immunotherapy, also known as chimeric antigen receptor (CAR) T cell immunotherapy, has added a new dimension to the world of cancer treatment. This is a gene-based treatment in which T cell...The discovery of CAR T cell immunotherapy, also known as chimeric antigen receptor (CAR) T cell immunotherapy, has added a new dimension to the world of cancer treatment. This is a gene-based treatment in which T cells from the patient’s body are taken and genetically engineered in the lab to grow receptors. T cells containing this receptor are then injected into the patient’s body to bind to the antigen on the surface area of the cancer cell and kill the cancer cell. Structurally, the co-stimulatory domain added to CAR T cells has now reached the 5<sup>th</sup> GEN of chimeric antigen receptor T cells. Chimeric antigen T cell immunotherapy is the first FDA-approved treatment for hematological malignancies that is both safe and effective. However, due to some challenges such as a lack of safety control, an immunosuppressive tumor microenvironment, ineffective T cell trafficking, and so on, CAR-T immunotherapy treatment for solid malignancy is still in the clinical phase. In the result and discussion, we have presented a survey of CAR T cell therapy with a combination of pharmacological drugs. The things we mentioned are that CAR T cell immunotherapy is innovative, suitable, elegant, and also controls synergistic anti-cancer effects. A better understanding of combinatory CAR T cell therapies provides fundamental information for improvement of those therapies, in addition to the article highlighting future opportunities, commercial advancements, and various applications of CAR T cell therapy in different cancer cells. In the entire review article, we have highlighted the neck and crop of CAR T cell therapy, from which it is easy to understand the therapy and the need for this therapy in cancer prevention and its progress.展开更多
The advent of chimeric antigen receptor(CAR)-T cell immunotherapies has led to breakthroughs in the treatment of hematological malignancies.However,their success in treating solid tumors has been limited.CAR-natural k...The advent of chimeric antigen receptor(CAR)-T cell immunotherapies has led to breakthroughs in the treatment of hematological malignancies.However,their success in treating solid tumors has been limited.CAR-natural killer(NK)cells have several advantages over CAR-T cells because NK cells can be made from pre-existing cell lines or allogeneic NK cells with a mismatched major histocompatibility complex(MHC),which means they are more likely to become an"off-the-shelf"product.Moreover,they can kill cancer cells via CAR-dependent/independent pathways and have limited toxicity.Macrophages are the most malleable immune cells in the body.These cells can efficiently infiltrate into tumors and are present in large numbers in tumor microenvironments(TMEs).Importantly,CAR-macrophages(CAR-Ms)have recently yielded exciting preclinical results in several solid tumors.Nevertheless,CAR-T,CAR-NK,and CAR-M all have their own advantages and limitations.In this review,we systematically discuss the current status,progress,and the major hurdles of CAR-T cells,CAR-NK cells,and CAR-M as they relate to five aspects:CAR structure,therapeutic mechanisms,the latest research progress,current challenges and solutions,and comparison according to the existing research in order to provide a reasonable option for treating solid tumors in the future.展开更多
Gastric cancer,a prevalent malignancy worldwide,ranks sixth in terms of frequency and third in fatality,causing over a million new cases and 769000 annual deaths.Predominant in Eastern Europe and Eastern Asia,risk fac...Gastric cancer,a prevalent malignancy worldwide,ranks sixth in terms of frequency and third in fatality,causing over a million new cases and 769000 annual deaths.Predominant in Eastern Europe and Eastern Asia,risk factors include family medical history,dietary habits,tobacco use,Helicobacter pylori,and Epstein-Barr virus infections.Unfortunately,gastric cancer is often diagnosed at an advanced stage,leading to a grim prognosis,with a 5-year overall survival rate below 5%.Surgical intervention,particularly with D2 Lymphadenectomy,is the mainstay for early-stage cases but offers limited success.For advanced cases,the National Comprehensive Cancer Network recommends chemotherapy,radiation,and targeted therapy.Emerging immunotherapy presents promise,especially for unresectable or metastatic cases,with strategies like immune checkpoint inhibitors,tumor vaccines,adoptive immunotherapy,and nonspecific immunomodulators.In this Editorial,with regards to the article“Advances and key focus areas in gastric cancer immunotherapy:A comprehensive scientometric and clinical trial review”,we address the advances in the field of immunotherapy in gastric cancer and its future prospects.展开更多
Systemic lupus erythematosus(SLE)is characterized by a systemic dysfunction of both the innate and adaptive immune systems,leading to an attack on healthy tissues of the body.During the development of SLE,pathogenic f...Systemic lupus erythematosus(SLE)is characterized by a systemic dysfunction of both the innate and adaptive immune systems,leading to an attack on healthy tissues of the body.During the development of SLE,pathogenic features,such as the formation of autoantibodies against self-nuclear antigens,cause tissue damage including necrosis and fibrosis,with increased expression levels of the typeⅠinterferon-regulated genes.Standard treatments for lupus with immunosuppressants and glucocorticoids are not effective enough but cause side effects.As an alternative,more effective immunotherapies have been developed,including monoclonal and bispecific antibodies that target B cells,T cells,co-stimulatory molecules,cytokines or their receptors,and signaling molecules.Encouraging results have been observed in clinical trials with some of these therapies.Furthermore,a chimeric antigen receptor T cell therapy has emerged as the most effective,safe,and promising treatment option for SLE,as demonstrated by successful pilot studies.Additionally,some emerging evidence suggests that gut microbiota dysbiosis may significantly contribute to the severity of SLE,and the normalization of the gut microbiota through methods such as fecal microbiota transplantation presents new opportunities for effective treatment of SLE.展开更多
Objective:Investigate the cytotoxic effect of CAR-NK cells targeting CEA on colorectal cancer cells with positive CEA expression.Methods:The mRNA and protein levels of CEA in different CRC cell lines were detected by ...Objective:Investigate the cytotoxic effect of CAR-NK cells targeting CEA on colorectal cancer cells with positive CEA expression.Methods:The mRNA and protein levels of CEA in different CRC cell lines were detected by qRT-PCR and Western blot analysis.Lentiviral transduction was used to construct CAR-NK cells and empty vector CON-NK cells targeting CEA.Fluorescence microscopy and WB were used to determine whether the cells successfully constructed and expressed CAR structures.The effector NK cells were co-cultured with target cells,and the levels of LDH,IFN-γ,and GM-CSF were detected.The killing rate of effector cells was calculated,and the release of cytokines during the killing of target cells by different effector cells was compared.Results:The expression level of CEA in colorectal cancer patients was significantly higher than that in normal samples and other tumor samples,and the prognosis survival time of patients with high CEA expression was lower than that of CRC patients with low or no CEA expression(P<0.05).The CEA expression of the HT29 cell line was significantly higher than that of the SW1116 cell line at both the mRNA and protein levels.CEA-CAR-NK92 cells and CON-NK92 cells expressed green fluorescence under a microscope,and WB results showed that CEA-CAR-NK92 cells successfully expressed the CAR structure.Compared with CON-NK92 cells and NK92 cells,CEA-CAR-NK92 cells effectively killed HT29 cells(P<0.05).CEA-CAR-NK92 cells secreted a large amount of IFN-γand GM-CSF during the killing of HT29 cells,while the cytokine secretion of CON-NK92 cells and NK92 cells was not significant(P<0.05).Conclusion:CAR-NK92 cells targeting CEA can effectively kill CEA-positive colorectal cancer cells.展开更多
The successes achieved by chimeric antigen receptor-modified T (CAR-T) cells in hematological malignancies raised the pos- sibility of their use in non-small lung cancer (NSCLC). In this phase I clinical study (N...The successes achieved by chimeric antigen receptor-modified T (CAR-T) cells in hematological malignancies raised the pos- sibility of their use in non-small lung cancer (NSCLC). In this phase I clinical study (NCT01869166), patients with epidermal growth factor receptor (EGFR)-positive (〉50% expression), relapsed/refractory NSCLC received escalating doses of EGFR-targeted CAR-T cell infusions. The EGFR-targeted CAR-T cells were generated from peripheral blood after a 10 to 13-day in vitro expansion. Serum cytokines in peripheral blood and copy numbers of CAR-EGFR transgene in peripheral blood and in tissue biopsy were monitored periodically. Clinical responses were evaluated with RECISTI.1 and im- mune-related response criteria, and adverse events were graded with CTCAE 4.0. The EGFR-targeted CAR-T cell infusions were well-tolerated without severe toxicity. Of 11 evaluable patients, two patients obtained partial response and five had stable disease for two to eight months. The median dose of transfused CAR+ T cells was 0.97x 10^7 cells kg J (interquar- tile range (IQR), 0.45 to 1.09x 10^7 cells kg 1). Pathological eradication of EGFR positive tumor cells after EGFR-targeted CAR-T cell treatment can be observed in tumor biopsies, along with the CAR-EGFR gene detected in tumor-infiltrating T cells in all four biopsied patients. The EGFR-targeted CAR-T cell therapy is safe and feasible for EGFR-positive advanced re- lapsed/refractory NSCLC.展开更多
Introducing chimeric antigen receptor into immune cells against malignancies has contributed to a revolutionary innovation in cancer immunotherapy. As an important type of adaptive immune cells, T cells first caught r...Introducing chimeric antigen receptor into immune cells against malignancies has contributed to a revolutionary innovation in cancer immunotherapy. As an important type of adaptive immune cells, T cells first caught researchers' attention and became great success in chimeric antigen receptor-based immunotherapy. However, engineered T cells seem to hit their bottleneck when resistance of cancerous cells, less encouraging responses in solid tumors and unwanted toxicities to the host remain to be solved.Meanwhile, innate immune cells get to join the race. Representatives such as natural killer cells, natural killer T cells, γδT cells and macrophages also prove to be well redirected with chimeric antigen receptors. Compared to chimeric antigen receptor engineered T cells, these engineered innate immune cells may possess multiple targeting and killing mechanisms, have the potential to crack the barrier of solid tumors and have less side effects in the host. Besides, possible universal access to cell resources and improvements in expansion and transduction techniques make these cells promising candidates with huge potential in translational medicine. Therefore, innate immune cells claim a brand-new dimension and are likely to supplement T cells greatly in the field of chimeric antigen receptor-based immunotherapy.展开更多
Cellular therapies have revolutionized the treatment of hematological malignancies since their conception and rapid development.Chimeric antigen receptor(CAR)-T cell therapy is the most widely applied cellular therapy...Cellular therapies have revolutionized the treatment of hematological malignancies since their conception and rapid development.Chimeric antigen receptor(CAR)-T cell therapy is the most widely applied cellular therapy.Since the Food and Drug Administration approved two CD19-CAR-T products for clinical treatment of relapsed/refractory acute lymphoblastic leukemia and diffuse large B cell lymphoma in 2017,five more CAR-T cell products were subsequently approved for treating multiple myeloma or B cell malignancies.Moreover,clinical trials of CAR-T cell therapy for treating other hematological malignancies are ongoing.Both China and the United States have contributed significantly to the development of clinical trials.However,CAR-T cell therapy has many limitations such as a high relapse rate,adverse side effects,and restricted availability.Various methods are being implemented in clinical trials to address these issues,some of which have demonstrated promising breakthroughs.This review summarizes developments in CAR-T cell trials and advances in CAR-T cell therapy.展开更多
Adoptive cell therapy using chimeric antigen receptor T (CAR-T) cells, which is a promising cancer immunotherapy strategy, has been developing very rapidly in recent years. CAR-T cells are genetically modified T cells...Adoptive cell therapy using chimeric antigen receptor T (CAR-T) cells, which is a promising cancer immunotherapy strategy, has been developing very rapidly in recent years. CAR-T cells are genetically modified T cells that can specifically recognize tumor specific antigens on the surface of tumor cells, and then effectively kill tumor cells. At present, exciting results are being achieved in clinical applications of CAR-T cells for patients with hematological malignancies. The research and development of CAR-T cells for various targets and for the treatment of solid tumors have become a hot topic worldwide, so an increasing number of investigational new drug applications (INDAs) and new drug applications (NDAs) of CAR-T cell products are expected to be submitted in future. The quality control and nonclinical research of these products are of great significance in ensuring the safety and effectiveness of these products;however, they also present great challenges and difficulties. This article discusses the general principles of and key issues regarding the quality control and nonclinical research of CAR-T cell products based on their product characteristics and on relevant guidelines for gene and cell therapy products.展开更多
基金supported by Liaoning Natural Science Foundation(No.20180550229)
文摘Objective: Cytokine release syndrome (CRS) and tumor lysis syndrome (TLS) that occur after chimeric antigen receptor T (CAR-T) cells are reinfused, which severely affect the survival and prognosis of patients. Although several articles have reported on the care of CAR-T cell immunotherapy, the quality of the study and the effectiveness of holistic nursing interventions have not been systematically reviewed. The purpose of this study was to systematically evaluate the existing holistic nursing interventions of CAR-T cell immunotherapy. Methods: A literature search for keywords was performed in PubMed, EMBASE, the Cochrane Library, CNKI, CBM, and Wanfang Data from its inception until January 2018. Studies were deemed eligible if they comprised patients with tumor receiving CAR-T cell immunotherapy, described the holistic nursing process, and were published in Chinese and English. Results: A total of 6 articles on holistic nursing interventions of CAR-T cell immunotherapy are reported, and the nursing methods and results of each article are analyzed. The quality of the studies included was medium. All nursing measures were considered effective. Conclusions: Holistic nursing programs reduce the incidence of CRS and TLS and improve the quality of life of cancer patients.
文摘Relapses remain a major concern in acute leukemia. It is well known that leukemia stem cells(LSCs) hide in hematopoietic niches and escape to the immune system surveillance through the outgrowth of poorly immunogenic tumor-cell variants and the suppression of the active immune response. Despitethe introduction of new reagents and new therapeutic approaches, no treatment strategies have been able to definitively eradicate LSCs. However, recent adoptive immunotherapy in cancer is expected to revolutionize our way to fight against this disease, by redirecting the immune system in order to eliminate relapse issues. Initially described at the onset of the 90's, chimeric antigen receptors(CARs) are recombinant receptors transferred in various T cell subsets, providing specific antigens binding in a non-major histocompatibility complex restricted manner, and effective on a large variety of human leukocyte antigen-divers cell populations. Once transferred, engineered T cells act like an expanding "living drug" specifically targeting the tumor-associated antigen, and ensure long-term antitumor memory. Over the last decades, substantial improvements have been made in CARs design. CAR T cells have finally reached the clinical practice and first clinical trials have shown promising results. In acute lymphoblastic leukemia, high rate of complete and prolonged clinical responses have been observed after anti-CD19 CAR T cell therapy, with specific but manageable adverse events. In this review, our goal was to describe CAR structures and functions, and to summarize recent data regarding pre-clinical studies and clinical trials in acute leukemia.
文摘Background: Chimeric antigen receptor-engineered T-cell(CAR-T) therapy is a newly developed immunotherapy used in the treatment of cancers. Because CAR-T therapy has shown great success in treating CD19-positive hematological malignancies, its application has been explored in the treatment of solid tumors, such as liver cancer. In this review, we discuss the immune characteristics of liver cancer, the obstacles encountered during the application of CAR-T therapy, and preclinical and clinical progress in the use of CAR-T therapy in patients with liver cancer.Data sources: The data on CAR-T therapy related to liver cancers were collected by searching Pub Med and the Web of Science databases prior to December 2017 with the keywords "chimeric antigen receptor","CAR-T", "liver cancer", "hepatocellular carcinoma", and "solid tumor". Additional articles were identified by manual search of references found in the primary articles. The data for clinical trials were collected by searching Clinical Trials.gov.Results: The liver has a tolerogenic nature in the intrahepatic milieu and its tumor microenvironment significantly affects tumor progression. The obstacles that reduce the efficacy of CAR-T therapy in solid tumors include a lack of specific tumor antigens, limited trafficking and penetration of CAR-T cells to tumor sites, and an immunosuppressive tumor microenvironment. To overcome these obstacles, several strategies have emerged. In addition, several strategies have been developed to manage the side effects of CAR-T, including enhancing the selectivity of CARs and controlling CAR-T activity. To date, no clinical trials of CAR-T therapy against HCC have been completed. However, preclinical studies in vitro and in vivo have shown potent antitumor efficacy. Glypican-3, mucin-1, epithelial cell adhesion molecule, carcinoembryonic antigen, and other targets are currently being studied.Conclusions: The application of CAR-T therapy for liver cancer is just beginning to be explored and more research is needed. However, we are optimistic that CAR-T therapy will offer a new approach for the treatment of liver cancers in the future.
基金The National Natural Science Foundation of China,No.81972673.
文摘With the advance of genome engineering technology,chimeric antigen receptors(CARs)-based immunotherapy has become an emerging therapeutic strategy for tumors.Although initially designed for T cells in tumor immunotherapy,CARs have been exploited to modify the function of natural killer(NK)cells against a variety of tumors,including hepatocellular carcinoma(HCC).CAR-NK cells have the potential to sufficiently kill tumor antigen-expressing HCC cells,independent of major histocompatibility complex matching or prior priming.In this review,we summarize the recent advances in genetic engineering of CAR-NK cells against HCC and discuss the current challenges and prospects of CAR-NK cells as a revolutionary cellular immunotherapy against HCC.
文摘The adoptive transfer of T cells is a promising approach to treat cancers. Primary human T cells can be modified using viral and non-viral vectors to promote the specific targeting of cancer cells via the introduction of exogenous T-cell receptors(TCRs) or chimeric antigen receptors(CARs). This gene transfer displays the potential to increase the specificity and potency of the anticancer response while decreasing the systemic adverse effects that arise from conventional treatments that target both cancerous and healthy cells. This review highlights the generation of clinical-grade T cells expressing CARs for immunotherapy, the use of these cells to target B-cell malignancies and, particularly, the first clinical trials deploying the Sleeping Beauty gene transfer system, which engineers T cells to target CD19+ leukemia and non-Hodgkin's lymphoma.
文摘BACKGROUND Chimeric antigen receptor T-Cell(CAR-T)therapy is an effective new treatment for hematologic malignancies.Cytokine release syndrome(CRS)and neurologic toxicity are main toxicities.CRS-induced rhabdomyolysis(RM)followed by CART therapy treatment has not been previously reported.CASE SUMMARY We report a case of a 22-year-old woman with relapsed acute lymphoblastic leukemia obtained sequential cluster of differentiation(CD)19 and CD22 CAR-T infusion.This patient experienced grade 3 CRS with RM,mild hypotension requiring intravenous fluids,and mild hypoxia and was managed effectively with the IL-6 receptor antagonist tocilizumab.This patient had no signs of immune effector cell-associated neurologic syndrome.Restaging scans 30 d postCAR-T therapy demonstrated a complete remission,and the symptoms of muscle weakness improved through rehabilitation.CONCLUSION Myalgia is an easily overlooked symptom of severe CRS after CAR-T therapy.It is necessary to monitor myoglobin levels when a patient presents with symptoms of myalgia or acute renal insufficiency.
文摘BACKGROUND Diffuse large B-cell lymphoma(DLBCL)is curable with first-line chemoimmunotherapy but patients with relapsed/refractory(R/R)DLBCL still face a poor prognosis.For patients with R/R DLBCL,the complete response rate to traditional next-line therapy is only 7%and the median overall survival is 6.3 mo.Recently,CD19-targeting chimeric antigen receptor T cells(CAR-T)have shown promise in clinical trials.However,approximately 50%of patients treated with CAR-T cells ultimately progress and few salvage therapies are effective.CASE SUMMARY Here,we report on 7 patients with R/R DLBCL whose disease progressed after CAR-T infusion.They received a PD-1 inhibitor(sintilimab)and a histone deacetylase inhibitor(chidamide).Five of the 7 patients tolerated the treatment without any serious adverse events.Two patients discontinued the treatment due to lung infection and rash.At the 20-mo follow-up,the median overall survival of these 7 patients was 6 mo.Of note,there were 2 complete response rates(CRs)and 2 partial response rates(PRs)during this novel therapy,with an overall response rate(ORR)of 57.1%,and one patient had a durable CR that lasted at least 20 mo.CONCLUSION In conclusion,chidamide combined with sintilimab may be a choice for DLBCL patients progressing after CD19-targeting CAR-T therapy.
基金Supported by The Wellcome TrustCancer Research UK+9 种基金Bayerthe Medical Research CouncilBreast Cancer NowLeukaemia and Lymphoma ResearchWorldwide Cancer ResearchJune Hancock Mesothelioma FoundationJon Moulton Charitable FoundationPancreatic Cancer United Kingdomthe Experimental Cancer Medicine Centre at King’s College Londonthe National Institute for Health Research(NIHR) Biomedical Research Centre based at Guy’s and St Thomas’NHS Foundation Trust and King’s College London
文摘Chimeric antigen receptors (CARs) are fusion molecules that may be genetically delivered ex-vivo to T-cells and other immune cell populations, thereby conferring specifcity for native target antigens found on the surface of tumour and other target cell types. Antigen recognition by CARs is neither restricted by nor dependent upon human leukocyte antigen antigen expression, favouring widespread use of this technology across transplantation barriers. Signalling is delivered by a designer endodomain that provides a tailored and target-dependent activation signal to polyclonal circulating T-cells. Recent clinical data emphasise the enormous promise of this emer-ging immunotherapeutic strategy for B-cell malignancy, notably acute lymphoblastic leukaemia. In that context, CARs are generally targeted against the ubiquitous B-cell antigen, CD19. However, CAR T-cell immunotherapy is limited by potential for severe ontarget toxicity, notably due to cytokine release syndrome. Furthermore, effcacy in the context of solid tumours remains unproven, owing in part to lack of availability of safe tumourspecific targets, inadequate CAR T-cell homing and hostility of the tumour microenvironment to immune effector deployment. Manufacture and commercial development encountered with more traditional drug products. Finally, there is increasing interest in the application of this technology to the treatment of non-malignant disease states, such as autoimmunity, chronic infection and in the suppression of allograft rejection. Here, we consider the background and direction of travel of this emerging and highly promising treatment for malignant and other disease types.
基金grants from the National Natural Science Foundation of China (81788101, 81761128013,81771686, 81472646, 91842305, 31390443, and 91542000)the Chinese Academy of Science (XDB29030000).
文摘Natural killer (NK) cells are key innate immune cells that provide the first line of defense against viral infection and cancer. Although NK cells can discriminate between "self" and "non-self," recognize abnormal cells, and eliminate transformed cells and malignancies in real time, tumors develop several strategies to escape from NK cell attack. These strategies include upregulating ligands for the inhibitory receptors of NK cells and producing soluble molecules or immunosuppressive factors. Various types of NK cells are currently being applied in clinical trials, including autologous or allogeneic NK cells, umbilical cord blood (UCB) or induced pluripotent stem cell (iPSC)-derived NK cells, memory-like NK cells, and NK cell line NK-92 cells, for the treatment of different types of tumors. Chimeric antigen receptors (CARs)-NK cells have recently shown great potential due to their redirect specificity and effective antitumor activity. In this review, we summarize the mechanisms of tumor escape from NK cell recognition, the current status and advanced progress of NK cell-based immunotherapy, ways of enhancing the antitumor capacity of NK cells in vivo, and major challenges for clinical practice in this field.
基金This research was supported by the Clinical Frontier Technology Program of the First Affiliated Hospital of Jinan University,China(No.JNU1AF-CFTP-2022-a01223)Natural Science Foundation of Guangdong Province(2019A1515011763,2020A1515110639,2021A1515010994,2022A1515011695)Guangzhou Science and Technology Plan City-School Joint Funding Project(202201020084,202201020065).
文摘Neoantigen-targeted immunotherapy is a rapidly advancing field that holds great promise for treating cancer.The recognition of antigens by immune cells is a crucial step in tumor-specific killing,and neoantigens generated by mutations in cancer cells possess high immunogenicity and are selectively expressed in tumor cells,making them an attractive therapeutic target.Currently,neoantigens find utility in various domains,primarily in the realm of neoantigen vaccines such as DC vaccines,nucleic acid vaccines,and synthetic long peptide vaccines.Additionally,they hold promise in adoptive cell therapy,encompassing tumor-infiltrating cells,T cell receptors,and chimeric antigen receptors which are expressed by genetically modified T cells.In this review,we summarized recent progress in the clinical use of tumor vaccines and adoptive cell therapy targeting neoantigens,discussed the potential of neoantigen burden as an immune checkpoint in clinical settings.With the aid of state-of-the-art sequencing and bioinformatics technologies,together with significant advancements in artificial intelligence,we anticipated that neoantigens will be fully exploited for personalized tumor immunotherapy,from screening to clinical application.
基金Supported by The Key Research Projects of Science and Technology of Sichuan Province,No. 2022YFS0189
文摘Hepatocellular carcinoma(HCC)is associated with high morbidity and mortality,and is prone to intra-and extrahepatic metastasis due to the anatomical and functional characteristics of the liver.Due to the complexity and high relapse rate associated with radical surgery or radiofrequency ablation,immune checkpoint inhibitors(ICIs)are increasingly being used to treat HCC.Several immunotherapeutic agents,along with their combinations,have been clinically approved to treat advanced or recurrent HCC.This review discusses the leading ICIs in practice and those currently undergoing randomized phase 1-3 trials as monotherapy or combination therapy.Furthermore,we summarize the rapidly developing alternative strategies such as chimeric antigen receptor-engineered T cell therapy and tumor vaccines.Combination therapy is a promising potential treatment option.These immunotherapies are also summarized in this review,which provides insights into the advantages,limitations,and novel angles for future research in establishing viable and alternative therapies against HCC.
文摘The discovery of CAR T cell immunotherapy, also known as chimeric antigen receptor (CAR) T cell immunotherapy, has added a new dimension to the world of cancer treatment. This is a gene-based treatment in which T cells from the patient’s body are taken and genetically engineered in the lab to grow receptors. T cells containing this receptor are then injected into the patient’s body to bind to the antigen on the surface area of the cancer cell and kill the cancer cell. Structurally, the co-stimulatory domain added to CAR T cells has now reached the 5<sup>th</sup> GEN of chimeric antigen receptor T cells. Chimeric antigen T cell immunotherapy is the first FDA-approved treatment for hematological malignancies that is both safe and effective. However, due to some challenges such as a lack of safety control, an immunosuppressive tumor microenvironment, ineffective T cell trafficking, and so on, CAR-T immunotherapy treatment for solid malignancy is still in the clinical phase. In the result and discussion, we have presented a survey of CAR T cell therapy with a combination of pharmacological drugs. The things we mentioned are that CAR T cell immunotherapy is innovative, suitable, elegant, and also controls synergistic anti-cancer effects. A better understanding of combinatory CAR T cell therapies provides fundamental information for improvement of those therapies, in addition to the article highlighting future opportunities, commercial advancements, and various applications of CAR T cell therapy in different cancer cells. In the entire review article, we have highlighted the neck and crop of CAR T cell therapy, from which it is easy to understand the therapy and the need for this therapy in cancer prevention and its progress.
基金Natural Science Foundation of China(No.82270149)China Postdoctoral Science Foundation(Nos.2022T150592,and 2021M692930)Young Postdoctoral Innovators in Henan Province(WL),and Henan Province Medical Science and Technology Research Project(Nos.SBGJ202102063,and LHGJ20220305)
文摘The advent of chimeric antigen receptor(CAR)-T cell immunotherapies has led to breakthroughs in the treatment of hematological malignancies.However,their success in treating solid tumors has been limited.CAR-natural killer(NK)cells have several advantages over CAR-T cells because NK cells can be made from pre-existing cell lines or allogeneic NK cells with a mismatched major histocompatibility complex(MHC),which means they are more likely to become an"off-the-shelf"product.Moreover,they can kill cancer cells via CAR-dependent/independent pathways and have limited toxicity.Macrophages are the most malleable immune cells in the body.These cells can efficiently infiltrate into tumors and are present in large numbers in tumor microenvironments(TMEs).Importantly,CAR-macrophages(CAR-Ms)have recently yielded exciting preclinical results in several solid tumors.Nevertheless,CAR-T,CAR-NK,and CAR-M all have their own advantages and limitations.In this review,we systematically discuss the current status,progress,and the major hurdles of CAR-T cells,CAR-NK cells,and CAR-M as they relate to five aspects:CAR structure,therapeutic mechanisms,the latest research progress,current challenges and solutions,and comparison according to the existing research in order to provide a reasonable option for treating solid tumors in the future.
文摘Gastric cancer,a prevalent malignancy worldwide,ranks sixth in terms of frequency and third in fatality,causing over a million new cases and 769000 annual deaths.Predominant in Eastern Europe and Eastern Asia,risk factors include family medical history,dietary habits,tobacco use,Helicobacter pylori,and Epstein-Barr virus infections.Unfortunately,gastric cancer is often diagnosed at an advanced stage,leading to a grim prognosis,with a 5-year overall survival rate below 5%.Surgical intervention,particularly with D2 Lymphadenectomy,is the mainstay for early-stage cases but offers limited success.For advanced cases,the National Comprehensive Cancer Network recommends chemotherapy,radiation,and targeted therapy.Emerging immunotherapy presents promise,especially for unresectable or metastatic cases,with strategies like immune checkpoint inhibitors,tumor vaccines,adoptive immunotherapy,and nonspecific immunomodulators.In this Editorial,with regards to the article“Advances and key focus areas in gastric cancer immunotherapy:A comprehensive scientometric and clinical trial review”,we address the advances in the field of immunotherapy in gastric cancer and its future prospects.
基金funded by the Russian Science Foundation Grant No.21-74-10154 to A.K.
文摘Systemic lupus erythematosus(SLE)is characterized by a systemic dysfunction of both the innate and adaptive immune systems,leading to an attack on healthy tissues of the body.During the development of SLE,pathogenic features,such as the formation of autoantibodies against self-nuclear antigens,cause tissue damage including necrosis and fibrosis,with increased expression levels of the typeⅠinterferon-regulated genes.Standard treatments for lupus with immunosuppressants and glucocorticoids are not effective enough but cause side effects.As an alternative,more effective immunotherapies have been developed,including monoclonal and bispecific antibodies that target B cells,T cells,co-stimulatory molecules,cytokines or their receptors,and signaling molecules.Encouraging results have been observed in clinical trials with some of these therapies.Furthermore,a chimeric antigen receptor T cell therapy has emerged as the most effective,safe,and promising treatment option for SLE,as demonstrated by successful pilot studies.Additionally,some emerging evidence suggests that gut microbiota dysbiosis may significantly contribute to the severity of SLE,and the normalization of the gut microbiota through methods such as fecal microbiota transplantation presents new opportunities for effective treatment of SLE.
基金Henan Provincial Health Commission’s 2020 National Health Commission Science Research Fund Henan Provincial Medical Science and Technology Tackling Plan Provincial-Ministerial Joint Project and Soft Science Project“Clinical Study of CAR-NK Cells Targeting Carcinoembryonic Antigen on Gastric Cancer Cells”(Grant No.SBGJ202002093)Henan Province 2022 Science and Technology Development Plan“Study on Pyroglutamate Targeting DJ-1 to Trigger ROS-Induced Cell Death and Protective Autophagy in Pancreatic Cancer”(Grant No.222102310725)。
文摘Objective:Investigate the cytotoxic effect of CAR-NK cells targeting CEA on colorectal cancer cells with positive CEA expression.Methods:The mRNA and protein levels of CEA in different CRC cell lines were detected by qRT-PCR and Western blot analysis.Lentiviral transduction was used to construct CAR-NK cells and empty vector CON-NK cells targeting CEA.Fluorescence microscopy and WB were used to determine whether the cells successfully constructed and expressed CAR structures.The effector NK cells were co-cultured with target cells,and the levels of LDH,IFN-γ,and GM-CSF were detected.The killing rate of effector cells was calculated,and the release of cytokines during the killing of target cells by different effector cells was compared.Results:The expression level of CEA in colorectal cancer patients was significantly higher than that in normal samples and other tumor samples,and the prognosis survival time of patients with high CEA expression was lower than that of CRC patients with low or no CEA expression(P<0.05).The CEA expression of the HT29 cell line was significantly higher than that of the SW1116 cell line at both the mRNA and protein levels.CEA-CAR-NK92 cells and CON-NK92 cells expressed green fluorescence under a microscope,and WB results showed that CEA-CAR-NK92 cells successfully expressed the CAR structure.Compared with CON-NK92 cells and NK92 cells,CEA-CAR-NK92 cells effectively killed HT29 cells(P<0.05).CEA-CAR-NK92 cells secreted a large amount of IFN-γand GM-CSF during the killing of HT29 cells,while the cytokine secretion of CON-NK92 cells and NK92 cells was not significant(P<0.05).Conclusion:CAR-NK92 cells targeting CEA can effectively kill CEA-positive colorectal cancer cells.
基金supported by the Science and Technology Planning Project of Beijing City (Z151100003915076)the National Natural Science Foundation of China (31270820, 81230061, 81472612, 81402566)+1 种基金the National Basic Science and Development Programme of China (2013BAI01B04)the Nursery Innovation Fund (15KMM50)
文摘The successes achieved by chimeric antigen receptor-modified T (CAR-T) cells in hematological malignancies raised the pos- sibility of their use in non-small lung cancer (NSCLC). In this phase I clinical study (NCT01869166), patients with epidermal growth factor receptor (EGFR)-positive (〉50% expression), relapsed/refractory NSCLC received escalating doses of EGFR-targeted CAR-T cell infusions. The EGFR-targeted CAR-T cells were generated from peripheral blood after a 10 to 13-day in vitro expansion. Serum cytokines in peripheral blood and copy numbers of CAR-EGFR transgene in peripheral blood and in tissue biopsy were monitored periodically. Clinical responses were evaluated with RECISTI.1 and im- mune-related response criteria, and adverse events were graded with CTCAE 4.0. The EGFR-targeted CAR-T cell infusions were well-tolerated without severe toxicity. Of 11 evaluable patients, two patients obtained partial response and five had stable disease for two to eight months. The median dose of transfused CAR+ T cells was 0.97x 10^7 cells kg J (interquar- tile range (IQR), 0.45 to 1.09x 10^7 cells kg 1). Pathological eradication of EGFR positive tumor cells after EGFR-targeted CAR-T cell treatment can be observed in tumor biopsies, along with the CAR-EGFR gene detected in tumor-infiltrating T cells in all four biopsied patients. The EGFR-targeted CAR-T cell therapy is safe and feasible for EGFR-positive advanced re- lapsed/refractory NSCLC.
基金supported by grants from the National Natural Science Foundation of China(81873871)the Fundamental Research Funds for the Central Universities(BMU2018XY001)
文摘Introducing chimeric antigen receptor into immune cells against malignancies has contributed to a revolutionary innovation in cancer immunotherapy. As an important type of adaptive immune cells, T cells first caught researchers' attention and became great success in chimeric antigen receptor-based immunotherapy. However, engineered T cells seem to hit their bottleneck when resistance of cancerous cells, less encouraging responses in solid tumors and unwanted toxicities to the host remain to be solved.Meanwhile, innate immune cells get to join the race. Representatives such as natural killer cells, natural killer T cells, γδT cells and macrophages also prove to be well redirected with chimeric antigen receptors. Compared to chimeric antigen receptor engineered T cells, these engineered innate immune cells may possess multiple targeting and killing mechanisms, have the potential to crack the barrier of solid tumors and have less side effects in the host. Besides, possible universal access to cell resources and improvements in expansion and transduction techniques make these cells promising candidates with huge potential in translational medicine. Therefore, innate immune cells claim a brand-new dimension and are likely to supplement T cells greatly in the field of chimeric antigen receptor-based immunotherapy.
基金supported by grants from Tianjin Municipal Science and Technology Commission Grant(No.20JCZDJC00120)the Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Science(No.2020-I2M-C&T-A-019)
文摘Cellular therapies have revolutionized the treatment of hematological malignancies since their conception and rapid development.Chimeric antigen receptor(CAR)-T cell therapy is the most widely applied cellular therapy.Since the Food and Drug Administration approved two CD19-CAR-T products for clinical treatment of relapsed/refractory acute lymphoblastic leukemia and diffuse large B cell lymphoma in 2017,five more CAR-T cell products were subsequently approved for treating multiple myeloma or B cell malignancies.Moreover,clinical trials of CAR-T cell therapy for treating other hematological malignancies are ongoing.Both China and the United States have contributed significantly to the development of clinical trials.However,CAR-T cell therapy has many limitations such as a high relapse rate,adverse side effects,and restricted availability.Various methods are being implemented in clinical trials to address these issues,some of which have demonstrated promising breakthroughs.This review summarizes developments in CAR-T cell trials and advances in CAR-T cell therapy.
文摘Adoptive cell therapy using chimeric antigen receptor T (CAR-T) cells, which is a promising cancer immunotherapy strategy, has been developing very rapidly in recent years. CAR-T cells are genetically modified T cells that can specifically recognize tumor specific antigens on the surface of tumor cells, and then effectively kill tumor cells. At present, exciting results are being achieved in clinical applications of CAR-T cells for patients with hematological malignancies. The research and development of CAR-T cells for various targets and for the treatment of solid tumors have become a hot topic worldwide, so an increasing number of investigational new drug applications (INDAs) and new drug applications (NDAs) of CAR-T cell products are expected to be submitted in future. The quality control and nonclinical research of these products are of great significance in ensuring the safety and effectiveness of these products;however, they also present great challenges and difficulties. This article discusses the general principles of and key issues regarding the quality control and nonclinical research of CAR-T cell products based on their product characteristics and on relevant guidelines for gene and cell therapy products.