Chimeric antigen receptor T-cesll therapy(CAR–T)has achieved groundbreaking advancements in clinical application,ushering in a new era for innovative cancer treatment.However,the challenges associated with implementi...Chimeric antigen receptor T-cesll therapy(CAR–T)has achieved groundbreaking advancements in clinical application,ushering in a new era for innovative cancer treatment.However,the challenges associated with implementing this novel targeted cell therapy are increasingly significant.Particularly in the clinical management of solid tumors,obstacles such as the immunosuppressive effects of the tumor microenvironment,limited local tumor infiltration capability of CAR–T cells,heterogeneity of tumor targeting antigens,uncertainties surrounding CAR–T quality,control,and clinical adverse reactions have contributed to increased drug resistance and decreased compliance in tumor therapy.These factors have significantly impeded the widespread adoption and utilization of this therapeutic approach.In this paper,we comprehensively analyze recent preclinical and clinical reports on CAR–T therapy while summarizing crucial factors influencing its efficacy.Furthermore,we aim to identify existing solution strategies and explore their current research status.Through this review article,our objective is to broaden perspectives for further exploration into CAR–T therapy strategies and their clinical applications.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
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
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
We have developed and tested chimeric T-cell receptors (TCR) specific for p185HER2. In these experiments, retroviral vectors expressing the N29γ or N29ζ receptors were constructed in pRET6. Amphotropic viral produce...We have developed and tested chimeric T-cell receptors (TCR) specific for p185HER2. In these experiments, retroviral vectors expressing the N29γ or N29ζ receptors were constructed in pRET6. Amphotropic viral producer cells were established in the GALV-based PG13 packaging cell line. Ficoll purified human peripheral blood lymphocytes (PBL) were virally transduced using an optimized protocol incorporating activation with immobilized anti-CD3/anti-CD28 monoclonal anti- bodies, followed by viral infection in the presence of fibronectin fragment CH296. Transduced cells were co-cultured with human tumor cell lines that overexpress (SK-OV-3) or underexpress (MCF7) p185HER2 to assay for antigen specific im- mune responses. Both CM+ and CD8+ T-cells transduced with the N29γ or N29ζ chTCR demonstrated HER2-specific anti- gen responses, as determined by release of Th1 like cytokines, and cellular cytotoxicity assays. Our results support the fea- sibility of adoptive immunotherapy with genetically modified T-cells expressing a chTCR specific for p185HER2.展开更多
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
T cells engineered to express chimeric antigen receptors (CARs) combining an external antibody binding domain with the CD3ζ T cell receptor (TCR) signaling domain for triggering cell activation are being used for imm...T cells engineered to express chimeric antigen receptors (CARs) combining an external antibody binding domain with the CD3ζ T cell receptor (TCR) signaling domain for triggering cell activation are being used for immunotherapeutic targeting of tumor cells in a non-HLA restricted manner. In this study we transduced T cells with a CD19-CAR construct containing a truncated CD34 gene (tCD34) marker and used these to target the B cell antigen CD19 on the surface of a Hodgkin’s lymphoma (HL) cell line (L591) both in vitro and in vivo. Levels of tCD34 expression in transduced peripheral blood mononuclear cells (PBMCs) ranged from 6% - 20% and this was increased to 82% after selection for transduced tCD34+ cells. In vitro cytotoxicity testing on a CD19+ HL cell line (L591) showed specific cell lysis initiated by the CD19-CAR transduced PBMCs. Importantly, CD19-CAR T cells prevented the growth of L591 HL tumor cells when co-injected subcutaneously (sc) in 6/6 severe combined immunodeficient (SCID) mice. There was no evidence of anti-tumor activity when CD19-CAR T cells were infused intravenously (iv) at the same time as L591 HL tumor cells were injected sc. However, 3/6 SCID mice showed tumor rejection within 83 days after iv infusion of CD19-CAR T cells 3 - 9 days after establishment of L591 HL tumors, while all control animals succumbed to tumors within 60 days. Interestingly, immuno-histochemical analysis of L591 HL tumors demonstrated that CD19-CAR T cells were detected not earlier than 11 days after infusion within the tumor mass. These results suggest that CD19 is a potentially attractive target for the immunotherapy of HL.展开更多
c-Met is a hepatocyte growth factor receptor overexpressed in many tumors such as hepatocellular carcinoma(HCC).Therefore,c-Met may serve as a promising target for HCC immunotherapy.Modifying T cells to express c-Met-...c-Met is a hepatocyte growth factor receptor overexpressed in many tumors such as hepatocellular carcinoma(HCC).Therefore,c-Met may serve as a promising target for HCC immunotherapy.Modifying T cells to express c-Met-specific chimeric antigen receptor(CAR)is an attractive strategy in treating c-Met-positive HCC.This study aimed to systematically evaluate the inhibitory effects of 2^(nd)-and 3^(rd)-generation c-Met CAR-T cells on hepatocellular carcinoma(HCC)cells.Here,2^(nd)-and 3^(rd)-generation c-Met CARs containing an anti-c-Met singlechain variable fragment(scFv)as well as the CD28 signaling domain and CD3ζ(c-Met-28-3ζ),the CD137 signaling domain and CD3ζ(c-Met-137-3ζ),or the CD28 and CD137 signaling domains and CD3ζ(c-Met-28-137-3ζ)were constructed,and their abilities to target c-Met-positive HCC cells were evaluated in vitro and in vivo.All c-Met CARs were stably expressed on T cell membrane,and c-Met CAR-T cells aggregated around c-Met-positive HCC cells and specifically killed them in vitro.c-Met-28-137-3ζCAR-T cells secreted more interferon-gamma(IFN-γ)and interleukin 2(IL-2)than c-Met-28-3ζCAR-T cells and c-Met-137-3ζCAR-T cells.Compared with c-Met low-expressed cells,c-Met CAR-T cells secreted more cytokines when co-cultured with c-Met high-expressed cells.Moreover,c-Met-28-137-3ζCAR-T cells eradicated HCC more effectively in xenograft tumor models compared with the control groups.This study suggests that 3^(rd)-generation c-Met CAR-T cells are more effective in inhibiting c-Met-positive HCC cells than 2^(nd)-generation c-Met CAR-T cells,thereby providing a promising therapeutic intervention for c-Met-positive HCC.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
We have confirmed efficient anti-tumor activities of the peripheral lymphocytes transduced with a p185HEH2-specific chimeric T-cell receptor gene both in murine and in human in our previous studies. To further test th...We have confirmed efficient anti-tumor activities of the peripheral lymphocytes transduced with a p185HEH2-specific chimeric T-cell receptor gene both in murine and in human in our previous studies. To further test the feasibility of chimeric T-cell receptor in a bone marrow transplantation model, we first, made two routine tumor cell lines: MT901 and MCA-205, to express human p185HER2 by retroviral gene transduction. Murine bone marrow cells were retrovirally transduced to express the chimeric T-cell receptor and gene-modified bone marrow cells were transplanted into lethally irradiated mouse. Six months post transplantation, p185HER2-positive tumor ceils: MT-901/HER2 or MCA-205/ HER2 was subcutaneously or intravenously injected to make mouse models simulating primary breast cancer or pulmonary metastasis. The in vivo anti-tumor effects were monitored by the size of the subcutaneous tumor or counting the tumor nodules in the lungs after India ink staining. The size of the subcutaneous tumor was significantly inhibited and the number of pulmonary nodules were significantly decreased in mouse recipients transplanted with chimeric T-cell receptor modified bone marrow cells compared with the control group. Our results suggest the efficient in vivo anti-tumor activities of chimeric T-cell receptor gene modified bone marrow cells.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
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
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
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
Adoptive therapeutic immune cells, such as chimeric antigen receptor (CAR)-T cells and natural killer cells, have established a new generation of precision medicine based on which dramatic breakthroughs have been achi...Adoptive therapeutic immune cells, such as chimeric antigen receptor (CAR)-T cells and natural killer cells, have established a new generation of precision medicine based on which dramatic breakthroughs have been achieved in intractable lymphoma treatments. Currently, well-explored approaches focus on autologous cells due to their low immunogenicity, but they are highly restricted by the high costs, time consumption of processing, and the insufficiency of primary cells in some patients. Induced pluripotent stem cells (iPSCs) are cell sources that can theoretically produce indefinite well-differentiated immune cells. Based on the above facts, it may be reasonable to combine the iPSC technology and the CAR design to produce a series of highly controllable and economical "live" drugs. Manufacturing hypoimmunogenic iPSCs by inactivation or over-expression at the genetic level and then arming the derived cells with CAR have emerged as a form of "off-the-shelf" strategy to eliminate tumor cells efficiently and safely in a broader range of patients. This review describes the reasonability, feasibility, superiority, and drawbacks of such approaches, summarizes the current practices and relevant research progress, and provides insights into the possible new paths for personalized cell-based therapies.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
Glioblastoma remains as the most common and aggressive malignant brain tumor,standing with a poor prognosis and treatment prospective.Despite the aggressive standard care,such as surgical resection and chemoradiation,...Glioblastoma remains as the most common and aggressive malignant brain tumor,standing with a poor prognosis and treatment prospective.Despite the aggressive standard care,such as surgical resection and chemoradiation,median survival rates are low.In this regard,immunotherapeutic strategies aim to become more attractive for glioblastoma,considering its recent advances and approaches.In this review,we provide an overview of the current status and progress in immunotherapy for glioblastoma,going through the fundamental knowledge on immune targeting to promising strategies,such as Chimeric antigen receptor T-Cell therapy,immune checkpoint inhibitors,cytokine-based treatment,oncolytic virus and vaccine-based techniques.At last,it is discussed innovative methods to overcome diverse challenges,and future perspectives in this area.展开更多
Anti-CD19 chimeric antigen receptor(CAR)-T cell therapy has achieved 40%–50%long-term complete response in relapsed or refractory diffuse large B-cell lymphoma(DLBCL)patients.However,the underlying mechanism of alter...Anti-CD19 chimeric antigen receptor(CAR)-T cell therapy has achieved 40%–50%long-term complete response in relapsed or refractory diffuse large B-cell lymphoma(DLBCL)patients.However,the underlying mechanism of alterations in the tumor microenvironments resulting in CAR-T cell therapy failure needs further investigation.A multi-center phase I/II trial of anti-CD19 CD28z CAR-T(FKC876,ChiCTR1800019661)was conducted.Among 22 evaluable DLBCL patients,seven achieved complete remission,10 experienced partial remissions,while four had stable disease by day 29.Single-cell RNA sequencing results were obtained from core needle biopsy tumor samples collected from long-term complete remission and early-progressed patients,and compared at different stages of treatment.M2-subtype macrophages were significantly involved in both in vivo and in vitro anti-tumor functions of CAR-T cells,leading to CAR-T cell therapy failure and disease progression in DLBCL.Immunosuppressive tumor microenvironments persisted before CAR-T cell therapy,during both cell expansion and disease progression,which could not be altered by infiltrating CAR-T cells.Aberrant metabolism profile of M2-subtype macrophages and those of dysfunctional T cells also contributed to the immunosuppressive tumor microenvironments.Thus,our findings provided a clinical rationale for targeting tumor microenvironments and reprogramming immune cell metabolism as effective therapeutic strategies to prevent lymphoma relapse in future designs of CAR-T cell therapy.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
The host immune system plays an instrumental role in the surveillance and elimination of tumors by recognizing and destroying cancer cells. In recent decades, studies have mainly focused on adoptive immunotherapy usin...The host immune system plays an instrumental role in the surveillance and elimination of tumors by recognizing and destroying cancer cells. In recent decades, studies have mainly focused on adoptive immunotherapy using engineered T cells for the treatment of malignant diseases. Through gene engraftment of the patient's own T cells with chimeric antigen receptor(CAR),they can recognize tumor specific antigens effectively and eradicate selectively targeted cells in an MHC-independent fashion.To date, CAR-T cell therapy has shown great clinical utility in patients with B-cell leukemias. Owing to different CAR designs and tumor complex microenvironments, genetically redirected T cells may generate diverse biological properties and thereby impact their long-term clinical performance and outcome. Meanwhile some unexpected toxicities that result from CAR-T cell application have been examined and limited the curative effects. Diverse important parameters are closely related with adoptively transferred cell behaviors, including CAR-T cells homing, CAR constitutive signaling, T cell differentiation and exhaustion. Thus, understanding CARs molecular design to improve infused cell efficacy and safety is crucial to clinicians and patients who are considering this novel cancer therapeutics. In this review, the developments in CAR-T cell therapy and the limitations and perspectives in optimizing this technology towards clinical application are discussed.展开更多
基金funded by 2023 Sichuan Scientific and Technological Achievements Transformation Project.Project Number:2023JDZH0024.
文摘Chimeric antigen receptor T-cesll therapy(CAR–T)has achieved groundbreaking advancements in clinical application,ushering in a new era for innovative cancer treatment.However,the challenges associated with implementing this novel targeted cell therapy are increasingly significant.Particularly in the clinical management of solid tumors,obstacles such as the immunosuppressive effects of the tumor microenvironment,limited local tumor infiltration capability of CAR–T cells,heterogeneity of tumor targeting antigens,uncertainties surrounding CAR–T quality,control,and clinical adverse reactions have contributed to increased drug resistance and decreased compliance in tumor therapy.These factors have significantly impeded the widespread adoption and utilization of this therapeutic approach.In this paper,we comprehensively analyze recent preclinical and clinical reports on CAR–T therapy while summarizing crucial factors influencing its efficacy.Furthermore,we aim to identify existing solution strategies and explore their current research status.Through this review article,our objective is to broaden perspectives for further exploration into CAR–T therapy strategies and their clinical applications.
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.
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We have developed and tested chimeric T-cell receptors (TCR) specific for p185HER2. In these experiments, retroviral vectors expressing the N29γ or N29ζ receptors were constructed in pRET6. Amphotropic viral producer cells were established in the GALV-based PG13 packaging cell line. Ficoll purified human peripheral blood lymphocytes (PBL) were virally transduced using an optimized protocol incorporating activation with immobilized anti-CD3/anti-CD28 monoclonal anti- bodies, followed by viral infection in the presence of fibronectin fragment CH296. Transduced cells were co-cultured with human tumor cell lines that overexpress (SK-OV-3) or underexpress (MCF7) p185HER2 to assay for antigen specific im- mune responses. Both CM+ and CD8+ T-cells transduced with the N29γ or N29ζ chTCR demonstrated HER2-specific anti- gen responses, as determined by release of Th1 like cytokines, and cellular cytotoxicity assays. Our results support the fea- sibility of adoptive immunotherapy with genetically modified T-cells expressing a chTCR specific for p185HER2.
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T cells engineered to express chimeric antigen receptors (CARs) combining an external antibody binding domain with the CD3ζ T cell receptor (TCR) signaling domain for triggering cell activation are being used for immunotherapeutic targeting of tumor cells in a non-HLA restricted manner. In this study we transduced T cells with a CD19-CAR construct containing a truncated CD34 gene (tCD34) marker and used these to target the B cell antigen CD19 on the surface of a Hodgkin’s lymphoma (HL) cell line (L591) both in vitro and in vivo. Levels of tCD34 expression in transduced peripheral blood mononuclear cells (PBMCs) ranged from 6% - 20% and this was increased to 82% after selection for transduced tCD34+ cells. In vitro cytotoxicity testing on a CD19+ HL cell line (L591) showed specific cell lysis initiated by the CD19-CAR transduced PBMCs. Importantly, CD19-CAR T cells prevented the growth of L591 HL tumor cells when co-injected subcutaneously (sc) in 6/6 severe combined immunodeficient (SCID) mice. There was no evidence of anti-tumor activity when CD19-CAR T cells were infused intravenously (iv) at the same time as L591 HL tumor cells were injected sc. However, 3/6 SCID mice showed tumor rejection within 83 days after iv infusion of CD19-CAR T cells 3 - 9 days after establishment of L591 HL tumors, while all control animals succumbed to tumors within 60 days. Interestingly, immuno-histochemical analysis of L591 HL tumors demonstrated that CD19-CAR T cells were detected not earlier than 11 days after infusion within the tumor mass. These results suggest that CD19 is a potentially attractive target for the immunotherapy of HL.
基金grants from National Natural Science Foundation of China(81773268)Collaborative Innovation Center for Cancer Personalized Medicine,China(JX21817902/005).
文摘c-Met is a hepatocyte growth factor receptor overexpressed in many tumors such as hepatocellular carcinoma(HCC).Therefore,c-Met may serve as a promising target for HCC immunotherapy.Modifying T cells to express c-Met-specific chimeric antigen receptor(CAR)is an attractive strategy in treating c-Met-positive HCC.This study aimed to systematically evaluate the inhibitory effects of 2^(nd)-and 3^(rd)-generation c-Met CAR-T cells on hepatocellular carcinoma(HCC)cells.Here,2^(nd)-and 3^(rd)-generation c-Met CARs containing an anti-c-Met singlechain variable fragment(scFv)as well as the CD28 signaling domain and CD3ζ(c-Met-28-3ζ),the CD137 signaling domain and CD3ζ(c-Met-137-3ζ),or the CD28 and CD137 signaling domains and CD3ζ(c-Met-28-137-3ζ)were constructed,and their abilities to target c-Met-positive HCC cells were evaluated in vitro and in vivo.All c-Met CARs were stably expressed on T cell membrane,and c-Met CAR-T cells aggregated around c-Met-positive HCC cells and specifically killed them in vitro.c-Met-28-137-3ζCAR-T cells secreted more interferon-gamma(IFN-γ)and interleukin 2(IL-2)than c-Met-28-3ζCAR-T cells and c-Met-137-3ζCAR-T cells.Compared with c-Met low-expressed cells,c-Met CAR-T cells secreted more cytokines when co-cultured with c-Met high-expressed cells.Moreover,c-Met-28-137-3ζCAR-T cells eradicated HCC more effectively in xenograft tumor models compared with the control groups.This study suggests that 3^(rd)-generation c-Met CAR-T cells are more effective in inhibiting c-Met-positive HCC cells than 2^(nd)-generation c-Met CAR-T cells,thereby providing a promising therapeutic intervention for c-Met-positive HCC.
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We have confirmed efficient anti-tumor activities of the peripheral lymphocytes transduced with a p185HEH2-specific chimeric T-cell receptor gene both in murine and in human in our previous studies. To further test the feasibility of chimeric T-cell receptor in a bone marrow transplantation model, we first, made two routine tumor cell lines: MT901 and MCA-205, to express human p185HER2 by retroviral gene transduction. Murine bone marrow cells were retrovirally transduced to express the chimeric T-cell receptor and gene-modified bone marrow cells were transplanted into lethally irradiated mouse. Six months post transplantation, p185HER2-positive tumor ceils: MT-901/HER2 or MCA-205/ HER2 was subcutaneously or intravenously injected to make mouse models simulating primary breast cancer or pulmonary metastasis. The in vivo anti-tumor effects were monitored by the size of the subcutaneous tumor or counting the tumor nodules in the lungs after India ink staining. The size of the subcutaneous tumor was significantly inhibited and the number of pulmonary nodules were significantly decreased in mouse recipients transplanted with chimeric T-cell receptor modified bone marrow cells compared with the control group. Our results suggest the efficient in vivo anti-tumor activities of chimeric T-cell receptor gene modified bone marrow cells.
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.
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.
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supported by the Key Program of the National Natural Science Foundation of China(Nos.81830008 and 81630006)the National Natural Science Foundation of China(No.81570197)and the Natural Science Foundation of Hubei Province(No.2018ACA140).
文摘Adoptive therapeutic immune cells, such as chimeric antigen receptor (CAR)-T cells and natural killer cells, have established a new generation of precision medicine based on which dramatic breakthroughs have been achieved in intractable lymphoma treatments. Currently, well-explored approaches focus on autologous cells due to their low immunogenicity, but they are highly restricted by the high costs, time consumption of processing, and the insufficiency of primary cells in some patients. Induced pluripotent stem cells (iPSCs) are cell sources that can theoretically produce indefinite well-differentiated immune cells. Based on the above facts, it may be reasonable to combine the iPSC technology and the CAR design to produce a series of highly controllable and economical "live" drugs. Manufacturing hypoimmunogenic iPSCs by inactivation or over-expression at the genetic level and then arming the derived cells with CAR have emerged as a form of "off-the-shelf" strategy to eliminate tumor cells efficiently and safely in a broader range of patients. This review describes the reasonability, feasibility, superiority, and drawbacks of such approaches, summarizes the current practices and relevant research progress, and provides insights into the possible new paths for personalized cell-based therapies.
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.
基金Supported by the Scientific Initiation Scholarship Programme(PIBIC)of National Council for Scientific and Technological Development,CNPq,Brazilthe Scientific Initiation Scholarship Programme(PIBIC)of Bahia State Research Support Foundation,FAPESB,Brazil.
文摘Glioblastoma remains as the most common and aggressive malignant brain tumor,standing with a poor prognosis and treatment prospective.Despite the aggressive standard care,such as surgical resection and chemoradiation,median survival rates are low.In this regard,immunotherapeutic strategies aim to become more attractive for glioblastoma,considering its recent advances and approaches.In this review,we provide an overview of the current status and progress in immunotherapy for glioblastoma,going through the fundamental knowledge on immune targeting to promising strategies,such as Chimeric antigen receptor T-Cell therapy,immune checkpoint inhibitors,cytokine-based treatment,oncolytic virus and vaccine-based techniques.At last,it is discussed innovative methods to overcome diverse challenges,and future perspectives in this area.
基金the National Natural Science Foundation of China(Nos.81830007,82130004,81600155,and 81670716)Clinical Research Plan of SHDC(No.2020CR1032B),Shanghai Rising-Star Program(No.19QA145600)+5 种基金Municipal Human Resources Development Program for Outstanding Young Talents in Medical and Health Sciences in Shanghai(No.2017YQ075)Talent(Class A)of Guangci Excellence Youth Plan(No.GCQN-2019-A16)Clinical Research Plan of Shanghai Hospital Development Center(No.SHDC2020CR1032B)Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support(Nos.20152206 and 20152208)China CAR-T Clinical Research Fund Project(No.CARTFR-05)Samuel Waxman Cancer Research Foundation.
文摘Anti-CD19 chimeric antigen receptor(CAR)-T cell therapy has achieved 40%–50%long-term complete response in relapsed or refractory diffuse large B-cell lymphoma(DLBCL)patients.However,the underlying mechanism of alterations in the tumor microenvironments resulting in CAR-T cell therapy failure needs further investigation.A multi-center phase I/II trial of anti-CD19 CD28z CAR-T(FKC876,ChiCTR1800019661)was conducted.Among 22 evaluable DLBCL patients,seven achieved complete remission,10 experienced partial remissions,while four had stable disease by day 29.Single-cell RNA sequencing results were obtained from core needle biopsy tumor samples collected from long-term complete remission and early-progressed patients,and compared at different stages of treatment.M2-subtype macrophages were significantly involved in both in vivo and in vitro anti-tumor functions of CAR-T cells,leading to CAR-T cell therapy failure and disease progression in DLBCL.Immunosuppressive tumor microenvironments persisted before CAR-T cell therapy,during both cell expansion and disease progression,which could not be altered by infiltrating CAR-T cells.Aberrant metabolism profile of M2-subtype macrophages and those of dysfunctional T cells also contributed to the immunosuppressive tumor microenvironments.Thus,our findings provided a clinical rationale for targeting tumor microenvironments and reprogramming immune cell metabolism as effective therapeutic strategies to prevent lymphoma relapse in future designs of CAR-T cell therapy.
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 the grants from the National Key Research and Development Program of China (2016YFC1303501 and 2016YFC1303504)the Science and Technology Planning Project of Beijing City (Z151100003915076)the National Natural Science Foundation of China (81472612 and 81501682)
文摘The host immune system plays an instrumental role in the surveillance and elimination of tumors by recognizing and destroying cancer cells. In recent decades, studies have mainly focused on adoptive immunotherapy using engineered T cells for the treatment of malignant diseases. Through gene engraftment of the patient's own T cells with chimeric antigen receptor(CAR),they can recognize tumor specific antigens effectively and eradicate selectively targeted cells in an MHC-independent fashion.To date, CAR-T cell therapy has shown great clinical utility in patients with B-cell leukemias. Owing to different CAR designs and tumor complex microenvironments, genetically redirected T cells may generate diverse biological properties and thereby impact their long-term clinical performance and outcome. Meanwhile some unexpected toxicities that result from CAR-T cell application have been examined and limited the curative effects. Diverse important parameters are closely related with adoptively transferred cell behaviors, including CAR-T cells homing, CAR constitutive signaling, T cell differentiation and exhaustion. Thus, understanding CARs molecular design to improve infused cell efficacy and safety is crucial to clinicians and patients who are considering this novel cancer therapeutics. In this review, the developments in CAR-T cell therapy and the limitations and perspectives in optimizing this technology towards clinical application are discussed.