Colorectal cancer(CRC)is the third most common cancer worldwide and remains a major treatment challenge,particularly in advanced and metastatic stages.Current standard treatments have limited efficacy,underscoring the...Colorectal cancer(CRC)is the third most common cancer worldwide and remains a major treatment challenge,particularly in advanced and metastatic stages.Current standard treatments have limited efficacy,underscoring the urgent need for innovative strategies.Adoptive cell therapy(ACT),which involves in vitro expansion or genetic engineering of immune cells,is a promising approach to bolster anti-tumor immune responses.Key ACT modalities include chimeric antigen receptor(CAR)T cells,tumor-infiltrating lymphocytes(TILs),and T cell receptor(TCR)-engineered T cells.CAR-T cell therapy has shown success in hematological malignancies but faces significant challenges in solid tumors like CRC.These challenges include antigen heterogeneity,an immunosuppressive tumor microenvironment,on-target off-tumor toxicity,among other factors.To address these limitations,combinatorial approaches,such as immune checkpoint inhibitors,cytokines,and advanced gene-editing tools like CRISPR/Cas9,are being actively explored.These strategies aim to enhance CAR-T cell specificity,improve resistance to immunosuppressive signals,and optimize in vivo functionality.This review summarizes ACT approaches for CRC,with a focus on CAR-T therapy.It briefly introduces TILs and TCR-T cells,while emphasizing the major challenges faced by CAR-T therapy in solid tumors and discusses potential strategies to improve therapeutic outcomes.展开更多
Triple-negative breast cancer(TNBC)is one of the most lethal diseases and lack of feasible therapeutic methods.Herein,we developed a bioactive covalent organic framework(COF)for adoptive cell therapy(ACT)of TNBC.In ou...Triple-negative breast cancer(TNBC)is one of the most lethal diseases and lack of feasible therapeutic methods.Herein,we developed a bioactive covalent organic framework(COF)for adoptive cell therapy(ACT)of TNBC.In our design,Mn^(2+)functionalized COF was employed as a bioactive CpG carrier,which could simultaneously engineer and polarize macrophages to the antitumor phenotype,via the synergistic interaction of CpG and Mn^(2+).In the in vitro experiments,the engineered macrophages were found to secret high levels of antitumor cytokines for efficient TNBC cell inhibition.In the in vivo antitumor model,bioactive COF-engineered macrophages were found to relieve the hypoxia tumor microenvironment,enabling prevention of immune cell depletion during ACT.Thus,we realized efficient TNBC therapy and metastasis inhibition with the engineered macrophages in a long-term therapy model.This work provides a promising strategy for metastatic TNBC treatment and highlights the importance of bioactive COF in biomedicine.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
AIM:To assess the efficacy of immunotherapy with expanded activated autologous lymphocytes(EAALs) in gastric cancer.METHODS:An observational study was designed to retrospectively analyze the clinical data of 84 gastri...AIM:To assess the efficacy of immunotherapy with expanded activated autologous lymphocytes(EAALs) in gastric cancer.METHODS:An observational study was designed to retrospectively analyze the clinical data of 84 gastric cancer patients,of whom 42 were treated by EAAL immunotherapy plus conventional treatment and another 42 only received conventional treatment(control group).EAALs were obtained by proliferation of peripheral blood mononuclear cells from patients followed by phenotype determination.Clinical data including age,gender,clinical stage,chemotherapeutic regimens,hospitalization,surgical,radiotherapy,and survival data were collected along with EAAL therapy details and side effects.Patients were followed and the relationship between treatment and overall survival(OS) data obtained for the immunotherapy and control groups were compared retrospectively.The safety of EAAL immunotherapy was also evaluated.RESULTS:After in vitro culture and proliferation,the percentages of CD3+,CD3+CD8+,CD8+CD27+,CD8+CD28+,and CD3+CD16+/CD56+cells increased remarkably(P < 0.05),while the percentages of CD3+CD4+,CD4+CD25+,and CD3-CD16+/CD56+(natural killer cells) were overtly decreased(P < 0.05); no significant change was observed in CD4+CD25+CD127- cells(P =0.448).Interestingly,OS in the immunotherapy group was significantly higher than that in the control group,with 27.0 and 13.9 mo obtained for the two groups,respectively(P =0.028,HR =0.573,95%CI:0.347-0.945).These findings indicated a 42.7% decrease in the risk of death.In addition,we found that clinical stage and application of EAAL immunotherapy wereindependent prognostic factors for gastric cancer patients.Indeed,the OS in stage Ⅲc and Ⅳ patients that had received surgery was prolonged after EAAL immunotherapy(P < 0.05).Importantly,in vitro induction and proliferation of EAAL were easy and biologically safe.CONCLUSION:Overall,EAAL adoptive immunotherapy might prolong the OS in gastric cancer patients.展开更多
Objective To investigate the effect of FTY720-treated immature bone marrow-derived dendritic cells（BMDCs） on the embryo resorption rate in the CBA/J× DBA/2 abortion mouse model.Methods The dendritic cells（DCs...Objective To investigate the effect of FTY720-treated immature bone marrow-derived dendritic cells（BMDCs） on the embryo resorption rate in the CBA/J× DBA/2 abortion mouse model.Methods The dendritic cells（DCs） were derived from bone marrow of DBA/2 mice, and then co-cultured with FTY720. The abortion mouse models were established by mating female CBA/J mice with DBA/2 mice. Via the CBA/J×DBA/2 abortion mouse model, six groups were established, group A： normal pregnancy model; group B： abortion mouse model with no treatment; group C： abortion mouse model injected with DC culture medium（DCCM）; group D： abortion mouse model injected with DC; group E： abortion mouse model injected with FTY720; group F： abortion model mouse injected with FTY720-DC. The differences were compared in the embryo resorption rates of the CBA/J ×DBA/2 abortion mouse model treated with FTY720-DC or different controls observed on gestation day 12 to 14, and then the microenvironment in murine pregnancy was investigated.Results The embryo resorption rate was statistically significantly decreased in group D and group E when they compared with group B and group C（P〈0.05, respectively）.Furthermore, the embryo resorption rate in group F showed a statistically significant decrease when compared with the other groups except group A（P〈0.01）. These resultssuggest that FTY720-DCs possess a notable advantage over DCs or FTY720 in reducing the embryo resorption rate of the abortion mouse model. The percentage of Th17（IL-17＋CD4＋T cells） in peripheral blood mononuclear cell（PBMC） in the abortion mouse model was 4.35%±0.34% before treated with FTY720-DC, and was1.34%±0.28% after treated with FTY720-DC（P〈0.01）. The percentage of Tregs（CD4~＋CD25~＋Foxp3~＋T cells） in PBMC was significantly increased in group F（8.35%±1.80%） as compared with group B（2.68%±0.65%）（P〈0.01）.Conclusion Adoptive transfer of FTY720-DC can statistically significantly reduce the embryo resorption rate in the CBA/J×DBA/2 abortion mouse model. The lower embryo resorption rate in the FTY720-DC treated abortion mouse model may be caused by the imbalance of Treg/Th17.展开更多
Background: The importance of immunotherapy in cancer treatment has been increased owing to its non-toxicity and application to personalized medicine. However, precise estimation indices of immunotherapy have yet to b...Background: The importance of immunotherapy in cancer treatment has been increased owing to its non-toxicity and application to personalized medicine. However, precise estimation indices of immunotherapy have yet to be established. To determine effective evaluation indices of immunotherapy for cancer treatment, we analyzed the CD4/CD8 ratio under various conditions in clinical patients with advanced cancer. Patients and Methods: Thirty-four patients who underwent one course of adoptive activated immunotherapy with or without additional conventional chemotherapy were enrolled. Before and after one course of immunotherapy, changes in the CD4/CD8 ratio were estimated by flow cytometry. Results: All patients showed a tendency toward a decrease in the CD4/CD8 ratio during a 3-month period after one course of adoptive activated T lymphocyte immunotherapy. Patients who had undergone prior surgery showed a remarkable increase in CD8 T cell number. Thus, adoptive activated T lymphocyte immunotherapy improves immunological ability against cancer invasion. The Eastern Cooperative Oncology Group’s performance status during one course of immunotherapy was significantly improved in the antecedent surgery group, with no evidence of improved PS in the non-antecedent surgery group. Patients with an increased CD4/CD8 ratio (n = 6) may have a worse outcome during adoptive activated T lymphocyte immunotherapy even with an additional course of immunotherapy. Improved actuarial survival rate of patients in the antecedent surgery group showed significant long-term benefit compared to those in the non-antecedent surgery group (p = 0.0298), as previously reported. Conclusion: The CD4/CD8 ratio is a significant indicator of outcome of adoptive activated T lymphocyte immunotherapy.展开更多
In recent years, immunotherapy has been gradually established as the fourth frequently adopted antitumor therapy, following surgery, chemotherapy and radiotherapy, for advanced urologic malignancies with an improved u...In recent years, immunotherapy has been gradually established as the fourth frequently adopted antitumor therapy, following surgery, chemotherapy and radiotherapy, for advanced urologic malignancies with an improved understanding of theoretical basis, such as molecular biology and immunology. Thereinto, adoptive cellular immunotherapy （ACI） has become one of the hotspots, which comprises a variety of treatment approaches, such as TIL, CIK cell, ~＇~ T cell, CAR-engineered T cell and Allogeneie stem cell transplantation （alloSCT）. Although preclinical efficacy has been demonstrated remarkably, clinical trials could not consistently show the benefit due to multi-factors in complex immnnosuppressive microenvironment in vivo compared to that of in vitro. Here we review some timely aspects of ACI for advanced urologic malignancies, and describe the current status and limitation of immunotherapy from the cellular level. It＇s our expectation to provide prompting consideration of novel combinatorial ACI strategies and a resurgence of interest in ACI for advanced urologic malignancies.展开更多
The infused stem cell autograft in autologous stem cell transplantation(ASCT)has been viewed mainly as hematologic rescue from the myelosuppressive side effect of conditioning regimens.However,recent reports have show...The infused stem cell autograft in autologous stem cell transplantation(ASCT)has been viewed mainly as hematologic rescue from the myelosuppressive side effect of conditioning regimens.However,recent reports have shown that the immune effector cells collected at the same time as the stem cells can produce an autologous graft-versus-tumor effect,similar to the graft-versus-tumor effect seen in allogeneic stem cell transplantation without the detrimental effects of graftversus-host disease.In this article,we review the different immune effector cells collected and infused from the stem cell autograft and their association with clinical outcome post-ASCT,suggesting that ASCT can be viewed not only as a therapeutic maneuver to recover bone marrow function after deliver high-dose chemotherapy,but also as an adoptive immunotherapeutic intervention capable of eradicating residual tumor cells in patients with cancer.展开更多
Tumor recurrence is one of the major life-threatening complications after liver transplantation for liver cancer.In addition to the common mechanisms underlying tumor recurrence,another unavoidable problem is that the...Tumor recurrence is one of the major life-threatening complications after liver transplantation for liver cancer.In addition to the common mechanisms underlying tumor recurrence,another unavoidable problem is that the immunosuppressive therapeutic regimen after transplantation could promote tumor recurrence and metastasis.Transplant oncology is an emerging field that addresses oncological challenges in transplantation.In this context,a comprehensive therapeutic management approach is required to balance the anti-tumor treatment and immunosuppressive status of recipients.Double-negative T cells(DNTs)are a cluster of heterogeneous cells mainly consisting of two subsets stratified by T cell receptor(TCR)type.Among them,TCRαβ^(+)DNTs are considered to induce immune suppression in immune-mediated diseases,while TCRγδ^(+)DNTs are widely recognized as tumor killers.As a composite cell therapy,healthy donor-derived DNTs can be propagated to therapeutic numbers in vitro and applied for the treatment of several malignancies without impairing normal tissues or being rejected by the host.In this work,we summarized the biological characteristics and functions of DNTs in oncology,immunology,and transplantation.Based on the multiple roles of DNTs,we propose that a new balance could be achieved in liver transplant oncology using them as an off-the-shelf adoptive cell therapy(ACT).展开更多
T lymphocytes,the main participants of cellular immunity,can express a variety of surface molecules and form different lymphocyte subsets under the induction of different factors to play the functions of immune regula...T lymphocytes,the main participants of cellular immunity,can express a variety of surface molecules and form different lymphocyte subsets under the induction of different factors to play the functions of immune regulation and immune killing.Studies have shown that platelets play a crucial role in maintaining the stable differentiation of lymphocytes and the balance in immunomodulation.Therefore,it is necessary to study the effect of platelets on lymphocytes in vitro to better understand the role of platelets in the immune system and broaden the application of adoptive immunotherapy.Methods:Cell counting and microscopic observation were used to detect the effect of activated platelets on lymphocyte proliferation in vitro;Flow cytometry was used to detect whether changes in platelet activity affect the proportion of lymphocyte subpopulations in vitro,and to detect differences in the expression of granzyme B;lactate dehydrogenase assay(LDH)was used to determine the difference in lymphocyte killing activity caused by platelet activity in vitro.Results:This was the first to promote lymphocyte proliferation through the expression or release of certain molecules in vitro,demonstrating that platelet activation is one of the key factors.Secondly,activated platelets or inactivated platelets promoted lymphocyte subset differentiation by enhancing the proportion of CD3+CD8+T lymphocytes(CTL cells)but had a slight effect on the proportion of CD3+CD4+T(Th cells)and CD4+CD25+T lymphocytes(Treg cells).Then,it was found that either activated platelets or inactivated platelets down-regulated the proportion of natural killer(NK)T lymphocytes,while activated platelets significantly enhance the proportion of NK lymphocytes.Therefore,by further detecting the killing activity of PBMCs treated with platelets,it was found that activated platelets promoted the extensive anti-tumor activity of lymphocytes and significantly increased the expression of granzyme B.Conclusion:Our results suggest that activated platelets promote lymphocyte proliferation,optimize lymphocyte subpopulation ratio,and promote cytotoxic effect of lymphocytes in vitro,which may provide a new strategy for optimizing the adoptive immunotherapy culture system and improving its efficacy.展开更多
Adoptive T-cell therapy(ACT),which is an important type of live cell therapy,has achieved unprecedented success in treating hematological malignancies.Recent studies have shown that ACT is also a promising treatment f...Adoptive T-cell therapy(ACT),which is an important type of live cell therapy,has achieved unprecedented success in treating hematological malignancies.Recent studies have shown that ACT is also a promising treatment for solid tumors.Visualizing the in vivo fates(distribution,homing,infiltration,proliferation,and exhaustion)of the immune cells used for ACT(ACT immune cells)is of great importance to promote basic research and clinical translation of ACT.Optical imaging techniques,including bioluminescence,fluorescence,and photoacoustic imaging,have the advantages of high sensitivity,high spatiotemporal resolution,minimal exposure to harmful radiation,and simple instrumentation.Recently,various types of optical imaging probes,including bioluminescence,fluorescence,and photoacoustic imaging probes,have been used to visualize ACT immune cells in vivo and evaluate the molecular mechanism,efficacy,and side effects of ACT.In this review,the optical imaging probes and labeling methods that have been used for in vivo visualization ofACT immune cells are summarized,and the opportunities and challenges of using optical imaging to visualize ACT immune cells in vivo are discussed.展开更多
B cell malignancies pose challenges due to therapeutic resistance and repeated relapse.Advances in adoptive cellular therapies including chimeric antigen receptor(CAR)-T cells have the potential to transform the treat...B cell malignancies pose challenges due to therapeutic resistance and repeated relapse.Advances in adoptive cellular therapies including chimeric antigen receptor(CAR)-T cells have the potential to transform the treat-ment landscape in hematological and solid tumor cancers.Improvements in constructs of CAR-T have improved specificity in targeting malignant cells.Multiple clinical trials have demonstrated the efficacy of CAR-T and other cellular treatments.In spite of advances in cellular therapies,hurdles in managing toxicities and lingering resis-tance remain.This review aims to summarize current innovations in adoptive cellular therapies and introduces future paths of discovery that will enhance these therapies in the era of precision oncology.展开更多
Objective To generate a chronic lymphocytic leukemia(CLL) mouse model with intact immune competence and short latency by adoptively transferring(AT) splenocytes from immunoglobulin heavy-chain enhancer-driven T-cell l...Objective To generate a chronic lymphocytic leukemia(CLL) mouse model with intact immune competence and short latency by adoptively transferring(AT) splenocytes from immunoglobulin heavy-chain enhancer-driven T-cell leukemia/lymphoma 1 (Eμ-TCLl) transgenic donors into wild-type(WT) recipients.展开更多
The intricate tumor microenvironment presents formidable obstacles to the efficacy of adoptive T cell therapy in the management of solid tumors by limiting the infiltration and inducing exhaustion of the transferred T...The intricate tumor microenvironment presents formidable obstacles to the efficacy of adoptive T cell therapy in the management of solid tumors by limiting the infiltration and inducing exhaustion of the transferred T cells.Here,we developed a bacterial-based adjuvant approach that augments the efficacy of adoptive T-cell therapy for solid tumor treatment.Our study reveals that intratumor injection of E.coli MG1655 normalizes tumor vasculatures and reprograms tumor-associated macrophages into M1 phenotype that produce abundant CCL5,together facilitating tumor infiltration of adoptively transferred T cells.The depletion of tumor-associated macrophages or CCL5 neutralization in vivo leads to the significantly decreased solid tumor infiltration of adoptive T cells in the presence of bacteriotherapy.This combinatorial therapy,consisting of E.coli adjuvant and adoptive T-cell therapy,effectively eradicates early-stage melanoma and inhibits the progression of pancreatic tumors.Notably,this dual strategy also strengthened the distal tumor control capabilities of adoptive T-cell therapy through the induction of in situ tumor vaccination.This dual therapeutic approach involving bacterial therapy targeting the interior of solid tumors and adoptive T-cell therapy attacking the tumor periphery exhibits potent therapeutic efficacy in achieving the eradication of advanced-stage tumors,including melanoma and hepatocellular carcinoma,by converging attacks from both inside and outside the tumor tissues.展开更多
Adoptive immunotherapy,notably involving chimeric antigen receptor(CAR)-T cells,has obtained Food and Drug Administration(FDA)approval as a treatment for various hematological malignancies,demonstrating promising prec...Adoptive immunotherapy,notably involving chimeric antigen receptor(CAR)-T cells,has obtained Food and Drug Administration(FDA)approval as a treatment for various hematological malignancies,demonstrating promising preclinical efficacy against cancers.However,the intricate and resource-intensive autologous cell processing,encompassing collection,expansion,engineering,isolation,and administration,hamper the efficacy of this therapeutic modality.Furthermore,conventional CAR T therapy is presently confined to addressing solid tumors due to impediments posed by physical barriers,the potential for cytokine release syndrome,and cellular exhaustion induced by the immunosuppressive and heterogeneous tumor microenvironment.Consequently,a strategic integration of adoptive immunotherapy with synergistic multimodal treatments,such as chemotherapy,radiotherapy,and vaccine therapy etc.,emerges as a pivotal approach to surmount these inherent challenges.This collaborative strategy holds the key to addressing the limitations delineated above,thereby facilitating the realization of more precise personalized therapies characterized by heightened therapeutic efficacy.Such synergistic strategy not only serves to mitigate the constraints associated with adoptive immunotherapy but also fosters enhanced clinical applicability,thereby advancing the frontiers of therapeutic precision and effectiveness.展开更多
Background Adoptive transfer of allogeneic tumor-specific T cells often results in severe graft-versus-host disease （GVHD）. Here, we sought to maximize graft-versus-tumor and minimize GVHD by using haploidentical T ...Background Adoptive transfer of allogeneic tumor-specific T cells often results in severe graft-versus-host disease （GVHD）. Here, we sought to maximize graft-versus-tumor and minimize GVHD by using haploidentical T cells in pre-irradiated B16-melanoma bearing mice.展开更多
基金Supported by the Natural Science Foundation of the Science and Technology Commission of Shanghai Municipality,China,No.23ZR1458300Key Discipline Project of Shanghai Municipal Health System,China,No.2024ZDXK0004+1 种基金Doctoral Innovation Talent Base Project for Diagnosis and Treatment of Chronic Liver Diseases,China,No.RCJD2021B02Pujiang Project of Shanghai Magnolia Talent Plan,China,No.24PJD098.
文摘Colorectal cancer(CRC)is the third most common cancer worldwide and remains a major treatment challenge,particularly in advanced and metastatic stages.Current standard treatments have limited efficacy,underscoring the urgent need for innovative strategies.Adoptive cell therapy(ACT),which involves in vitro expansion or genetic engineering of immune cells,is a promising approach to bolster anti-tumor immune responses.Key ACT modalities include chimeric antigen receptor(CAR)T cells,tumor-infiltrating lymphocytes(TILs),and T cell receptor(TCR)-engineered T cells.CAR-T cell therapy has shown success in hematological malignancies but faces significant challenges in solid tumors like CRC.These challenges include antigen heterogeneity,an immunosuppressive tumor microenvironment,on-target off-tumor toxicity,among other factors.To address these limitations,combinatorial approaches,such as immune checkpoint inhibitors,cytokines,and advanced gene-editing tools like CRISPR/Cas9,are being actively explored.These strategies aim to enhance CAR-T cell specificity,improve resistance to immunosuppressive signals,and optimize in vivo functionality.This review summarizes ACT approaches for CRC,with a focus on CAR-T therapy.It briefly introduces TILs and TCR-T cells,while emphasizing the major challenges faced by CAR-T therapy in solid tumors and discusses potential strategies to improve therapeutic outcomes.
基金supported by the National Natural Science Foundation of China(No.22304073)the Dongguan Science and Technology of Social Development Program(No.20231800935782)。
文摘Triple-negative breast cancer(TNBC)is one of the most lethal diseases and lack of feasible therapeutic methods.Herein,we developed a bioactive covalent organic framework(COF)for adoptive cell therapy(ACT)of TNBC.In our design,Mn^(2+)functionalized COF was employed as a bioactive CpG carrier,which could simultaneously engineer and polarize macrophages to the antitumor phenotype,via the synergistic interaction of CpG and Mn^(2+).In the in vitro experiments,the engineered macrophages were found to secret high levels of antitumor cytokines for efficient TNBC cell inhibition.In the in vivo antitumor model,bioactive COF-engineered macrophages were found to relieve the hypoxia tumor microenvironment,enabling prevention of immune cell depletion during ACT.Thus,we realized efficient TNBC therapy and metastasis inhibition with the engineered macrophages in a long-term therapy model.This work provides a promising strategy for metastatic TNBC treatment and highlights the importance of bioactive COF in biomedicine.
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.
基金Supported by National Science and Technology Infrastructure Program of China,No.2009BAI86B05
文摘AIM:To assess the efficacy of immunotherapy with expanded activated autologous lymphocytes(EAALs) in gastric cancer.METHODS:An observational study was designed to retrospectively analyze the clinical data of 84 gastric cancer patients,of whom 42 were treated by EAAL immunotherapy plus conventional treatment and another 42 only received conventional treatment(control group).EAALs were obtained by proliferation of peripheral blood mononuclear cells from patients followed by phenotype determination.Clinical data including age,gender,clinical stage,chemotherapeutic regimens,hospitalization,surgical,radiotherapy,and survival data were collected along with EAAL therapy details and side effects.Patients were followed and the relationship between treatment and overall survival(OS) data obtained for the immunotherapy and control groups were compared retrospectively.The safety of EAAL immunotherapy was also evaluated.RESULTS:After in vitro culture and proliferation,the percentages of CD3+,CD3+CD8+,CD8+CD27+,CD8+CD28+,and CD3+CD16+/CD56+cells increased remarkably(P < 0.05),while the percentages of CD3+CD4+,CD4+CD25+,and CD3-CD16+/CD56+(natural killer cells) were overtly decreased(P < 0.05); no significant change was observed in CD4+CD25+CD127- cells(P =0.448).Interestingly,OS in the immunotherapy group was significantly higher than that in the control group,with 27.0 and 13.9 mo obtained for the two groups,respectively(P =0.028,HR =0.573,95%CI:0.347-0.945).These findings indicated a 42.7% decrease in the risk of death.In addition,we found that clinical stage and application of EAAL immunotherapy wereindependent prognostic factors for gastric cancer patients.Indeed,the OS in stage Ⅲc and Ⅳ patients that had received surgery was prolonged after EAAL immunotherapy(P < 0.05).Importantly,in vitro induction and proliferation of EAAL were easy and biologically safe.CONCLUSION:Overall,EAAL adoptive immunotherapy might prolong the OS in gastric cancer patients.
基金supported by the National Natural Science Foundation of China(Grant No.81200477)
文摘Objective To investigate the effect of FTY720-treated immature bone marrow-derived dendritic cells（BMDCs） on the embryo resorption rate in the CBA/J× DBA/2 abortion mouse model.Methods The dendritic cells（DCs） were derived from bone marrow of DBA/2 mice, and then co-cultured with FTY720. The abortion mouse models were established by mating female CBA/J mice with DBA/2 mice. Via the CBA/J×DBA/2 abortion mouse model, six groups were established, group A： normal pregnancy model; group B： abortion mouse model with no treatment; group C： abortion mouse model injected with DC culture medium（DCCM）; group D： abortion mouse model injected with DC; group E： abortion mouse model injected with FTY720; group F： abortion model mouse injected with FTY720-DC. The differences were compared in the embryo resorption rates of the CBA/J ×DBA/2 abortion mouse model treated with FTY720-DC or different controls observed on gestation day 12 to 14, and then the microenvironment in murine pregnancy was investigated.Results The embryo resorption rate was statistically significantly decreased in group D and group E when they compared with group B and group C（P〈0.05, respectively）.Furthermore, the embryo resorption rate in group F showed a statistically significant decrease when compared with the other groups except group A（P〈0.01）. These resultssuggest that FTY720-DCs possess a notable advantage over DCs or FTY720 in reducing the embryo resorption rate of the abortion mouse model. The percentage of Th17（IL-17＋CD4＋T cells） in peripheral blood mononuclear cell（PBMC） in the abortion mouse model was 4.35%±0.34% before treated with FTY720-DC, and was1.34%±0.28% after treated with FTY720-DC（P〈0.01）. The percentage of Tregs（CD4~＋CD25~＋Foxp3~＋T cells） in PBMC was significantly increased in group F（8.35%±1.80%） as compared with group B（2.68%±0.65%）（P〈0.01）.Conclusion Adoptive transfer of FTY720-DC can statistically significantly reduce the embryo resorption rate in the CBA/J×DBA/2 abortion mouse model. The lower embryo resorption rate in the FTY720-DC treated abortion mouse model may be caused by the imbalance of Treg/Th17.
文摘Background: The importance of immunotherapy in cancer treatment has been increased owing to its non-toxicity and application to personalized medicine. However, precise estimation indices of immunotherapy have yet to be established. To determine effective evaluation indices of immunotherapy for cancer treatment, we analyzed the CD4/CD8 ratio under various conditions in clinical patients with advanced cancer. Patients and Methods: Thirty-four patients who underwent one course of adoptive activated immunotherapy with or without additional conventional chemotherapy were enrolled. Before and after one course of immunotherapy, changes in the CD4/CD8 ratio were estimated by flow cytometry. Results: All patients showed a tendency toward a decrease in the CD4/CD8 ratio during a 3-month period after one course of adoptive activated T lymphocyte immunotherapy. Patients who had undergone prior surgery showed a remarkable increase in CD8 T cell number. Thus, adoptive activated T lymphocyte immunotherapy improves immunological ability against cancer invasion. The Eastern Cooperative Oncology Group’s performance status during one course of immunotherapy was significantly improved in the antecedent surgery group, with no evidence of improved PS in the non-antecedent surgery group. Patients with an increased CD4/CD8 ratio (n = 6) may have a worse outcome during adoptive activated T lymphocyte immunotherapy even with an additional course of immunotherapy. Improved actuarial survival rate of patients in the antecedent surgery group showed significant long-term benefit compared to those in the non-antecedent surgery group (p = 0.0298), as previously reported. Conclusion: The CD4/CD8 ratio is a significant indicator of outcome of adoptive activated T lymphocyte immunotherapy.
基金supported by a grant from National Natural Science Foundation of China(No.30901481,81372752,81472411)Wu-Jie Ping Medical Foundation(320.6750.13261)
文摘In recent years, immunotherapy has been gradually established as the fourth frequently adopted antitumor therapy, following surgery, chemotherapy and radiotherapy, for advanced urologic malignancies with an improved understanding of theoretical basis, such as molecular biology and immunology. Thereinto, adoptive cellular immunotherapy （ACI） has become one of the hotspots, which comprises a variety of treatment approaches, such as TIL, CIK cell, ~＇~ T cell, CAR-engineered T cell and Allogeneie stem cell transplantation （alloSCT）. Although preclinical efficacy has been demonstrated remarkably, clinical trials could not consistently show the benefit due to multi-factors in complex immnnosuppressive microenvironment in vivo compared to that of in vitro. Here we review some timely aspects of ACI for advanced urologic malignancies, and describe the current status and limitation of immunotherapy from the cellular level. It＇s our expectation to provide prompting consideration of novel combinatorial ACI strategies and a resurgence of interest in ACI for advanced urologic malignancies.
文摘The infused stem cell autograft in autologous stem cell transplantation(ASCT)has been viewed mainly as hematologic rescue from the myelosuppressive side effect of conditioning regimens.However,recent reports have shown that the immune effector cells collected at the same time as the stem cells can produce an autologous graft-versus-tumor effect,similar to the graft-versus-tumor effect seen in allogeneic stem cell transplantation without the detrimental effects of graftversus-host disease.In this article,we review the different immune effector cells collected and infused from the stem cell autograft and their association with clinical outcome post-ASCT,suggesting that ASCT can be viewed not only as a therapeutic maneuver to recover bone marrow function after deliver high-dose chemotherapy,but also as an adoptive immunotherapeutic intervention capable of eradicating residual tumor cells in patients with cancer.
基金supported by the Key Research&Development Plan of Zhejiang Province(Nos.2019C03050 and 2021C03118)the National Key Research and Development Program of China(No.2021YFA1100500)the National Natural Science Foundation of China(No.92159202)。
文摘Tumor recurrence is one of the major life-threatening complications after liver transplantation for liver cancer.In addition to the common mechanisms underlying tumor recurrence,another unavoidable problem is that the immunosuppressive therapeutic regimen after transplantation could promote tumor recurrence and metastasis.Transplant oncology is an emerging field that addresses oncological challenges in transplantation.In this context,a comprehensive therapeutic management approach is required to balance the anti-tumor treatment and immunosuppressive status of recipients.Double-negative T cells(DNTs)are a cluster of heterogeneous cells mainly consisting of two subsets stratified by T cell receptor(TCR)type.Among them,TCRαβ^(+)DNTs are considered to induce immune suppression in immune-mediated diseases,while TCRγδ^(+)DNTs are widely recognized as tumor killers.As a composite cell therapy,healthy donor-derived DNTs can be propagated to therapeutic numbers in vitro and applied for the treatment of several malignancies without impairing normal tissues or being rejected by the host.In this work,we summarized the biological characteristics and functions of DNTs in oncology,immunology,and transplantation.Based on the multiple roles of DNTs,we propose that a new balance could be achieved in liver transplant oncology using them as an off-the-shelf adoptive cell therapy(ACT).
文摘T lymphocytes,the main participants of cellular immunity,can express a variety of surface molecules and form different lymphocyte subsets under the induction of different factors to play the functions of immune regulation and immune killing.Studies have shown that platelets play a crucial role in maintaining the stable differentiation of lymphocytes and the balance in immunomodulation.Therefore,it is necessary to study the effect of platelets on lymphocytes in vitro to better understand the role of platelets in the immune system and broaden the application of adoptive immunotherapy.Methods:Cell counting and microscopic observation were used to detect the effect of activated platelets on lymphocyte proliferation in vitro;Flow cytometry was used to detect whether changes in platelet activity affect the proportion of lymphocyte subpopulations in vitro,and to detect differences in the expression of granzyme B;lactate dehydrogenase assay(LDH)was used to determine the difference in lymphocyte killing activity caused by platelet activity in vitro.Results:This was the first to promote lymphocyte proliferation through the expression or release of certain molecules in vitro,demonstrating that platelet activation is one of the key factors.Secondly,activated platelets or inactivated platelets promoted lymphocyte subset differentiation by enhancing the proportion of CD3+CD8+T lymphocytes(CTL cells)but had a slight effect on the proportion of CD3+CD4+T(Th cells)and CD4+CD25+T lymphocytes(Treg cells).Then,it was found that either activated platelets or inactivated platelets down-regulated the proportion of natural killer(NK)T lymphocytes,while activated platelets significantly enhance the proportion of NK lymphocytes.Therefore,by further detecting the killing activity of PBMCs treated with platelets,it was found that activated platelets promoted the extensive anti-tumor activity of lymphocytes and significantly increased the expression of granzyme B.Conclusion:Our results suggest that activated platelets promote lymphocyte proliferation,optimize lymphocyte subpopulation ratio,and promote cytotoxic effect of lymphocytes in vitro,which may provide a new strategy for optimizing the adoptive immunotherapy culture system and improving its efficacy.
基金Natural Science Foundation of China,Grant/Award Number:92159304Key Laboratory for Magnetic Resonance and Multimodality Imaging of Guangdong Province,Grant/Award Number:2020B1212060051+3 种基金Basic and Applied Basic Research Foundation of Guangdong Province,Grant/Award Numbers:2022A1515010384,2023A1515010747CAS Key Laboratory of Health Informatics,Grant/Award Number:2011DP173015Science and Technology Key Project of Shenzhen,Grant/Award Numbers:JCYJ20190812163614809,JCYJ20200109114612308,JCYJ20210324120011030Shenzhen Key Laboratory of Ultrasound Imaging and Therapy,Grant/Award Number:ZDSYS201802061806314。
文摘Adoptive T-cell therapy(ACT),which is an important type of live cell therapy,has achieved unprecedented success in treating hematological malignancies.Recent studies have shown that ACT is also a promising treatment for solid tumors.Visualizing the in vivo fates(distribution,homing,infiltration,proliferation,and exhaustion)of the immune cells used for ACT(ACT immune cells)is of great importance to promote basic research and clinical translation of ACT.Optical imaging techniques,including bioluminescence,fluorescence,and photoacoustic imaging,have the advantages of high sensitivity,high spatiotemporal resolution,minimal exposure to harmful radiation,and simple instrumentation.Recently,various types of optical imaging probes,including bioluminescence,fluorescence,and photoacoustic imaging probes,have been used to visualize ACT immune cells in vivo and evaluate the molecular mechanism,efficacy,and side effects of ACT.In this review,the optical imaging probes and labeling methods that have been used for in vivo visualization ofACT immune cells are summarized,and the opportunities and challenges of using optical imaging to visualize ACT immune cells in vivo are discussed.
文摘B cell malignancies pose challenges due to therapeutic resistance and repeated relapse.Advances in adoptive cellular therapies including chimeric antigen receptor(CAR)-T cells have the potential to transform the treat-ment landscape in hematological and solid tumor cancers.Improvements in constructs of CAR-T have improved specificity in targeting malignant cells.Multiple clinical trials have demonstrated the efficacy of CAR-T and other cellular treatments.In spite of advances in cellular therapies,hurdles in managing toxicities and lingering resis-tance remain.This review aims to summarize current innovations in adoptive cellular therapies and introduces future paths of discovery that will enhance these therapies in the era of precision oncology.
文摘Objective To generate a chronic lymphocytic leukemia(CLL) mouse model with intact immune competence and short latency by adoptively transferring(AT) splenocytes from immunoglobulin heavy-chain enhancer-driven T-cell leukemia/lymphoma 1 (Eμ-TCLl) transgenic donors into wild-type(WT) recipients.
基金supported by the National Key R&D Program of China(2021YFA0909900)the National Natural Science Foundation of China(52173142,52233013)+1 种基金the“Pioneer”and“Leading Goose”R&D Program of Zhejiang(2024C03168)the Startup Package of Zhejiang University.
文摘The intricate tumor microenvironment presents formidable obstacles to the efficacy of adoptive T cell therapy in the management of solid tumors by limiting the infiltration and inducing exhaustion of the transferred T cells.Here,we developed a bacterial-based adjuvant approach that augments the efficacy of adoptive T-cell therapy for solid tumor treatment.Our study reveals that intratumor injection of E.coli MG1655 normalizes tumor vasculatures and reprograms tumor-associated macrophages into M1 phenotype that produce abundant CCL5,together facilitating tumor infiltration of adoptively transferred T cells.The depletion of tumor-associated macrophages or CCL5 neutralization in vivo leads to the significantly decreased solid tumor infiltration of adoptive T cells in the presence of bacteriotherapy.This combinatorial therapy,consisting of E.coli adjuvant and adoptive T-cell therapy,effectively eradicates early-stage melanoma and inhibits the progression of pancreatic tumors.Notably,this dual strategy also strengthened the distal tumor control capabilities of adoptive T-cell therapy through the induction of in situ tumor vaccination.This dual therapeutic approach involving bacterial therapy targeting the interior of solid tumors and adoptive T-cell therapy attacking the tumor periphery exhibits potent therapeutic efficacy in achieving the eradication of advanced-stage tumors,including melanoma and hepatocellular carcinoma,by converging attacks from both inside and outside the tumor tissues.
基金supported by start-up package funding from The Hong Kong Polytechnic University(Y.C.).
文摘Adoptive immunotherapy,notably involving chimeric antigen receptor(CAR)-T cells,has obtained Food and Drug Administration(FDA)approval as a treatment for various hematological malignancies,demonstrating promising preclinical efficacy against cancers.However,the intricate and resource-intensive autologous cell processing,encompassing collection,expansion,engineering,isolation,and administration,hamper the efficacy of this therapeutic modality.Furthermore,conventional CAR T therapy is presently confined to addressing solid tumors due to impediments posed by physical barriers,the potential for cytokine release syndrome,and cellular exhaustion induced by the immunosuppressive and heterogeneous tumor microenvironment.Consequently,a strategic integration of adoptive immunotherapy with synergistic multimodal treatments,such as chemotherapy,radiotherapy,and vaccine therapy etc.,emerges as a pivotal approach to surmount these inherent challenges.This collaborative strategy holds the key to addressing the limitations delineated above,thereby facilitating the realization of more precise personalized therapies characterized by heightened therapeutic efficacy.Such synergistic strategy not only serves to mitigate the constraints associated with adoptive immunotherapy but also fosters enhanced clinical applicability,thereby advancing the frontiers of therapeutic precision and effectiveness.
文摘Background Adoptive transfer of allogeneic tumor-specific T cells often results in severe graft-versus-host disease （GVHD）. Here, we sought to maximize graft-versus-tumor and minimize GVHD by using haploidentical T cells in pre-irradiated B16-melanoma bearing mice.
