Use of CAR-T cells for the treatment of relapsed and refractory multiple myeloma: a systematic review / Uso de células CAR-T no tratamento de mieloma múltiplo recidivado e refratário: uma revisão sistemática

A systematic review of published articles based on randomized clinical trials was conducted to ascertain the efficacy or perspective of using CAR-T cell therapy for refractory multiple myeloma. The PubMed database was searched with the combination of terms "multiple myeloma", "refractory multiple myeloma", "CAR T-cell", and the PRISMA criteria were followed. Of the 78 articles found, only 5 were selected. The studies used different treatment protocols and four different types of CAR-T cells. All studies obtained interesting results in terms of increased progression-free survival and negative minimal residual disease responses. Some authors detected an expansion of CAR-T cells and noted dose-dependent relationship between treatment effectiveness and serum BCMA levels. Although the results were promising, a small number of patients still relapsed a few months after CAR-T cell infusion. Therefore, this new line of therapy should be further investigated, as it significantly increases progression-free survival and improves quality of life.

Uma revisão sistemática de artigos publicados com base em ensaios clínicos randomizados foi realizada para verificar a eficácia ou perspectiva do uso da terapia com células CAR-T para mieloma múltiplo refratário. Foi pesquisada a base de dados PubMed com a combinação dos termos "multiple myeloma", "refratory multiple myeloma", "CAR T-cell" e foram seguidos os critérios PRISMA. Dos 78 artigos encontrados, apenas 5 foram selecionados. Os estudos utilizaram diferentes protocolos de tratamento e quatro tipos diferentes de células CAR-T. Todos os estudos obtiveram resultados interessantes em termos de aumento da sobrevida livre de progressão e respostas negativas à doença residual mínima. Alguns autores detectaram uma expansão das células CAR-T e observaram uma relação dose-dependente entre a eficácia do tratamento e os níveis séricos de BCMA. Embora os resultados tenham sido promissores, um pequeno número de pacientes ainda apresentou recaída alguns meses após a infusão de células CAR-T. Portanto, esta nova linha de terapia deve ser mais investigada, pois aumenta significativamente a sobrevida livre de progressão e melhora a qualidade de vida.

Clinical research progress of immunotherapy for nasopharyngeal carcinoma / 国际肿瘤学杂志

Immunotherapy mainly uses the effector units of the body's immune system to overcome the immune escape or adaptive immune resistance of tumors, accurately identify and remove tumor cells, and normalize or enhance the function of the immune system, which mainly includes cytokine therapy, immune checkpoint inhibition therapy, adoptive cell immunotherapy, tumor vaccine and antibody targeted therapy. The immune characteristics of nasopharyngeal carcinoma make the patients potentially suitable for immunotherapy or combined therapy with radiotherapy and chemotherapy. In recent years, PD-1 inhibitors alone and in combination with chemotherapy have shown good anti-tumor activity and safety in the treatment of recurrent/metastatic nasopharyngeal carcinoma. The incorporation of immune checkpoint inhibitors into the treatment paradigms of nasopharyngeal carcinoma has become a clinical research hot spot.

Progress of companion diagnostics in chimeric antigen receptor T-cell therapy / 白血病·淋巴瘤

Chimeric antigen receptor T-cell (CAR-T) immunotherapy has achieved good efficacy in treatment of hematological malignancies. As a precise and individualized treatment method, CAR-T is gradually moving towards commercialization. In addition to the introduction of corresponding policies and guiding principles, the related detection protocols should also be updated and improved to maximize its effect and achieve precise individualization. This article introduces and expands the concept of "companion diagnostics" that first appeared in targeted drugs, and introduces the significances of various detection technologies and biomarkers for patient screening, safety monitoring and evaluation of efficacy and CAR-T function in the whole process of CAR-T treatment.

Aplicación de células madres autólogas en pacientes con aterosclerosis obliterante grado IV / Application of autologous stem cells in patients with grade IV atherosclerosis obliterans

RESUMEN Introducción: la enfermedad arterial periférica de los miembros inferiores afecta a un elevado porcentaje de la población mundial, con las células madres autólogas obtenidas de sangre periférica se logra una mayor síntesis de factores de crecimiento que inducen la angiogénesis. Objetivo: describir el autotrasplante de células madres autólogas obtenidas de sangre periférica en pacientes con aterosclerosis obliterante grado IV, de Pinar del Río, atendidos en el período de 2009-2019. Métodos: se realizó un estudio descriptivo, longitudinal, con 296 pacientes que presentaban aterosclerosis obliterante grado IV durante en el período de 2009-2019. Se obtuvo el concentrado de células madres autólogas de sangre periférica. Las células se analizaron por citometría de flujo, donde mostraron una viabilidad celular del 99,3 %. Se les inyectó por vía intramuscular un concentrado de células madres con un número de células inyectadas de ocho, seis, diez. Las variables estudiadas fueron: índice de presión tobillo-brazo en reposo, distancia de claudicación libre de dolor, evaluación de la escala del dolor y criterio de amputación. Resultado: se observó alivio del dolor a las cuatro semanas y aumento de la distancia de claudicación libre de dolor. La angiografía post tratamiento mostró formación de vasos colaterales. Presentaron criterio de amputación 95 casos (32 %) se logró salvar la extremidad en 201 pacientes (68 %). El proceder realizado no se asoció con ninguna complicación. Conclusión: la aplicación de células madres autólogas de sangre periférica es segura y eficaz para el tratamiento de la aterosclerosis obliterante grado IV.

ABSTRACT Introduction: peripheral arterial disease of the lower limbs affects a high percentage of the world population; with autologous stem cells obtained from peripheral blood a greater synthesis of growth factors that induce angiogenesis is achieved. Objective: to describe the auto-transplantation of autologous stem cells obtained from peripheral blood in patients with grade IV atherosclerosis obliterans in Pinar del Rio treated during period 2009-2019. Methods: a descriptive, longitudinal study was carried out with 296 patients with grade IV atherosclerosis obliterans during the period 2009-2019. Autologous peripheral blood stem cell concentrate was obtained. The cells were analyzed by flow cytometry, where they showed a cell viability of 99,3 %. Stem cell concentrate was injected intramuscularly with a number of cells injected of eight, six and ten. The variables studied were ankle-brachial pressure index at rest, pain-free claudication distance, pain scale assessment and amputation criteria. Result: pain relief was observed at four weeks and increase in pain-free claudication distance. Post-treatment angiography showed collateral vessel formation. Amputation criteria were met in 95 cases (32 %) and the limb was saved in 201 patients (68 %). The procedure carried out was not associated with complications. Conclusion: the application of autologous peripheral blood stem cells is safe and effective for the treatment of grade IV atherosclerosis obliterans.

Neurologic adverse events of cancer immunotherapy / Eventos adversos neurológicos da imunoterapia contra o câncer

ABSTRACT Cancer immunotherapy encompasses a wide range of treatment modalities that harness the anti-tumor effects of the immune system and have revolutionized oncological treatment in recent years, with approval for its use in more and more cancers. However, it is not without side effects. Several neurological adverse events have been recognized associated with immune checkpoint inhibitors (ICI) and chimeric antigen receptor (CAR) T-cell therapy, the two main classes of cancer immunotherapy. With the increase in the prevalence of oncological diseases and this type of therapy, it is improbable that neurologists, oncologists, hematologists, and other healthcare professionals who deal with cancer patients will not encounter this type of neurologic complication in their practice in the following years. This article aims to review the epidemiology, clinical manifestations, diagnosis, and management of neurological complications associated with ICI and CAR T-cell therapy.

RESUMO A imunoterapia contra o câncer engloba uma gama de modalidades de tratamento que aumentam os efeitos antitumorais do próprio sistema imunológico do paciente e revolucionaram o tratamento oncológico nos últimos anos, com aprovação para seu uso em cada vez mais neoplasias. No entanto, não é sem efeitos colaterais. Vários eventos adversos neurológicos foram reconhecidos associados aos inibidores de checkpoint imunológico (ICI) e à terapia de células T com receptor de antígeno quimérico (CAR-T), as duas principais classes de imunoterapia contra o câncer. Com o aumento da prevalência de doenças oncológicas e desse tipo de terapia, é improvável que neurologistas, oncologistas, hematologistas e demais profissionais de saúde que lidam com pacientes com câncer não encontrem esse tipo de complicação neurológica em sua prática nos próximos anos. Este artigo tem como objetivo revisar a epidemiologia, as manifestações clínicas, o diagnóstico e o manejo das complicações neurológicas associadas à terapia com ICI e células CAR-T

Chimeric antigen receptor T cell immunotherapy for refractory and relapsed acute lymphoblastic leukemia: Challenge and Countermeasures / 中华检验医学杂志

Chimeric antigen receptor(CAR)-T cell immunotherapy for refractory and relapsed acute lymphoblastic leukemia (R/R ALL) is one of the breakthroughs in the field of hematological malignant disease treatment. However, several challenges remain, such as immune rejection of allogeneic CAR-T cells, leukemia relapse, as well as could we apply CAR-T cell immunotherapy to ALL patients with positive measurable residual disease and those of newly diagnosed cases. The safety and efficiency of CAR-T therapy will be further improved for patients with ALL only by establishing appropriate strategies to address these challenges.

Advances in immunotherapy of gastric cancer / 肿瘤研究与临床

Gastric cancer is a common digestive tract tumor derived from the gastric mucosal epithelial cells. Adenocarcinoma is the most common pathological type of gastric cancer, and its treatment is determined by the stage and pathological type. The current treatments of gastric cancer include endoscopic or surgical resection of tumor, chemotherapy and radiotherapy, etc. Although the treatment strategies of gastric cancer have made progress, the efficacy is still not ideal. Immunotherapy has the characteristics of precise effect on tumor microenvironment and long-lasting response, and it has become an important treatment method for various tumors, including gastric cancer.

Effect of cellular immunotherapy combined with chemotherapy on apoptosis-related genes and immune function in patients with non-small cell lung cancer / 中国基层医药

Objective:To investigate the effect of immunotherapy with dendritic cells and cytokine-induced killer cells combined with chemotherapy on apoptosis-related genes and immune function in patients with middle- and advanced-stage non-small cell lung cancer.Methods:A total of 100 patients with middle- and advanced-stage non-small cell lung cancer who received treatment in Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, China from February 2018 to May 2019 were included in this study. They were randomly divided into control and observation groups ( n = 50/group). The two groups were given chemotherapy with pemetrexed and cisplatin. The observation group was given immunotherapy with dendritic cells and cytokine-induced killer cells based on chemotherapy with pemetrexed and cisplatin. Changes in apoptosis-related genes [primary autosomal recessive microcephaly gene (MCPH1), ataxia-telangiectasia mutated (ATM), ataxia telangiectasia mutated and Rad3 related (ATR), transcription factor 21 (TCF21)] and immune function were monitored. Clinical efficacy of immunotherapy with dendritic cells and cytokine-induced killer cells combined with chemotherapy with pemetrexed and cisplatin in the treatment middle-and advanced-stage non-small cell lung cancer was assessed. Results:After treatment, expression of MCPH1, ATM, ATR and TCF21 in the observation group was 301.11 ± 41.12, 239.98 ± 30.15, 270.01 ± 36.01, 270.01 ± 34.02, respectively, which was significantly higher than that in the control group [101.32 ± 15.32, 103.00 ± 13.97, 101.12 ± 14.90, 100.20 ± 14.99, t = 32.194, 29.149, 30.644, 32.299, all P < 0.001]. The proportion of the number of Th1-positive cells in the number of CD +4 T cells in the observation group was significantly higher than that in the control group [(29.00 ± 3.41)% vs. (22.61 ± 3.22)%, t = 9.634, P < 0.001]. The proportion of the number of Th17-,Th2 and CD +4CD +25Treg-positive cells in the number of CD +4 T cells in the observation group were (0.89 ± 0.10)%, (12.01 ± 1.36)%, (11.02 ± 1.92)%, respectively, which were significantly lower than those in the control group [(1.70 ± 0.20)%, (17.61 ± 2.20)%, (18.70 ± 2.40%)%, t = 25.614, 15.310, 17.670, all P < 0.001]. Total effective rate in the observation group was significantly higher than that in the control group [52.0% (26/50) vs. 30.0% (15/50), χ2 = 5.002, P < 0.05]. Conclusion:Immunotherapy with dendritic cells and cytokine-induced killer cells combined with chemotherapy with pemetrexed and cisplatin can induce apoptosis and regulate immune function. The combined therapy exhibits better clinical efficacy in the treatment of non-small cell lung than chemotherapy alone.

Research advances in adoptive cell transfer immunotherapy for hepatocellular carcinoma / 临床肝胆病杂志

The mortality rate of liver cancer patients in China is increasing constantly, which greatly threatens human health, and therefore, it is urgent to explore more effective treatment methods to prolong the survival time of patients. Because of its special physiological structure, the liver plays an immunoregulatory role, and thus immunotherapy for liver cancer gradually shows its clinical advantages and has become the fourth-generation therapy for liver cancer after surgical resection, chemotherapy, and radiotherapy. Adoptive cell transfer immunotherapy has been developed rapidly in the treatment of hepatocellular carcinoma (HCC) in recent years. CIK, NK, DC-CIK, TIL, and CAR-T cells are immune cells used for adoptive cell transfer immunotherapy. This article briefly summarizes the research advances in these immune cells in the treatment of HCC.

Experiment research of natural killer cells amplification in vitro and the killing effect on ovarian cancer cells / 中华妇产科杂志

Objective To amplify natural killer (NK) cells in vitro and explore its killing effect on ovarian cancer cells.Methods (1) The separation of NK cells and identification.A total of 20 ml peripheral blood of one healthy volunteer was collected in Nov.2015,Peking University People's Hospital.The peripheral blood mononuclear cells of normal volunteers were isolated,cultured in vitro and amplificated cultivation for 14 days with K562 cells transfected and expressing interleukin 21 (IL-21-K562) as nourish cells.The number and dynamic state of the growth cells were monitored during the cultured process.Cells were harvested and counted after 14 days cultured.The NK cells phenotypes were detected by flow cytometry.(2) The killing effect of NK cells on ovarian cancer cells:the ratio of effector cells (NK cells) and target cells (ovarian cancer cells and its control) was 50∶ 1,20∶ 1,10∶ 1,5∶1 or 1 ∶ 1,NK cells killing effect on ovarian cancer cells was detected by the lactate dehydrogenase (LDH) release experiments.Results (1) The results of NK cells establishment and phenotypic characterization:the cells were induced in vitro for 14 days by amplification culture.With the extension of incubation time,the number of NK cells increased constantly,from 2.0× 107 on day 0 to 5.1 × 109 on day 14.Obvious amplification of the total number of cells were detected for 255 times.Living cells unstained by trypan blue eventually reached 95％ above.Before and after the induction and amplification in vitro,the percentage of NK cells (CD3-CD56+cells) in CD3-cells were 2.33％ and 85.32％,respectively (P＜0.01),which covered the whole lymphocytes 1.06％ and 69.42％,respectively (P＜0.01),which showed that NK was the main cell type in the amplificated lymphocytes.(2) The killing rate of NK cells on ovarian cancer cells in vitro:the results detected by LDH release experiments showed that NK cells could performed strong nonspecific killing effect on ovarian cancer cell lines SKOV3,HOC1A,3AO and CAOV3,as well the normal ovarian cell line T29 and NK sensitive cell line K562,and the killing effect increased significantly along with the increase of effector cells and target cells ratio (P＜0.01).When the ratio was 1 ∶ 1,the killing rate was 37％ for K562,while the rate of killing of other cells was around 10％ (P＜0.05).When the effect-target ratio was 20∶1 and 50∶ 1,in addition to CAOV3 cells (more than 70％),NK cells had a kill rate of more than 80％ for other ovarian cancer cells lines and their control cell K562 and T29 cells (P＞0.05).Conclusion NK cells could be established in vitro and have a good non-specific killing effect on ovarian cancer cells.

Experimental study of WT1 specific CD8+T cells in the treatment of breast cancer / 天津医药

Objective To investigate the feasibility of Wilms’tumor gene 1 (WT1)-specific CD8+T cells from periph?eral blood for the treatment of breast cancer by detecting the killing activity of WT1 specific CD8+T cells on breast cancer cells. Methods Flow cytometry was used to detect WT1-specific CD8+T cells in the peripheral blood of 20 samples from HLA-A2 seropositive healthy donors, which were isolated by WT1/MHC streptamer magnetic beads and cultured. The func?tion of WT1-specific CD8+ T cells were analysis by cytotoxicity assay. Results Twelve of 20 healthy donors had naive WT1-specific CD8+T-cell frequencies of>0.5%, and 4 of 20 even>1.0%of all CD8+T cells. After positive selection by magnetic cell separation, a purity of up to 80%can be achieved. WT1 specific CD8+T cells can specifically kill breast can?cer cell line with WT1 polypeptide. Conclusion WT1 specific CD8+T cells can be detected in peripheral blood of healthy volunteers. WT1 specific CD8+T cells have killing effect on breast cancer cells, suggesting the feasibility of adoptive immu?notherapy for breast cancer.

Th17 cells adoptive immunotherapy impacts tumor growth of diffuse large B-cell lymphoma-bearing mice / 白血病·淋巴瘤

Objective To explore the impact of Th17 cells adoptive immunity on tumor growth of diffuse large B cell lymphoma (DLBCL)-bearing mice.Methods The CD4+ CD62L+ na(i)ve T cells purified by Mini MACS immunomagnetic beads were stimulated under the condition of TGF-β, IL-6, anti-IFN-γ, anti-IL-4, IL-23.IL-17 expression was detected by ELISA.SCID mice were inoculated with DLBCL cells line SUDHL-4 to estaldish the model of DLBCL-bearing mice, and then they received Th17 cells adoptive immunotherapy at the 0, 8 th or 18th day (3 groups in total, 5 mice pre-group).The tumor volume and the survival of tumor model were observed.Results Formation of tumor nodules in mice was observed at about the 8th day after the mice received the Th17 SUDHL-4 cells.The tumors volume of DLBCL-bearing mice that had received Th17 cells adoptive immunotherapy was obviously smaller than that of the mice had not (P ＜ 0.05).The survival time of the tumor-bearing mice that had received Th17 cells adoptive immunotherapy was also longer than that of the tumor-bearing mice had not (P ＜ 0.05).Conclusion Th17 cells adoptive immunotherapy displays an anti-tumor effect on DLBCL-bearing mice.

Research advances in cellular immunotherapy for primary hepatocellular carcinoma / 临床肝胆病杂志

The present therapy for primary hepatocellular carcinoma (HCC)consists of surgery as well as local radiotherapy and chemother-apy.However,the majority of patients are susceptible to recurrence after comprehensive treatment,and the overall treatment outcome is not ideal due to the lack of effective drugs and strategies.Increasing evidence has demonstrated that the immune system is closely related to the development,progression,metastasis,and recurrence of HCC.Thus,immune therapy,especially cellular immunotherapy,could regulate immune function and induce specific antitumor immunity to achieve the goal of controlling HCC and reducing its recurrence and metastasis, which has become an essential part in the comprehensive treatment of HCC.The findings in preclinical and clinical studies on cellular immu-notherapy for HCC data are reviewed,and the current problems are discussed.

Study on positive rate of blocking antibody in women with recurrent spontaneous abortion administered by route and frequency of paternal lymphocyte immunotherapy / 中华妇产科杂志

Objective To investigates factors affecting the positive rate of blocking antibody treated by paternal lymphocyte immunotherapy in patients with recurrent spontaneous abortion (RSA).Methods From January 2008 to August 2012,326 RSA cases undergoing treatment in Infertility Center of Qilu Hospital were studied retrospectively.Those patients were divided into 2 groups randomly:260 cases in intradermal injection group were administered via bilateral forearm intradermal injections for immunotherapy once 21 days,then the blocking antibody was determined after 2 (23 cases),3 (73 cases),4 (74 cases),5(90 cases) times respectively,while in subcutaneous injection group,the 66 cases were administered via subcutaneous injection once 21 days,the blocking antibody measured after 3 times; In both cases,the blocking antibody was all determined 2 weeks later.The positive rate of blocking antibodies and the rate of successful pregnancy was recorded,and then followed up after the blocking antibody turning positive.Results (1)Positive rate of blocking antibodies:the positive rate of blocking antibodies were 17％ (4/23),58％ (42/73),72％ (53/74) and 84％ (76/90) in the 2,3,4,and 5 times of intradermal injection group,respectively (P ＜ 0.05).In subcutaneous injection group,the positive rate of blocking antibodies was 38 ％ (25/66),which was significantly lower than that in group intradermal injection receiving 3 times immunotherapy (P ＜0.05).(2) The rate of pregnancy:the 176 patients out of 200 patients were pregnant when antibody was positive after immunotherapy,with 71.6％ (126/176)of patients gained successful pregnancy(the length of pregnancy more than 5 months).Conclusions The route and frequency of administration of immunotherapy could influence the positive rate of blocking antibody.The rate of successful pregnancy will be increased after blocking antibody turning positive.

Advance in research on CML therapy by gene silence and adoptive cellular immunotherapy / 军事医学

Chronic myeloid leukemia is a kind of malignant cloning hyperplastic disease of hematopoietic stem cell .The treatments based on molecular biological and immunological techniques will become the new therapies .Gene silence can improve the effects of molecular targeted therapeutic drugs through two ways: one is the target mRNA can be digested by siRNA and the other is target gene lose the stability and reduce the generation of protein mediated by miRNA .Adoptive cel-lular immunotherapy is a treatment method through injecting immunocompetent cells such as CIK , NK, etc into the body of cancerous person .This can improve the immunity of body and the effects of molecular targeted therapeutic drugs .The fur-ther study about basic theory , molecular mechanism and clinical effects will be continued .

Controversies on the allogeneic immunotherapy to optimize the graft-versus-tumor effect / 白血病·淋巴瘤

Cellular immunodeficiency is an important factor related to relapse of hematological malignancy post stem cell transplantation. On the other hand, allogeneic stem cell transplantation can be considered the adoptive immunotherapy, which can overcome the host immunodeficiency and promote graftversus-tumor (GVT) effect for elimination of minimal residual disease and prevention of relapse. How to optimize the GVT induction is required to be defined more clearly. In this review, advance knowledge concerning the optimized and clinical setting of GVT induction from 2011 ASH annual meeting is summarized.

Clinical reaserch on DCTAA and CIK from stem in treating patients of moderate and advanced stage lung cancer / 肿瘤研究与临床

ObjectiveTo observe the treatment effects in 48 cases of advanced lung cancer patients,with the immune therapy of the dendritic cells loading of tumor autologous antigen (DCTAA) combining with the cells induced factor of the killer cells(CIK)from the matched umbilical cord blood cells.MethodsThe peripheral blood mononuclear cell(PBMC)from the matched umbilical cord blood cells was seperated,and induced to CIK and DC with some cytokines in vitro, such as CD3McAb, IL-2, IFN-γ IL-1α, etc. After 12 to 15 days, the amplified CIK cells obtained were obtained, with the strict quality control, infused the CIK cells to the patients body back in six times,about(5-8)×109 CIK cells in each time.In the fifth day of the cultivation,DETAA cells were loaded and DCTAA cells were collected in the eighth day,and then hypodermic injection was done. The patient' s general situation after the immune treatment was observed, such as the size of the tumors, clinical symptom score, the quality of life and immune indexes. Karnofsky score, weight, toxic side effects and the patient's survival were also studied.ResultsIn the 48 cases with the DCTAA-CIK treatment, complete remission (CR), partial remission (PR)was 37 cases, the overall remission rate was 77.1％. The improvement rate of clinical symptom scores was from 78.9 ％ to 84.7 ％, the increasing rate of Karnofsky score was 89.6 ％ (43/48). 1-year survival reached to 80.6 ％. There were significant difference in little toxic side effects(P ＜ 0.01). The proportion of CD3, CD4 and NK cells in peripheral blood cells increased significantly (P ＜ 0.01) after DCTAA-CIK cells treatment[(42.21±6.12)％, (24.42±3.01)％, 0.99±0.34, (24.98±3.02) ％; (71.58±7.64) ％, (37.25±2.13) ％, 1.62±0.45, (35.23±4.11) ％](t = 6.34, 5.67, 0.25, 4.43, P ＜0.01).ConclusionThe DCTAA-CIK immune therapy is benefit for advanced lung cancer,not only improve the immune function but also ameliorate the clinical symptoms.

Influence of times of CIK cell treatment on survival of elderly patients with gastric cancer / 中华老年医学杂志

Objective To investigate the relevance between the times of cytokine-induced killer cell (CIK cell) adoptive immunotherapy and the survival of the elderly patients with gastric cancer.Methods Lymphocyte separation medium was used to isolate mononuclear cells, and then the cultured CIK cells were infused back into the patients with gastric cancer. A retrospective cohort study was adopted by using Kaplan-Meier to estimate median survival time and survival rate, using Log-rank test to analyze the impact of clinical factors on survival rate, and using RR and 95% CI to estimate the contact intensity of death outcome, survival time and CIK cell treatment. Results There were nostatistically significant differences in gender,age, tumor site, histological type, invasion depth, lymph node metastasis, pathological grade, tumor size or tumor distribution between chemotherapy group and CIK treatment group (all P＞0.05). The median survival time of patients with gastric cancer was significantly longer in CIK treatment group than in chemotherapy group (61 vs. 21, χ2=10.215, P=0.001). Compared with the patients treated by chemotherapy alone, the increased times of CIK treatment induced more survival rate and 2-5 years life spans (χ2=12. 461, P=0.006). Conclusions With the treatment that CIK cells are infused back into the elderly patients with gastric cancer, the risk of death is reduced, and the lifespan is prolonged, which is associated with the CIK cell treatment times.

Selective addition of CXCR3+CCR4-CD4+ Th1 cells enhances generation of cytotoxic T cells by dendritic cells in vitro

Increasing importance is being given to the stimulation of Th1 response in cancer immunotherapy because its presence can shift the direction of adaptive immune responses toward protective immunity. Based on chemokine receptor expression, CXCR3+CCR4-CD4+ T cells as Th1-type cells were investigated its capacity in monocyte-derived dendritic cell (DC) maturation and polarization, and induction of antigen specific cytotoxic T lymphocytes (CTL) in vitro. The levels of IL-4, IL-5 and IL-10 were decreased to the basal level compared with high production of IFN-gamma, TNF-alpha, and IL-2 in CXCR3+CCR4-CD4+ T cells stimulated with anti-CD3 and anti-CD28 antibodies. Co-incubation of activated CD4+ or CXCR3+CCR4-CD4+ T cells with DC (CD4+/DC or CXCR3+CD4+/DC, respectively) particularly up-regulated IL-12 and CD80 expression compared with DC matured with TNF-alpha and LPS (mDC). Although there was no significant difference between the effects of the CXCR3+CCR4-CD4+ and CD4+ T cells on DC phenotype expression, CXCR3+CD4+/DC in CTL culture were able to expand number of CD8+ T cells and increased frequencies of IFN-gamma secreting cells and overall cytolytic activity against tumor antigen WT-1. These results demonstrated that the selective addition of CXCR3+CCR4-CD4+ T cells to CTL cultures could enhance the induction of CTLs by DC in vitro, and implicated on a novel strategy for adoptive T cell therapy.

Effects of dendritic cell stimulation on cytotoxic activity of cord blood derived cytokine-induced killer cells,natural killer cells and CD45RO expression in CIK cells / 中国病理生理杂志

AIM: To investigate the efficacy of dendritic cells (DCs) that augments the cytotoxic activity of cytokine-induced killer (CIK) cells, natural killer (NK) cells from a same donor and the CD45RO expression on CIK cells. METHODS: The expanded killer cells were divided into two groups: group A was pre-cocultured with DCs for 6 days, group B was the control that without any stimulation. Cytotoxicity of CIK and NK cells was measured at different effect-target ratio against K562 and HL-60. CD45RO and CD45RA expression on CIK cells in different groups were detected by flow cytometry. RESULTS: Cytotoxicity of CB derived killer cells was positive correlation with effect-target ratio. The cytotoxicity of group A against HL-60 was higher than that of group B significantly. At 20∶1 effector-target ratio, the lytic activity of group A CIK, NK cells against K562 was higher than that of group B significantly, but no significant difference between them at 10∶1 effector-target ratio. The CD45RO expression on CIK cells in groups A was significantly higher than that in groups B. CONCLUSION: CIK and NK cells cocultured with DCs can augment the killer's cytotoxicity against tumor cells and promote the CD45RO expression on CIK cells.