Vaccine and radiation for the therapy of human cancers

使用螯合放射性核素（钐-153- edtmp）来调节肿瘤细胞的表型并增强t细胞介导的杀伤。将人类肿瘤细胞暴露于亚致死剂量的外部束辐射会上调肿瘤抗原和辅助分子的表达，使肿瘤细胞更容易被抗原特异性细胞毒性T淋巴细胞（ctl）杀死。该项目探讨了暴露于姑息剂量的放射性药物制剂可能改变肿瘤细胞的表型，使其更容易受到t细胞介导的杀伤的可能性。在这里，10个人类肿瘤细胞系（4个前列腺，2个乳腺和4个肺）暴露于增加剂量的放射性药物钐-153-乙二胺四亚甲基膦酸盐（153Sm-EDTMP），用于治疗癌症患者因骨转移引起的疼痛。荧光活化细胞分选分析和实时定量聚合酶链反应（PCR）分析了5种表面分子和几种肿瘤相关抗原在前列腺癌中的表达。将LNCaP人类前列腺癌细胞暴露于153Sm-EDTMP中，并与肿瘤相关抗原特异性CTL一起培养，进行CTL杀伤实验，以确定暴露于153Sm-EDTMP是否使LNCaP细胞更容易受到t细胞介导的杀伤。肿瘤细胞对153Sm-EDTMP的反应上调了表面分子Fas（100%的细胞系上调Fas）、癌胚抗原（90%）、粘蛋白-1（60%）、主要组织相容性复合体（MHC） I类（50%）和细胞间粘附分子-1（40%）。实时荧光定量PCR分析发现了其他上调的肿瘤抗原。暴露于153Sm-EDTMP使LNCaP细胞更容易被前列腺特异性抗原、癌胚抗原（CEA）和粘蛋白-1特异性ctl杀死。153Sm-EDTMP的剂量相当于给骨的缓解剂量，可改变肿瘤细胞的表型，这表明153Sm-EDTMP可能与免疫疗法协同作用，增加肿瘤细胞对CTL杀伤的易感性。利用放射性标记单克隆抗体增强疫苗介导的t细胞应答。放射标记单克隆抗体（mAb）在血液系统恶性肿瘤中显示出可测量的抗肿瘤作用。对于实体肿瘤来说，这一结果更难实现，因为在很大程度上，难以将足够数量的单克隆抗体输送到肿瘤肿块。先前的研究表明，非溶解水平的外部束辐射可以使肿瘤细胞更容易受到T细胞介导的杀伤。这些研究的目的是确定选择性地将放射性标记的单抗传递到肿瘤是否会调节肿瘤细胞表型，从而增强疫苗介导的t细胞杀伤。在这里，将转人CEA的小鼠与表达CEA的小鼠癌细胞系移植。放射免疫治疗由钇-90 （Y-90）标记的抗cea单抗组成，可单独使用或与疫苗治疗联合使用。单剂量y -90标记的抗cea单抗与疫苗治疗相结合，导致荷瘤小鼠的生存比单独接种疫苗或单抗显著增加；这被证明是通过Fas/Fas配体途径的参与介导的。与单独接种疫苗相比，接受联合治疗的小鼠也显示出活的肿瘤浸润性cea特异性CD8+ T细胞的百分比显著增加。肿瘤治愈的小鼠表现出抗原级联反应，不仅对CEA，而且对p53和gp70产生CD4+和CD8+ t细胞反应。这些发现表明，放射标记单抗形式的全身放射治疗与疫苗联合可促进有效的抗肿瘤反应，这可能对未来临床试验的设计具有指导意义。使用螯合放射性核素（钐-153- edtmp）来调节肿瘤细胞的表型并增强t细胞介导的杀伤。将人类肿瘤细胞暴露于亚致死剂量的外部束辐射会上调肿瘤抗原和辅助分子的表达，使肿瘤细胞更容易被抗原特异性细胞毒性T淋巴细胞（ctl）杀死。该项目探讨了暴露于姑息剂量的放射性药物制剂可能改变肿瘤细胞的表型，使其更容易受到t细胞介导的杀伤的可能性。在这里，10个人类肿瘤细胞系（4个前列腺，2个乳腺和4个肺）暴露于增加剂量的放射性药物钐-153-乙二胺四亚甲基膦酸盐（153Sm-EDTMP），用于治疗癌症患者因骨转移引起的疼痛。荧光活化细胞分选分析和实时定量聚合酶链反应（PCR）分析了5种表面分子和几种肿瘤相关抗原在前列腺癌中的表达。将LNCaP人类前列腺癌细胞暴露于153Sm-EDTMP中，并与肿瘤相关抗原特异性CTL一起培养，进行CTL杀伤实验，以确定暴露于153Sm-EDTMP是否使LNCaP细胞更容易受到t细胞介导的杀伤。肿瘤细胞对153Sm-EDTMP的反应上调了表面分子Fas（100%的细胞系上调Fas）、癌胚抗原（90%）、粘蛋白-1（60%）、主要组织相容性复合体（MHC） I类（50%）和细胞间粘附分子-1（40%）。实时荧光定量PCR分析发现了其他上调的肿瘤抗原。暴露于153Sm-EDTMP使LNCaP细胞更容易被前列腺特异性抗原、癌胚抗原（CEA）和粘蛋白-1特异性ctl杀死。153Sm-EDTMP的剂量相当于给骨的缓解剂量，可改变肿瘤细胞的表型，这表明153Sm-EDTMP可能与免疫疗法协同作用，增加肿瘤细胞对CTL杀伤的易感性。利用放射性标记单克隆抗体增强疫苗介导的t细胞应答。放射标记单克隆抗体（mAb）在血液系统恶性肿瘤中显示出可测量的抗肿瘤作用。对于实体肿瘤来说，这一结果更难实现，因为在很大程度上，难以将足够数量的单克隆抗体输送到肿瘤肿块。先前的研究表明，非溶解水平的外部束辐射可以使肿瘤细胞更容易受到T细胞介导的杀伤。这些研究的目的是确定选择性地将放射性标记的单抗传递到肿瘤是否会调节肿瘤细胞表型，从而增强疫苗介导的t细胞杀伤。在这里，将转人CEA的小鼠与表达CEA的小鼠癌细胞系移植。放射免疫治疗由钇-90 （Y-90）标记的抗cea单抗组成，可单独使用或与疫苗治疗联合使用。单剂量y -90标记的抗cea单抗与疫苗治疗相结合，导致荷瘤小鼠的生存比单独接种疫苗或单抗显著增加；这被证明是通过Fas/Fas配体途径的参与介导的。与单独接种疫苗相比，接受联合治疗的小鼠也显示出活的肿瘤浸润性cea特异性CD8+ T细胞的百分比显著增加。肿瘤治愈的小鼠表现出抗原级联反应，不仅对CEA，而且对p53和gp70产生CD4+和CD8+ t细胞反应。这些发现表明，放射标记单抗形式的全身放射治疗与v[摘要截断为7800个字符]相结合

The use of chelated radionuclide (Samarium-153-EDTMP) to modulate phenotype of tumor cells and enhance T-cell-mediated killing. Exposing human tumor cells to sublethal doses of external beam radiation upregulates expression of tumor antigen and accessory molecules, rendering tumor cells more susceptible to killing by antigen-specific cytotoxic T lymphocytes (CTLs). This project explored the possibility that exposure to palliative doses of a radiopharmaceutical agent could alter the phenotype of tumor cells to render them more susceptible to T-ell-mediated killing. Here, 10 human tumor cell lines (4 prostate, 2 breast, and 4 lung) were exposed to increasing doses of the radiopharmaceutical samarium-153- ethylenediaminetetramethylenephosphonate (153Sm-EDTMP) used in cancer patients to treat pain due to bone metastasis. Fluorescence-activated cell sorting analysis and quantitative real-time polymerase chain reaction (PCR) analysis for expression of five surface molecules and several tumor-associated antigens involved in prostate cancer were done. LNCaP human prostate cancer cells were exposed to153Sm-EDTMPand incubated with tumor-associated antigen-specific CTL in a CTL killing assay to determine whether exposure to 153Sm-EDTMP rendered LNCaP cells more susceptible to T-cell-mediated killing. Tumor cells up-regulated the surface molecules Fas (100% of cell lines upregulated Fas), carcinoembryonic antigen (90%), mucin-1 (60%), major histocompatibility complex (MHC) class I (50%), and intercellular adhesion molecule-1 (40%) in response to 153Sm-EDTMP. Quantitative real-time PCR analysis revealed additional upregulated tumor antigens. Exposure to 153Sm-EDTMP rendered LNCaP cells more susceptible to killing by CTLs specific for prostate-specific antigen, carcinoembryonic antigen (CEA), and mucin-1. Doses of 153Sm-EDTMP equivalent to palliative doses delivered to bone alter the phenotype of tumor cells, suggesting that 153Sm-EDTMP may work synergistically with immunotherapy to increase the susceptibility of tumor cells to CTL killing. The use of radiolabeled monoclonal antibody to enhance vaccine-mediated T-cell responses. Radiolabeled monoclonal antibodies (mAb) have demonstrated measurable antitumor effects in hematologic malignancies. This outcome has been more difficult to achieve for solid tumors due, for the most part, to difficulties in delivering sufficient quantities of mAb to the tumor mass. Previous studies have shown that nonlytic levels of external beam radiation can render tumor cells more susceptible to T cell-mediated killing. The goal of these studies was to determine if the selective delivery of a radiolabeled mAb to tumors would modulate tumor cell phenotype so as to enhance vaccine-mediated T-cell killing. Here, mice transgenic for human CEA were transplanted with a CEA expressing murine carcinoma cell line. Radioimmunotherapy consisted of yttrium-90 (Y-90)-labeled anti-CEA mAb, used either alone or in combination with vaccine therapy. A single dose of Y-90-labeled anti-CEA mAb, in combination with vaccine therapy, resulted in a statistically significant increase in survival in tumor-bearing mice over vaccine or mAb alone; this was shown to be mediated by engagement of the Fas/Fas ligand pathway. Mice receiving the combination therapy also showed a significant increase in the percentage of viable tumor-infiltrating CEA-specific CD8+ T cells compared to vaccine alone. Mice cured of tumors demonstrated an antigen cascade resulting in CD4+ and CD8+ T-cell responses not only for CEA, but for p53 and gp70. These findings show that systemic radiotherapy in the form of radiolabeled mAb, in combination with vaccine, promotes effective antitumor response, which may have implications in the design of future clinical trials.The use of chelated radionuclide (Samarium-153-EDTMP) to modulate phenotype of tumor cells and enhance T-cell-mediated killing. Exposing human tumor cells to sublethal doses of external beam radiation upregulates expression of tumor antigen and accessory molecules, rendering tumor cells more susceptible to killing by antigen-specific cytotoxic T lymphocytes (CTLs). This project explored the possibility that exposure to palliative doses of a radiopharmaceutical agent could alter the phenotype of tumor cells to render them more susceptible to T-ell-mediated killing. Here, 10 human tumor cell lines (4 prostate, 2 breast, and 4 lung) were exposed to increasing doses of the radiopharmaceutical samarium-153- ethylenediaminetetramethylenephosphonate (153Sm-EDTMP) used in cancer patients to treat pain due to bone metastasis. Fluorescence-activated cell sorting analysis and quantitative real-time polymerase chain reaction (PCR) analysis for expression of five surface molecules and several tumor-associated antigens involved in prostate cancer were done. LNCaP human prostate cancer cells were exposed to153Sm-EDTMPand incubated with tumor-associated antigen-specific CTL in a CTL killing assay to determine whether exposure to 153Sm-EDTMP rendered LNCaP cells more susceptible to T-cell-mediated killing. Tumor cells up-regulated the surface molecules Fas (100% of cell lines upregulated Fas), carcinoembryonic antigen (90%), mucin-1 (60%), major histocompatibility complex (MHC) class I (50%), and intercellular adhesion molecule-1 (40%) in response to 153Sm-EDTMP. Quantitative real-time PCR analysis revealed additional upregulated tumor antigens. Exposure to 153Sm-EDTMP rendered LNCaP cells more susceptible to killing by CTLs specific for prostate-specific antigen, carcinoembryonic antigen (CEA), and mucin-1. Doses of 153Sm-EDTMP equivalent to palliative doses delivered to bone alter the phenotype of tumor cells, suggesting that 153Sm-EDTMP may work synergistically with immunotherapy to increase the susceptibility of tumor cells to CTL killing. The use of radiolabeled monoclonal antibody to enhance vaccine-mediated T-cell responses. Radiolabeled monoclonal antibodies (mAb) have demonstrated measurable antitumor effects in hematologic malignancies. This outcome has been more difficult to achieve for solid tumors due, for the most part, to difficulties in delivering sufficient quantities of mAb to the tumor mass. Previous studies have shown that nonlytic levels of external beam radiation can render tumor cells more susceptible to T cell-mediated killing. The goal of these studies was to determine if the selective delivery of a radiolabeled mAb to tumors would modulate tumor cell phenotype so as to enhance vaccine-mediated T-cell killing. Here, mice transgenic for human CEA were transplanted with a CEA expressing murine carcinoma cell line. Radioimmunotherapy consisted of yttrium-90 (Y-90)-labeled anti-CEA mAb, used either alone or in combination with vaccine therapy. A single dose of Y-90-labeled anti-CEA mAb, in combination with vaccine therapy, resulted in a statistically significant increase in survival in tumor-bearing mice over vaccine or mAb alone; this was shown to be mediated by engagement of the Fas/Fas ligand pathway. Mice receiving the combination therapy also showed a significant increase in the percentage of viable tumor-infiltrating CEA-specific CD8+ T cells compared to vaccine alone. Mice cured of tumors demonstrated an antigen cascade resulting in CD4+ and CD8+ T-cell responses not only for CEA, but for p53 and gp70. These findings show that systemic radiotherapy in the form of radiolabeled mAb, in combination with v [summary truncated at 7800 characters]