EXPANSION OF ANTITUMOR T CELLS FROM TUMOR-BEARING HOSTS

描述：(申请者摘要)当前过继免疫疗法(AIT) 需要繁琐的细胞培养才能产生足够数量的 淋巴细胞。申请人描述了一种新技术，即 Bryostatin 1和钙离子载体(B/1)对淋巴细胞的刺激 这会导致肿瘤致敏T细胞的快速扩张，这些细胞具有 体内治疗活性。这已被转换为第一阶段 临床试验。为了确定T细胞的药理激活是否 淋巴细胞可以用来放大微弱的免疫反应并诱导 弱免疫原性肿瘤的消退，不需要延长细胞 培养后，申请人将确定：a)是否只激活T细胞 B/I在体外短暂地介导极弱免疫原性4T1的消退 乳腺肿瘤；b)是否参与了细胞因子的抗肿瘤作用 这些药物的抗肿瘤作用；c)Bryo、AS101和/或 IL-2增强彼此的抗肿瘤作用；d)Bryo和AS101 增强转基因疫苗诱导保护性免疫的效果； 以及e)这种方法是否可以导致已建立的肿瘤的消退。至 了解Bryo激活的T细胞疗效的潜在机制， 申请人将确定B/I是否选择性地激活存储器T 细胞，可能是不同的蛋白激酶C模式的结果 表达和/或激活，以及DLN细胞的激活是否 与开始时相比，优先扩展某些TCR系列 人口。确定B/I激活的T淋巴细胞是否来自DLN 乳腺癌患者对一种相关的肿瘤抗原有反应 申请者将检验以下假设：a)B/I激活的T细胞来自 乳腺癌患者对HER-2/neu衍生表位的反应 B)DLN细胞对HER-2/neu的反应比 是来自同一患者的外周血淋巴细胞；c)T细胞 患有HER-2/neu的患者对HER-2/neu的反应性较低或较弱 转移到淋巴结；和d)乳腺癌的反应 患者T细胞对HER-2/neu的过度表达与Her-2/neu的过度表达 通过它们的肿瘤细胞。

DESCRIPTION: (Applicant's Abstract) Current adoptive immunotherapy (AIT) requires cumbersome cell culture to generate adequate numbers of lymphocytes. The applicant has described a novel technique, namely stimulation of lymphocytes with bryostatin 1 and a calcium ionophore (B/1), which leads to the rapid expansion of tumor-sensitized T cells that have therapeutic activity in vivo. This has been translated to a Phase I clinical trial. To determine whether pharmacologic activation of T lymphocytes can be used to amplify weak immune responses and induce regression of weakly immunogenic tumors, without the need for prolonged cell culture, the applicant will determine: a) whether T cells activated only briefly in vitro with B/I mediate regression of very weakly immunogenic 4T1 mammary tumors; b) whether the anti-tumor effects of cytokines are involved in the anti-tumor effects of these drugs; c) whether Bryo, AS101, and/or IL-2 augment each other's anti-tumor effects; d) whether Bryo and AS101 augment the effect of gene-modified vaccines to induce protective immunity; and e) whether this approach can cause regression of established tumors. To understand the mechanisms underlying the efficacy of Bryo-activated T cells, the applicant will determine whether B/I selectively activates memory T cells, perhaps as a result of different patterns of protein kinase C expression and/or activation, and whether activation of DLN cells will preferentially expand certain TcR families compared to the starting population. To determine whether B/I-activated T lymphocytes from DLN of patients with breast cancer respond to a relevant tumor antigen, the applicant will test the following hypotheses: a) B/I-activated T cells from breast cancer patients respond to HER-2/neu-derived epitopes presented by HLA-A2; b) DLN cells are more likely to manifest responses to HER-2/neu than are peripheral blood lymphocytes from the same patients; c) T cell reactivity to HER-2/neu will be less likely or weaker in patients with metastases to the lymph nodes; and d) the responses of breast cancer patients' T cells to HER-2/neu are related to over-expression of HER-2/neu by their tumor cells.