EXPANSION OF ANTITUMOR T CELLS FROM TUMOR-BEARING HOSTS

描述：（申请人的摘要）当前过继免疫疗法（AIT） 需要繁琐的细胞培养以产生足够数量的 淋巴细胞 申请人描述了一种新技术，即 用苔藓抑素1和钙离子载体（B/1）刺激淋巴细胞， 这导致了肿瘤致敏T细胞的快速扩增， 体内治疗活性。 这已转化为第一阶段 临床试验 为了确定T细胞的药理学激活是否 淋巴细胞可用于放大弱免疫应答， 弱免疫原性肿瘤的消退，而不需要延长细胞周期， 培养后，申请人将确定：a）T细胞是否仅活化 在体外用B/I短暂介导极弱免疫原性4 T1消退 乳腺肿瘤; B）是否涉及细胞因子的抗肿瘤作用 c）Bryo、AS 101和/或AS 102是否具有抗肿瘤作用; IL-2增强彼此的抗肿瘤作用; d）Bryo和AS 101是否 增强基因修饰疫苗诱导保护性免疫的效果; 以及e）该方法是否可以引起已建立的肿瘤的消退。 到 了解苔藓激活T细胞功效的机制， 申请人将确定B/I是否选择性地激活存储器T 细胞，也许是由于不同模式的蛋白激酶C 表达和/或活化，以及DLN细胞的活化是否将 与起始TcR相比， 人口 为了确定是否B/I活化的T淋巴细胞从DLN的， 乳腺癌患者对相关肿瘤抗原有反应， 申请人将检验以下假设：a）来自以下的B/I-活化的T细胞： 乳腺癌患者对HER-2/neu衍生表位的应答 HLA-A2; B）DLN细胞比其他细胞更可能表现出对HER-2/neu的应答。 是来自相同患者的外周血淋巴细胞; c）T细胞 HER-2/neu的反应性将不太可能或更弱， 转移到淋巴结;和d）乳腺癌的反应 HER-2/neu的过度表达与患者T细胞对HER-2/neu的反应有关 被他们的肿瘤细胞。

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.