Phase-I-II Study of DAB389 (ONTAK) in Patients with Adv. Refractory Breast Cancer

描述（由申请人提供）：作为一线治疗，晚期乳腺癌的联合化疗方案通常会产生客观反应。然而，完全缓解的患者不到20%，中位生存期有限。治疗策略，将引起临床反应难治性晚期乳腺癌是需要的。ONTAK是一种由白喉毒素（DT）片段和IL-2氨基酸序列组成的细胞毒性融合蛋白，旨在指导DT对表达IL-2受体（CD25）高亲和力形式的恶性细胞的杀伤作用，同时最大限度地减少对不表达该受体的正常细胞的损伤。临床研究表明，ONTAK是一种安全有效的治疗表达CD25的皮肤T细胞淋巴瘤（CTCL）的药物。其在CTCL中的作用机制是与白介素-2受体（IL-2R）结合，诱导药物摄取，随后白喉毒素抑制蛋白质合成。研究清楚地表明，该药物具有阻断蛋白质合成和诱导细胞死亡的能力。乳腺癌，如CTCL，已被证明表达CD25，而CD25的表达增加与肿瘤的恶性潜能有关。因此，我们提出，与其在CTCL中的作用类似，ONTAK可能在过表达IL-2R的乳腺癌中具有直接的抗肿瘤活性。越来越多的证据表明，组成性表达IL-2Ra链的CD4+ T细胞群可能具有“专业”抑制细胞或T调节细胞（Tregs）的功能。Tregs是CD4+和CD8+ T细胞的有效抑制因子，并且已被证明可以下调对自身抗原（如肿瘤抗原）的免疫反应。此外，乳腺癌患者外周血中的Tregs也有所增加。我们假设ONTAK对Tregs的消耗可能导致功能性免疫效应细胞的产生和内源性肿瘤特异性免疫的增强。该方案是一项用于晚期难治性乳腺癌患者的ONTAK I-II期研究。本研究的具体目的是(i)评估晚期难治性乳腺癌患者使用ONTAK的安全性，(2)确定晚期乳腺癌患者使用ONTAK是否会减少循环T调节细胞和增强内源性免疫，以及(3)评估乳腺癌中IL-2R表达与使用ONTAK诱导的任何临床反应之间的关系。

DESCRIPTION (provided by applicant): Combination chemotherapy regimens for advanced breast cancer usually result in objective responses as first line treatment. However, complete remissions occur in fewer than 20% of patients, and median survival is limited. Therapeutic strategies that would elicit a clinical response in refractory advanced stage breast cancer are needed. ONTAK, a cytotoxic fusion protein composed of diptheria toxin (DT) fragments and amino acid sequences of IL-2, is designed to direct the cytocidal action of DT to malignant cells that express the high affinity form of the IL-2 receptor (CD25) while minimizing damage to normal cells that do not express the receptor. Clinical studies have shown ONTAK to be a safe and effective agent in the treatment of cutaneous T cell lymphomas (CTCL) that express CD25. Its putative mechanism of action in CTCL is to bind to the interleukin-2 receptor (IL-2R) and induce uptake of the drug with subsequent inhibition of protein synthesis by the diptheria toxin. Studies have clearly shown the capacity of the drug to block protein synthesis and induce cell death. Breast cancer, like CTCL, has been shown to express CD25, and this increased expression of CD25 is associated with the malignant potential of the tumor. Thus, we propose that, similar to its action in CTCL, ONTAK may have direct anti-tumor activity in breast cancers that overexpress IL-2R. Accumulating evidence suggests that a population of CD4+ T cells that constitutively express the IL-2Ra chain may function as "professional" suppressor or T regulatory cells (Tregs). Tregs are potent suppressors of CD4+ and CD8+ T cells and have been shown to down-regulate immune responses to self antigens, such as tumor antigens. Additionally, Tregs have been shown to be increased in the peripheral blood of patients with breast cancer. We hypothesize that depletion of Tregs by ONTAK may result in generation of functional immune effector cells and enhancement of endogenous tumor-specific immunity. This proposal is a phase I-II study of ONTAK administered to patients with advanced refractory breast cancer. The specific aims of this study are to (i) evaluate the safety of ONTAK administration in patients with advanced refractory breast cancer, (2) determine whether administration of ONTAK in patients with advanced stage breast cancer will decrease circulating T regulatory cells and augment endogenous immunity, and (3) evaluate an association between IL-2R expression in breast cancer and any clinical response induced by ONTAK administration.