PSK as Neoadjuvant Therapy for Locally Advanced Breast Cancer

摘要： 局部晚期乳腺癌(LABC)是指局部进展但尚未进展的乳腺癌。 临床上扩散到乳房和区域淋巴结外。LABC残留物的临床处理 具有挑战性，因为患者复发的风险很高。对于HER2+/ER-和Triple来说尤其如此 LABC阴性(HER2-ER-PR-)型。手术后的新辅助(术前)化疗有 演变为新诊断的LABC的标准治疗策略。病理完全性疾病患者 通过新辅助治疗获得的反应(PCR)术后复发率较低，且改善了 与那些有微小残留疾病的患者相比，患者的总存活率更高。然而，由于目前 HER2+BC可用的新辅助治疗，包括化疗和单抗治疗 而对于TNBC的化疗，仅在少数患者中实现了PCR。新的治疗策略是 这是彻底根除肿瘤所必需的。我们建议添加多糖Krestin(PSK)，一种无毒的 从药用蘑菇提取的免疫调节剂，到标准的新辅助治疗，以提高治愈率 聚合酶链式反应和操作系统。化疗通过从垂死的肿瘤细胞释放抗原而产生免疫原性。 PSK是Toll样受体2(TLR2)的强效激动剂及其对DC和T细胞的免疫刺激作用 细胞是通过TLR2介导的。PSK的TLR激动剂活性可能向DC和 加强交叉拼写。因此，紫杉醇和PSK可能会共同作用，使患者自身免疫。 肿瘤，导致肿瘤破坏性免疫。我们的初步研究还表明，PSK可以增强 曲祖单抗介导的ADCC。因此，我们假设在标准新佐剂中添加PSK 使用紫杉醇和曲妥珠单抗治疗将增强抗肿瘤免疫，并导致提高的PCR率和 HER2+/ER-和TN LABC模型小鼠的总存活率。这一假说将在新奥尔良大学进行检验。 转基因小鼠，HER2+/ER-LABC模型；C3(1)T-Ag小鼠，TN LABC模型。 该提案的具体目的是：(1)确定是否将PSK添加到标准新佐剂中 HER2+/ER-和TN LABC的治疗将提高neu转基因小鼠的PCR率和总存活率 和C3(1)-TAG小鼠；(2)确定在标准的新辅助治疗中是否添加PSK HER2+/ER-和TN LABC将导致产生促炎的肿瘤微环境， 是否支持抗肿瘤免疫以及这种作用是否依赖于TLR2的激活；(3)确定 通过将PSK加入标准中而引起的系统(适应性)免疫反应的潜在增强 HER2+/ER-LABC的新辅助治疗以及这种效果是否依赖于TLR2的激活。数据 将为补充医学和替代医学的潜在整合奠定基础 将钙调蛋白(CaM)治疗纳入LABC的新辅助治疗。

Summary: Locally advanced breast cancer (LABC) refers to a breast cancer that has progressed locally but has not yet clinically spread beyond the breast and regional lymph nodes. Clinical management of LABC remains challenging as the patients have a high risk for relapse. This is particularly true for HER2+/ER- and triple negative (HER2-ER-PR-) types of LABC. Neoadjuvant (pre-operative) chemotherapy followed by surgery has evolved as the standard treatment strategy for newly diagnosed LABC. Patients with pathological complete response (PCR) achieved by neoadjuvant therapy have a lower relapse rate after surgery and an improved overall survival compared to those patients with residual microscopic disease. However, with the currently available neoadjuvant therapy, including chemotherapy and monoclonal antibody (mAb) therapy for HER2+ BC and chemotherapy for TNBC, PCR is achieved only in a minority of patients. Novel therapeutic strategies are required to result in complete tumor eradication. We propose to add polysaccharide Krestin (PSK), a non-toxic immunomodulator extracted from medicinal mushroom, to standard neoadjuvant therapy to increase the rate of PCR and OS. Chemotherapy has immunogenic effect due to the release of antigens from dying tumor cells PSK is a potent agonist of toll-like receptor 2 (TLR2) and the immunostimulatory effect of PSK on DC and T cells are mediated via TLR2. The TLR agonist activity of PSK may provide a "danger signal" to DC and enhance crosspriming. Thus paclitaxel and PSK may work together to autoimmunize the patients of their own tumors, resulting in tumor-destructive immunity. Our preliminary study also showed that PSK can enhance traztuzumab-mediated ADCC. Therefore, we hypothesize that the addition of PSK to standard neoadjuvant therapy with paclitaxel and trastuzumab will augment anti-tumor immunity and result in improved PCR rate and overall survival in mouse models of HER2+/ER- and TN LABC. This hypothesis will be tested in neu transgenic mice, a model of HER2+/ER- LABC, and C3(1)T-Ag mice, a model of TN LABC. The Specific Aims of the proposal are to: (1) Determine whether the addition of PSK to standard neoadjuvant therapy for HER2+/ER- and TN LABC will increase the rate of PCR and overall survival in neu-transgenic mice and C3(1)-TAg mice; (2) Determine whether the addition of PSK to standard neoadjuvant therapy for HER2+/ER- and TN LABC will result in the generation of a pro-inflammatory tumor microenvironment that supports anti-tumor immunity and whether this effect is dependent on TLR2 activation; (3) Determine the potential augmentation of a systemic (adaptive) immune response elicited by incorporating PSK into standard neoadjuvant therapy for HER2+/ER- LABC and whether this effect is dependent on TLR2 activation. Data generated here will lay the foundation for the potential integration of complementary and alternative medicine (CAM) therapy into the neoadjuvant treatment of LABC.