Maximizing Memory T Cell Responses by Matured Post Chemotherapy Dendritic Cells

通过成熟的化疗后树突状细胞最大化记忆 T 细胞反应

基本信息

批准号：
8220861
负责人：
MARK P RUBINSTEIN
金额：
$ 29.69万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8220861
关键词：
Address Adjuvant Adoptive Immunotherapy Adoptive Transfer Agonist Antigens Antineoplastic Agents CD4 Positive T Lymphocytes CD8B1 gene Cells Clinical Cyclophosphamide Dendritic Cells Dose Frequencies Generations Helper-Inducer T-Lymphocyte Immune response Immunity Immunotherapeutic agent In Vitro Inflammatory Interleukin-2 Intervention Knowledge Lead Learning Lymphoid Lymphopenia MHC Class I Genes Malignant Neoplasms Measures Mediating Memory Modality Mus Natural Killer Cells Peptides Pharmaceutical Preparations Phase Physiologic pulse Play Poly I-C Recovery Regimen Regulatory T-Lymphocyte Role Shapes Solid Neoplasm T cell response T cell therapy T-Lymphocyte TLR3 gene Therapeutic Time Transgenic Mice Tumor Immunity Vaccination base cancer immunotherapy chemotherapy clinical application clinically significant cytokine design gp100 Antigen immunogenic improved in vivo irradiation lymph nodes melanoma migration mouse model novel preclinical study preconditioning public health relevance research study response tumor uptake

项目摘要

DESCRIPTION (provided by applicant): Recent preclinical studies have demonstrated that adoptive T cell transfer into a host rendered lymphodepleted followed by vaccination and IL-2 therapy favors differentiation of memory cells capable of curing relatively advanced solid tumors. Although several mechanisms have been suggested, recent studies have demonstrated that these mechanisms might not be the principal means by which lymphodepletion augments adoptive T cell therapy. Therefore, a better understanding of the mode of action of lymphodepletion would open new avenues for improving anti-tumor memory responses of adoptive T cell therapy. We recently have found that CTX treatment induces the expansion of immature DCs during the lymphoid recovery phase from day 9 to day 16, peaking on day 12. These DCs demonstrated normal phagocytic ability in vitro and antigen uptake in vivo. Administration of the TLR3 agonist poly(I:C) at the peak of DC expansion induced a rapid inflammatory milieu that was associated with significant increases in the numbers of activated DCs in lymph nodes. Using the pmel- 1 TCR transgenic mouse model, in which CD8+ T cells recognize gp100 melanoma peptide, we have demonstrated that priming of the CTX-treated mice with gp100 peptide plus poly(I:C) at the lymphopenic phase followed by boosting at the recovery phase (the peak of DC expansion) resulted in significant increases in the number of activated DCs in lymph nodes with a temporal increase in the expansion of pmel-1 cells, resulting in a robust therapeutic anti-tumor effects toward a bulky (advanced) tumor of the poorly immunogenic B16 melanoma. Therefore, we hypothesize that providing the inflammatory milieu induced by TLRs agonists optimally timed to be in combination with a unique expanded presence of post CTX DCs can lead to robust long-lasting anti-tumor immunity. To address this hypothesis, we will compare the anti-tumor effects of our treatment modality consisting of vaccination with hgp100 peptide and poly(I:C) to those of the established modality consisting of vaccination with ex vivo hgp100-pulsed DCs and IL-2. We will then determine if overlapping (by addition or substitution) of the adjuvant components of our modality to those of the established modality can results in a much higher anti-tumor responses. Finally, we will define the intrinsic and extrinsic mechanisms mediating these anti-tumor effects. We do believe that the increased frequencies of DCs during the recovery phase post CTX-induced lymphodepletion represents a novel opportunity to improve the rationale design and clinical application of chemotherapy in combination with tumor immunotherapeutic strategies. PUBLIC HEALTH RELEVANCE: Adoptive T cell transfer into tumor-bearing hosts rendered lymphopenic by irradiation or treatment with anti- cancer chemotherapeutic drugs markedly enhances the anti-tumor T cell responses, however, the mechanisms underlying these beneficial effects of lymphodepleting regimens are poorly understood. We have made the novel observation that treatment with the anti-cancer drug cyclophosphamide induces a marked expansion of dendritic cells, which play central roles in shaping the immune responses against cancer, representing a novel mechanism underlying the beneficial effects of this drug to adoptive immunotherapy. Further analysis of our observation would open new avenues for the rationale applications of anti-cancer adoptive immunotherapies.

描述（由申请人提供）：最近的临床前研究表明，收养T细胞转移到宿主的淋巴结中，然后进行疫苗接种，IL-2治疗有利于能够治愈相对晚期实体瘤的记忆细胞的分化。尽管已经提出了几种机制，但最近的研究表明，这些机制可能不是淋巴结扩大增强过继的T细胞疗法的主要手段。因此，更好地理解淋巴结序列的作用方式将开辟新的途径，以改善养子T细胞疗法的抗肿瘤记忆反应。我们最近发现，CTX处理从第9天到第16天诱导了未成熟DC的扩张，在第12天达到峰值。这些DC在体外表现出正常的吞噬能力，体内抗原吸收。 DC膨胀峰值在DC峰值上的TLR3激动剂聚（I：C）引起了快速的炎症环境，这与淋巴结中活化DC的数量显着增加有关。使用PMEL-1 TCR转基因小鼠模型，其中CD8+ T细胞识别GP100黑色素瘤肽，我们已经证明，用GP100肽加上CTX处理的小鼠启动在淋巴细胞增生阶段，在恢复阶段增加了dc expaction n of Activion n of Activion n of Activion n of Active n of dc nocive n of dc nocy n of d. PMEL-1细胞膨胀的时间增加，从而对不良免疫原性B16黑色素瘤的笨重（晚期）肿瘤产生了强大的治疗性抗肿瘤作用。因此，我们假设提供最佳时间与TLRS激动剂诱导的炎症环境与独特的CTX DC的独特存在相结合，可以导致强大的长期持久抗肿瘤免疫。为了解决这一假设，我们将比较包括用HGP100肽和聚（I：C）疫苗接种的治疗方式的抗肿瘤作用与由实体HGP100螺旋的DCS和IL-2的疫苗接种组成的已建立方式的抗肿瘤作用。然后，我们将确定我们形态的佐剂组成部分与已建立方式的佐剂组成部分的重叠是否会导致更高的抗肿瘤反应。最后，我们将定义介导这些抗肿瘤作用的固有和外在机制。我们确实认为，在CTX诱导的淋巴结序列后的恢复阶段，DC的频率增加代表了改善化学疗法与肿瘤免疫治疗策略相结合的基本原理设计和临床应用的新机会。公共卫生相关性：通过辐射或用抗癌化学治疗药物进行辐射或治疗使淋巴细胞减少症的产物T细胞转移显着增强了抗肿瘤T细胞反应，但是，淋巴结治疗方案的这些有益作用的机制尚不清楚。我们已经做出了新的观察，即用抗癌药物环磷酰胺治疗可引起树突状细胞的显着扩展，这在塑造针对癌症的免疫反应中起着核心作用，代表了这种药物对生育免疫疗法的有益作用的新机制。对我们的观察结果的进一步分析将为抗癌免疫疗法的理由应用开辟新的途径。