Vaccines to promote Tc-1-based targeting of tumor stroma

促进基于 Tc-1 的肿瘤基质靶向的疫苗

• 批准号: 8213498
• 负责人: Walter J. Storkus
• 金额: $ 29.64万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8213498
• 关键词: Adverse effects; Angiogenic Factor; Animals; Antigen Targeting; Antigen-Presenting Cells; Antigens; Autoimmune Process; Blood; Blood - brain barrier anatomy; Blood Vessels; CD8B1 gene; Carboplatin; Cell Death; Cells; Chronic; Clinical; Collaborations; Complex; Cross-Priming; Cues; Data; Development; Diagnostic Neoplasm Staging; Disease; Disease model; Dose; Drug Kinetics; Effector Cell; Epitopes; Excision; Fertility; Genetic; HLA-A2 Antigen; Hematopoietic; Hemorrhage; Histologic; Human; Hypoxia; Imaging Techniques; Immune; Immune system; Immunotherapy; Infiltration; Inflammation; Intercellular Fluid; Large Intestine Carcinoma; Lesion; Leukocytes; Maintenance; Malignant Neoplasms; Mediating; Mesenchymal; Modality; Modeling; Monitor; Mus; Neoplasm Metastasis; Neoplasms in Vascular Tissue; Normal tissue morphology; Organ; Pathologic; Pathology; Patients; Peptides; Pericytes; Peripheral; Pharmaceutical Preparations; Pharmacodynamics; Platelet-Derived Growth Factor; Population; Primary Neoplasm; Process; Recruitment Activity; Reporting; Retina; Safety; Secondary Immunization; Site; Staging; Stromal Cells; Structure; T cell response; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; Time; Treatment Efficacy; Tube; Tumor stage; Vaccinated; Vaccine Design; Vaccines; Variant; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; Vascular Permeabilities; Vascularization; Work; Wound Healing; antibody inhibitor; base; cancer cell; cell type; chemotherapeutic agent; chemotherapy; expectation; improved; in vivo; inhibitor/antagonist; irinotecan; melanoma; mouse model; neoplastic cell; neovascularization; novel; oxaliplatin; pre-clinical; pressure; prevent; prophylactic; public health relevance; research clinical testing; small molecule; temozolomide; therapeutic target; therapeutic vaccine; tumor; tumor growth; tumor vascular supply; vaccine efficacy

DESCRIPTION (provided by applicant): In addition to targeting tumor cells, the supportive tumor microenvironment may be destabilized or destroyed by therapeutic strategies targeting tumor-associated stromal cell types, such as those involved with neoangiogenesis or neovasculogenesis. While formation of blood vessels from the surrounding vasculature is typical of wound healing and peripheral neoangiogenesis, similar structures in progressive tumors may also involve the process of neovascularization. In particular, tumor vascular endothelial tubes and stabilizing perivascular pericytes are typically recruited into tumors as (mesenchymal or hematopoietic) precursors and induced to differentiate and integrate into higher order complexes based on tumor-produced or -induced angiogenic factors, such as VEGF, PDGF, and TGF-¿. Given such operational (and potentially component) differences, it has now become feasible to consider the immune- based targeting of vascular endothelial cells (VEC) or pericytes within the tumor microenvironment (TME), with an expectation for safety (i.e. lack of inhibitory effects on wound-healing or crucial vascular barriers within the blood-brain barrier or the retina). Vaccines designed to elicit T cell-mediated eradication of VEC or pericytes in the tumor microenvironment would conceivably provide durable inhibition of the tumor blood supply with a reduced concern for antigen-loss target variants, as may occur in heterogeneous tumor cell populations under chronic immune-editing/-selection. As a consequence of blunting nascent, and destabilizing existing, vessels in the TME, enhanced tumor cell death and corollary cross-priming of anti-tumor T cells sponsored by host antigen presenting cells (APC) would be expected. Furthermore, the immune-mediated removal of pericytes from tumor blood vessels would be anticipated to result in enhanced vessel hemorrhaging/leakiness yielding elevated vascular permeability and a normalization in the interstitial fluid pressure within the tumor core. Such conditions would favor increased and potentially selective delivery of systemic agents (including pharmacologic compounds or adoptively transferred T cells) into the TME, yielding the possibility for improved therapeutic efficacy. In Preliminary Data, we show that prophylactic and therapeutic vaccines promoting CD8+ T cell responses against pericyte- or VEC-associated antigens prevent the vascularization of murine tumors in vivo, in the absence of detectable autoimmune pathology via a mechanism that prompts normalization in tumor IFP and a reduction in intratumoral hypoxia. Based on this paradigm, we propose to: test the hypotheses that vaccines targeting tumor VEC/pericytes are safe and capable of promoting CD8+ T cell-mediated regression of late-stage tumors in vivo (Specific Aim 1), and that co-therapies integrating such vaccines will improve the (co)delivery of chemo/immunotherapy agents into the TME, yielding enhanced therapy benefit via a broadening in the therapeutic T cell repertoire (Specific Aim 2). PUBLIC HEALTH RELEVANCE: Progressively growing tumors are supported by additional cell types that are collectively called the stroma. Stromal cells include vascular endothelial cells and pericytes that are required for the construction and maintenance of the tumor blood supply. Since stromal cells are normal and not subject to the genetic instability common to cancer cells, they provide a static target for the development of therapeutic agents. Over the past decade, therapeutic targeting of the tumor vasculature has become increasingly attractive, leading to the development of small molecule and antibody inhibitors. Clinically, these agents normalize the tumor vasculature and when applied alone or in combination with other drugs, such as chemotherapy, they have resulted in anti-tumor effects in patients with cancer. Unfortunately, as these drugs are applied systemically, there are substantial side effects in patients that preclude their chronic administration. An alternative to these modalities are vaccines designed to elicit specific T cell responses against antigens expressed by cells making up the tumor vasculature. Based on our preliminary data, such vaccines provide potent anti-tumor protection and do not target normal tissue vasculature, making them both effective and safe. Since such T cells may be renewed periodically by booster vaccination, they may provide novel and potent inhibitors of tumor growth. The studies we propose will assess the safety and efficacy of this modality in a mouse model that approximates the human immune system. These results may provide the translational inertia to develop vaccine and combinational therapies targeting the tumor stroma that can be applied to patients harboring any type of vascularized cancer.

描述（由适用提供）：除了靶向肿瘤细胞外，受支持的肿瘤微环境可能会因靶向肿瘤相关的基质细胞类型的治疗策略而破坏或破坏，例如新血管生成或新生血管生成。虽然周围脉管系统的血管形成是典型的伤口愈合和周围的新血管生成，但进行性肿瘤中的相似结构也可能涉及新血管形成的过程。特别是，肿瘤血管内皮管和稳定血管周周细胞通常通常被募集到肿瘤中，例如（间充质或造血性）前体，并诱导出基于肿瘤产生或诱导的诸如VEVGF，pDGF，pDGF，以及TGFF，以及TGFF，以及TGFF-and TOM的脉络性因素，并将其整合到高阶复合物中。现在可以考虑对肿瘤微环境（TME）内血管内皮细胞（VEC）或周细胞的基于免疫的靶向，并期望安全性（即缺乏对血液障碍物或视网膜内的血管性血管屏障的抑制作用）。旨在引起T细胞介导的肿瘤微环境中VEC或周细胞的放射线的疫苗可以想象，可以抑制对肿瘤血液供应的持久抑制作用，从而减少了对抗原损伤靶标变异的关注，因为在慢性免疫和 - 编辑/-Ectection下，异质性肿瘤细胞种群可能发生。由于TME中的新生和稳定的血管，肿瘤细胞死亡和抗肿瘤抗原抗原呈递细胞（APC）赞助的抗肿瘤T细胞的肿瘤细胞死亡和推论交叉染色的结果将被预期增强。此外，预计免疫介导的肿瘤血管上的周围会导致血管出血/泄漏增强，从而导致血管通透性升高，并且在肿瘤核心内的间质流体压力中归一化。这样的条件将有利于增加并有可能选择性地递送全身性剂（包括药物化合物或适当转移的T细胞），从而有可能改善治疗有效的可能性。在初步数据中，我们表明，预防性和治疗性疫苗促进CD8+ T细胞反应针对周细胞或vec相关抗原的抗原可阻止体内鼠肿瘤的血管化，而在没有可检测的自身免疫病理学的情况下通过促使肿瘤的归一化机制在肿瘤中归一化和内部肿瘤，并促进了肿瘤的归一化。基于此范式，我们提出：测试靶向肿瘤VEC/周细胞的疫苗的假设是安全的，并且能够促进体内晚期肿瘤的CD8+ T细胞介导的回归（特定目标1）的回归（特定的目标1），并且通过将这种疫苗通过（CO）促进化学疗法的交付量来提高TME疗法的范围，以增强TME疗法的范围，以提高TME疗法的范围治疗性T细胞库（特定目标2）。 公共卫生相关性：逐渐生长的肿瘤得到了其他称为基质的细胞类型的支持。基质细胞包括肿瘤血液供应所需的血管内皮细胞和周细胞。由于基质细胞是正常的，并且不受癌细胞共同的遗传不稳定性的影响，因此它们为开发治疗剂提供了静态靶标。在过去的十年中，靶向肿瘤脉管系统的治疗量变得越来越有吸引力，导致小分子和抗体抑制剂的发展。在临床上，这些药物使肿瘤脉管系统正常化，并且在单独使用或与其他药物（例如化学疗法）结合使用时，它们对癌症患者产生了抗肿瘤作用。不幸的是，由于这些药物是系统地应用的，因此患者有很大的副作用排除了他们的慢性给药。这些模式的一种替代方法是旨在引起针对由肿瘤脉管系统表达的抗原的特异性T细胞反应的疫苗。根据我们的初步数据，这种疫苗提供了潜在的抗肿瘤保护，并且不瞄准正常的组织脉管系统，使其既有效又安全。由于这种T细胞可以通过增强疫苗定期更新，因此它们可以提供新颖的肿瘤生长抑制剂。我们提出的研究将在近似人类免疫系统的小鼠模型中评估这种方式的安全性和效率。这些结果可能提供了转化的惯性，以开发针对肿瘤基质的疫苗和联合疗法，该疗法可应用于具有任何类型的血管化癌症的患者。