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: 7885077
• 负责人: Walter J. Storkus
• 金额: $ 30.56万
• 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/7885077
• 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（由申请人提供）：除了靶向肿瘤细胞外，靶向肿瘤相关基质细胞类型（如参与新血管生成或新血管发生的基质细胞）的治疗策略可能会破坏或破坏支持性肿瘤微环境。虽然从周围脉管系统形成血管是伤口愈合和外周新血管生成的典型特征，但进行性肿瘤中的类似结构也可能涉及新血管生成过程。特别地，肿瘤血管内皮管和稳定血管周细胞通常作为（间充质或造血）前体募集到肿瘤中，并基于肿瘤产生或诱导的血管生成因子（如VEGF、PDGF和TGF-β）被诱导分化和整合成更高级的复合物。考虑到这种操作（和潜在的组分）差异，现在考虑基于免疫靶向肿瘤微环境（TME）内的血管内皮细胞（VEC）或周细胞变得可行，并期望安全性（即对血脑屏障或视网膜内的伤口愈合或关键血管屏障缺乏抑制作用）。设计用于引发肿瘤微环境中T细胞介导的VEC或周细胞根除的疫苗将可想象地提供对肿瘤血液供应的持久抑制，同时减少对抗原丢失靶变体的关注，如在慢性免疫编辑/选择下异质肿瘤细胞群体中可能发生的那样。作为钝化新生的和不稳定的现有的TME中的血管的结果，增强的肿瘤细胞死亡和由宿主抗原呈递细胞（APC）赞助的抗肿瘤T细胞的必然交叉致敏将是预期的。此外，预期免疫介导的周细胞从肿瘤血管中的去除将导致增强的血管扩张/渗漏，从而产生升高的血管渗透性和肿瘤核心内的间质液压力的正常化。这样的条件将有利于全身性药剂（包括药理学化合物或过继转移的T细胞）向TME中的增加的和潜在的选择性递送，从而产生改善治疗功效的可能性。在初步数据中，我们表明，预防性和治疗性疫苗促进CD 8 + T细胞对周细胞或血管内皮细胞相关抗原的反应，在体内预防小鼠肿瘤血管化，在没有可检测的自身免疫病理通过一种机制，促使肿瘤IFP正常化和减少瘤内缺氧。基于这一模式，我们建议：测试靶向肿瘤VEC/周细胞的疫苗是安全的并且能够在体内促进CD 8 + T细胞介导的晚期肿瘤消退的假设（具体目标1），并且整合此类疫苗的共治疗将改善化疗/免疫治疗剂向TME中的（共）递送，通过治疗性T细胞库的拓宽产生增强的治疗益处（特异性目的2）。 公共卫生相关性：进行性生长的肿瘤由统称为基质的其他细胞类型支持。基质细胞包括血管内皮细胞和周细胞，它们是构建和维持肿瘤血液供应所必需的。由于基质细胞是正常的，并且不受癌细胞常见的遗传不稳定性的影响，因此它们为治疗剂的开发提供了静态靶标。在过去的十年中，肿瘤血管系统的治疗靶向已经变得越来越有吸引力，导致小分子和抗体抑制剂的开发。在临床上，这些药物使肿瘤血管系统正常化，并且当单独或与其他药物如化疗联合应用时，它们在癌症患者中产生抗肿瘤作用。不幸的是，由于这些药物是全身性应用的，因此在患者中存在大量的副作用，这妨碍了它们的长期施用。这些模式的替代方案是设计用于引发针对由构成肿瘤脉管系统的细胞表达的抗原的特异性T细胞应答的疫苗。根据我们的初步数据，这种疫苗提供了有效的抗肿瘤保护，并且不靶向正常组织血管，使它们既有效又安全。由于这种T细胞可以通过加强疫苗接种定期更新，它们可以提供新的和有效的肿瘤生长抑制剂。我们提出的研究将评估这种模式在接近人类免疫系统的小鼠模型中的安全性和有效性。这些结果可以提供翻译惯性，以开发靶向肿瘤间质的疫苗和组合疗法，其可以应用于携带任何类型的血管化癌症的患者。