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

描述(申请人提供)：除了以肿瘤细胞为靶点外，支持肿瘤的微环境还可能被针对肿瘤相关基质细胞类型的治疗策略破坏或破坏，例如与新血管生成或新血管生成有关的那些。虽然从周围血管形成的血管是伤口愈合和周围新血管生成的典型过程，但在进展性肿瘤中，类似的结构也可能涉及新生血管的过程。特别是，肿瘤血管内皮管和稳定的血管周细胞通常作为(间充质或造血细胞)前体被招募到肿瘤中，并基于肿瘤产生或诱导的血管生成因子，如血管生成因子，如血管内皮生长因子、血小板衍生生长因子和转化生长因子-β，诱导分化并整合成更高阶的复合体。考虑到这种操作(和潜在成分)的差异，现在已经可以考虑以免疫为基础的靶向肿瘤微环境(TME)内的血管内皮细胞(VEC)或周细胞，以期安全(即对伤口愈合或血脑屏障或视网膜内的关键血管屏障缺乏抑制作用)。可以想象，旨在诱导T细胞介导的肿瘤微环境中血管内皮细胞或周细胞被清除的疫苗将持久地抑制肿瘤的血液供应，并减少对抗原丢失靶标变体的担忧，就像在慢性免疫编辑/选择下的异质肿瘤细胞群中可能发生的那样。由于TME中新生血管的钝化和现有血管的不稳定，肿瘤细胞的死亡增加和宿主抗原提呈细胞(APC)支持的抗肿瘤T细胞的必然交叉激发是可望的。此外，免疫介导的周细胞从肿瘤血管中移除有望导致血管出血/渗漏增加，导致血管通透性增加，肿瘤核心内组织间质液体压力正常化。这种条件将有利于增加和潜在地选择性地将全身药物(包括药理化合物或过继转移的T细胞)输送到TME中，从而产生改善治疗效果的可能性。在初步数据中，我们表明，在没有可检测到的自身免疫病理的情况下，促进CD8+T细胞对周细胞或血管内皮细胞相关抗原的反应的预防性和治疗性疫苗在体内阻止了小鼠肿瘤的血管形成，其机制是促进肿瘤IFP的正常化和减少肿瘤内的缺氧。基于这一范式，我们建议：测试以下假设：针对肿瘤VEC/周细胞的疫苗是安全的，并且能够促进体内CD8+T细胞介导的晚期肿瘤的消退(特定目标1)，以及整合这些疫苗的共同疗法将改善化疗/免疫治疗药物进入TME的(共同)输送，通过扩大治疗性T细胞库(特定目标2)来产生增强的治疗益处。 公共卫生相关性：渐进性生长的肿瘤由其他类型的细胞支持，这些细胞类型统称为间质。间质细胞包括构建和维持肿瘤血供所需的血管内皮细胞和周细胞。由于基质细胞是正常的，不受癌细胞常见的遗传不稳定性的影响，它们为治疗药物的开发提供了一个静态靶点。在过去的十年里，针对肿瘤血管的治疗性靶向越来越受到人们的关注，导致了小分子和抗体抑制剂的发展。临床上，这些药物使肿瘤血管正常化，当单独使用或与其他药物(如化疗)联合使用时，它们对癌症患者产生了抗肿瘤效果。不幸的是，由于这些药物是系统应用的，患者会有很大的副作用，不能长期服用。这些模式的另一种选择是疫苗，旨在诱导针对组成肿瘤血管系统的细胞所表达的抗原的特异性T细胞反应。根据我们的初步数据，这种疫苗提供了强大的抗肿瘤保护，并且不针对正常组织血管系统，使它们既有效又安全。由于这种T细胞可以通过加强免疫定期更新，它们可能会提供新的和有效的肿瘤生长抑制因子。我们提出的研究将在接近人类免疫系统的小鼠模型中评估这种方式的安全性和有效性。这些结果可能为开发针对肿瘤间质的疫苗和联合疗法提供翻译惯性，这些疗法可以应用于任何类型的血管化癌患者。

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.