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

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的治疗策略可能会破坏或破坏支持性肿瘤微环境，例如那些涉及新血管生成或新血管生成的基质细胞。从周围血管形成血管是伤口愈合和周围新血管生成的典型特征，在进展性肿瘤中类似的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的血管周围周细胞通常被招募到肿瘤中作为（间充质或造血）前体，并被诱导分化和整合成基于肿瘤产生或诱导的血管生成因子（如VEGF、PDGF和TGF-¿）的高阶复合物。鉴于这种操作（和潜在成分）差异，现在考虑肿瘤微环境（TME）内血管内皮细胞（VEC）或周细胞的免疫靶向已经变得可行，并期望安全性（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，设计用于诱导T细胞介导的肿瘤微环境中VEC或周细胞根除的疫苗可以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异体的关注，这可能发生在慢性免疫编辑/选择的异质肿瘤细胞群中。由于TME中新生血管变钝，现有血管不稳定，肿瘤细胞死亡增加，并且由宿主抗原呈递细胞（APC）支持的抗肿瘤T细胞必然交叉启动，这是预期的结果。此外，免疫介导的肿瘤血管周细胞去除预计会导致血管出血/渗漏增强，从而提高血管通透性，并使肿瘤核心内的间质液压力正常化。这样的条件有利于增加系统性药物（包括药物化合物或过继性转移的T细胞）进入TME的潜在选择性递送，从而有可能提高治疗效果。在初步数据中，我们表明，预防性和治疗性疫苗促进CD8+ T细胞对周细胞或vec相关抗原的反应，在体内通过促进肿瘤IFP正常化和减少肿瘤内缺氧的机制，在没有可检测到的自身免疫病理的情况下，阻止小鼠肿瘤的血管化。基于这一范式，我们建议：验证以下假设：针对肿瘤VEC/周细胞的疫苗是安全的，能够促进体内CD8+ T细胞介导的晚期肿瘤消退（Specific Aim 1），以及整合这些疫苗的联合疗法将改善化疗/免疫疗法药物进入TME的（co）递送，通过扩大治疗性T细胞库产生增强的治疗效果（Specific Aim 2）。

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.