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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA140375-05
Application #
8610143
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Muszynski, Karen
Project Start
2010-04-01
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
5
Fiscal Year
2014
Total Cost
$266,796
Indirect Cost
$85,648
Name
University of Pittsburgh
Department
Dermatology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Lowe, Devin B; Taylor, Jennifer L; Storkus, Walter J (2014) Monitoring antigen-specific T cell responses using real-time PCR. Methods Mol Biol 1186:65-74
Chen, L; Taylor, J L; Sabins, N C et al. (2013) Extranodal induction of therapeutic immunity in the tumor microenvironment after intratumoral delivery of Tbet gene-modified dendritic cells. Cancer Gene Ther 20:469-77
Chi Sabins, Nina; Taylor, Jennifer L; Fabian, Kellsye P L et al. (2013) DLK1: a novel target for immunotherapeutic remodeling of the tumor blood vasculature. Mol Ther 21:1958-68
Bose, Anamika; Lowe, Devin B; Rao, Aparna et al. (2012) Combined vaccine+axitinib therapy yields superior antitumor efficacy in a murine melanoma model. Melanoma Res 22:236-43
Qu, Yanyan; Chen, Lu; Lowe, Devin B et al. (2012) Combined Tbet and IL12 gene therapy elicits and recruits superior antitumor immunity in vivo. Mol Ther 20:644-51
Qu, Y; Taylor, J L; Bose, A et al. (2011) Therapeutic effectiveness of intratumorally delivered dendritic cells engineered to express the pro-inflammatory cytokine, interleukin (IL)-32. Cancer Gene Ther 18:663-73
Lowe, Devin B; Storkus, Walter J (2011) Chronic inflammation and immunologic-based constraints in malignant disease. Immunotherapy 3:1265-74