The incidence of melanoma continues to rise at an alarming pace, with estimates of the 70,000 patients diagnosed and 8,700 deaths attributable to this disease in 2011. Despite recent successes for BRAF inhibitors and ipilumimab (anti-CTLA-4 mAb) in providing objective clinical responses in melanoma patients, such benefits are typically of short duration, with durable responses observed in only 5-15% of treated individuals. A major reason for disease recurrence and the development of treatment-refractory disease reflects the genetic heterogeneity of tumor cells in a given lesion and the ability of subsets of tumor cells to select for compensatory growth and survival pathways that circumvent specific therapeutic blockade. As an attempt to bypass such tumor-intrinsic limitations, we have recently developed vaccines that promote CD8+ T cell targeting of tumor-, but not normal tissue-, associated blood vessel cells. In melanoma models applied to HLA-A2 transgenic (Tg) mice, these vaccines can promote tumor regression and durable disease-free status. We have also determined that therapeutic vaccines may become increasingly efficacious based on the co-administration of tyrosine kinase inhibitors, such as dasatinib (DAS), based on the "off target" abilities of this drg to diminish immune regulatory cells, to increase vaccine-induced T effector cells in the tumor-bearing host, and to alter chemokine and integrin expression in the tumor microenvironment to facilitate the recruitment of protective CD8+ T cells. Based on these preliminary findings, we hypothesize that combination therapies consisting of tumor blood vessel antigen-based vaccines and dasatinib will prove safe and of increased effectiveness in the setting of HLA-A2+ patients with advanced stage melanoma (Aim 1). Given our findings of dormant, occult melanomas in a subset of HLA-A2 Tg mice that have been effectively treated with anti-vascular vaccines, we will also test the hypothesis that the rate of complete "molecular cures" in these animals may be improved by combination therapies that allow for enhanced CD8+ T cell recognition and regulation of melanoma initiating cells (aka melanoma stem cells or self-renewing melanoma cells) or that block the tumor (pro-survival) autophagy pathway in vivo (Aim 2). Based on our pre-clinical modeling, we believe that the successful completion of these studies will define a novel therapeutic paradigm for the effective treatment of a broad range of solid (vascularized) cancers.

Public Health Relevance

Current cancer therapies for solid tumors have failed to provide durable clinical benefit based on both tumor intrinsic (drug resistance, immune evasion, self-renewing subpopulations of tumor cells) and extrinsic (recruitment of suppressor/regulatory cells, prevention of recruiting protective immune cells, immune anergy) factors. The current proposal will study combination vaccine therapies to activate and appropriately direct immune (CD8+ T) cells that can selectively and negatively regulate tumor blood vessels in vivo. This treatment paradigm will evaluated in an innovative phase II pilot clinical trial involving patients with advanced-stage melanoma, as well as, novel melanoma models of minimal residual disease applied to HLA-A2 transgenic recipient mice that display human-like immune (CD8+ T cell) responses.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA169118-01
Application #
8345990
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Song, Min-Kyung H
Project Start
2012-09-20
Project End
2017-07-31
Budget Start
2012-09-20
Budget End
2013-07-31
Support Year
1
Fiscal Year
2012
Total Cost
$419,449
Indirect Cost
$130,781
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; Bose, Anamika; Taylor, Jennifer L et al. (2014) Dasatinib promotes the expansion of a therapeutically superior T-cell repertoire in response to dendritic cell vaccination against melanoma. Oncoimmunology 3:e27589
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