This project will evaluate an entirely novel approach to skin cancer treatment applicable to a broad range of topically accessible skin cancers. We propose to co-deliver a potent chemotherapeutic agent and an immune modifier to kill topically accessible cancer cells and simultaneously convert a cutaneous neoplasm into a highly potent patient specific immunogen capable of inducing innate, adaptive, and tumor specific memory immune responses. The strategy is enabled by a unique microneedle array (MNA) delivery device developed and produced in our laboratory. The therapeutic approach is polyfunctional and synergistic. Chemotherapy and adjuvant therapy are combined temporally and spatially. Chemotherapy is used to kill existing tumor cells through immunogenic "good death" mechanisms that convert dying cells into a rich source of tumor antigen. Simultaneously, a potent adjuvant is delivered to the tumor bed to recruit and activate innate immune responses and antigen presenting cells. This combined therapy is expected to result in both chemotherapeutic and immune-mediated tumor lysis, providing a rich source of full-length autologous tumor antigens in a pro-immunogenic environment that will promote the development of antigenically broad tumor-specific cellular and humoral immunity. This approach has the additional advantage of affording patient and tumor specific immunity by utilizing the patient's tumor directly as a source of immunogen, obviating obstacles related to antigen and tumor heterogeneity. The dissolvable MNAs we have developed can simultaneously deliver chemotherapeutic agent(s) and immune adjuvant(s) to the same cutaneous microenvironment, enabling manipulation of the tumor microenvironment through low dose delivery, with virtually no systemic exposure or toxicity. Further, the biologically active cargos loaded into MNA devices are extremely stable, and eliminate dependency on the cold chain. Together with the ease of fabrication and minimal dosing, these features enable an economically feasible patient specific chemo-immunization. In this project, we will test our hypothesis that in situ topical MNA-directed chemo-immunotherapy will kill tumor cells locally and alter the tumor microenvironment to induce durable systemic tumor specific immunity. In this, the first clinical application of this strategy, our goal is to evaluate MNA-directed chemoimmunotherapy in patients with in-transit melanoma and in CTCL patients through phase l/ll clinical trials. We will evaluate clinical responses and therapy induced immune effects locally and systemically.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-M (M1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
United States
Zip Code
Dulmage, B O; Feng, H; Mirvish, E et al. (2015) Black cat in a dark room: the absence of a directly oncogenic virus does not eliminate the role of an infectious agent in cutaneous T-cell lymphoma pathogenesis. Br J Dermatol 172:1449-51
Sabbatino, Francesco; Wang, Yangyang; Wang, Xinhui et al. (2014) PDGFR? up-regulation mediated by sonic hedgehog pathway activation leads to BRAF inhibitor resistance in melanoma cells with BRAF mutation. Oncotarget 5:1926-41
Tarhini, Ahmad A; Edington, Howard; Butterfield, Lisa H et al. (2014) Immune monitoring of the circulation and the tumor microenvironment in patients with regionally advanced melanoma receiving neoadjuvant ipilimumab. PLoS One 9:e87705
Ng, Yuen-Keng; Lee, Jia-Ying; Supko, Kathryn M et al. (2014) Pan-erbB inhibition potentiates BRAF inhibitors for melanoma treatment. Melanoma Res 24:207-18
Tarhini, Ahmad A; Shin, Donghoon; Lee, Sandra J et al. (2014) Serologic evidence of autoimmunity in E2696 and E1694 patients with high-risk melanoma treated with adjuvant interferon alfa. Melanoma Res 24:150-7
Pancoska, Petr; Kirkwood, John M; Bouros, Spyros et al. (2014) A new mathematical model for the interpretation of translational research evaluating six CTLA-4 polymorphisms in high-risk melanoma patients receiving adjuvant interferon. PLoS One 9:e86375
Tarhini, Ahmad A; Lin, Yan; Yeku, Oladapo et al. (2014) A four-marker signature of TNF-RII, TGF-?, TIMP-1 and CRP is prognostic of worse survival in high-risk surgically resected melanoma. J Transl Med 12:19
Geskin, Larisa J; Akilov, Oleg E; Lin, Yan et al. (2014) Distinct age-matched serum biomarker profiles in patients with cutaneous T-cell lymphoma. Exp Dermatol 23:598-600
Schowalter, Michael K; Dulmage, Brittany O; Ho, Jonhan et al. (2014) Comparative proteomic analysis reveals unique tumor protein composition among the melanoma subtypes pure desmoplastic and superficial spreading. Melanoma Res 24:397-400
McArthur, Grant A; Chapman, Paul B; Robert, Caroline et al. (2014) Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol 15:323-32

Showing the most recent 10 out of 59 publications