While adoptive immunotherapy is a promising treatment for a variety of cancers, progress has been impeded by the lack of a reproducible and economical method for generating therapeutic numbers of antigen-specific CTL. To address this issue, we developed an HLA-Ig, bead-based artificial Antigen-Presenting Cell (aAPC) which reliably induced and expanded melanoma and other tumor antigen-specific CTL in vitro. During the last funding period, we developed the aAPC into a multifunctional platform technology. We demonstrated that aAPC-induced melanoma antigen, Mart-1 specific CTL functioned in both in vivo protection and treatment models and that MHC-Ig based aAPC could also be used for in vivo administration to stimulate low affinity melanoma- specific CTL. In addition we characterized CTL polyfunctionality in different human antigen-specific CTL populations stimulated with DC or APC. We also developed a novel assay that uses the fluorescence of quantum dots to characterize TCR microclusters on cells. The goals of the proposed research are: to optimize aAPC-induced CTL function in vivo by studying the characteristics of CTL populations that track to and eliminate tumors, to understand mechanistically how in vivo aAPC administration increases CTL function and to understand the regulation of CTL polyfunctionality. These studies will facilitate our understanding of how to optimize CTL for adoptive immunotherapy and further develop the potential uses of HLA-Ig-based aAPC for melanoma immunotherapy.

Public Health Relevance

A major goal in cancer immunotherapy is to generate an effective anti-tumor immune response. To address this issue, we developed a platform artificial Antigen-Presenting Cell (aAPC) technology and used aAPC to stimulate T cells specific for melanoma skin cancer. We have also developed an imaging technique that can detect subtle changes in TCR reorganization that appear important in helping the T cell function effectively. Based on our findings during the previous funding period we propose to study the characteristics and regulation of T cell populations that track to and eliminate tumors. These studies will help elucidate basic mechanisms involved in stimulating optimal anti-melanoma tumor specific T cell responses and define the potential uses of HLA-based aAPC immunotherapy for the treatment of melanoma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA108835-06A2
Application #
8107927
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Mccarthy, Susan A
Project Start
2004-07-01
Project End
2016-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
6
Fiscal Year
2011
Total Cost
$318,780
Indirect Cost
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Kosmides, A K; Meyer, R A; Hickey, J W et al. (2017) Biomimetic biodegradable artificial antigen presenting cells synergize with PD-1 blockade to treat melanoma. Biomaterials 118:16-26
Tiper, Irina V; Temkin, Sarah M; Spiegel, Sarah et al. (2016) VEGF Potentiates GD3-Mediated Immunosuppression by Human Ovarian Cancer Cells. Clin Cancer Res 22:4249-58
Schütz, Christian; Varela, Juan Carlos; Perica, Karlo et al. (2016) Antigen-specific T cell Redirectors: a nanoparticle based approach for redirecting T cells. Oncotarget 7:68503-68512
Perica, Karlo; Bieler, Joan Glick; Schütz, Christian et al. (2015) Enrichment and Expansion with Nanoscale Artificial Antigen Presenting Cells for Adoptive Immunotherapy. ACS Nano 9:6861-71
Perica, Karlo; Kosmides, Alyssa K; Schneck, Jonathan P (2015) Linking form to function: Biophysical aspects of artificial antigen presenting cell design. Biochim Biophys Acta 1853:781-90
Bruns, Heiko; Bessell, Catherine; Varela, Juan Carlos et al. (2015) CD47 Enhances In Vivo Functionality of Artificial Antigen-Presenting Cells. Clin Cancer Res 21:2075-83
Perica, Karlo; Tu, Ang; Richter, Anne et al. (2014) Magnetic field-induced T cell receptor clustering by nanoparticles enhances T cell activation and stimulates antitumor activity. ACS Nano 8:2252-60
Perica, Karlo; De León Medero, Andrés; Durai, Malarvizhi et al. (2014) Nanoscale artificial antigen presenting cells for T cell immunotherapy. Nanomedicine 10:119-29
Sunshine, Joel C; Perica, Karlo; Schneck, Jonathan P et al. (2014) Particle shape dependence of CD8+ T cell activation by artificial antigen presenting cells. Biomaterials 35:269-277
Schütz, Christian; Fleck, Martin; Schneck, Jonathan P et al. (2014) Killer artificial antigen presenting cells (KaAPC) for efficient in vitro depletion of human antigen-specific T cells. J Vis Exp :e51859

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