Marina Caskey, MD

Marina Caskey Dr. Caskey's research is focused on the development and clinical testing of HIV vaccines and vaccine adjuvants, particularly vaccines that work by directly targeting infectious antigens to dendritic cells.

Dendritic cells are the sentinels of the immune system. In the steady state, dendritic cells capture and process antigens, travel to lymphoid tissues and present the processed antigen to T cells, stimulating a robust immune response. Dr. Caskey is a member of the Steinman laboratory, which is developing a novel vaccine strategy that exploits this pivotal role of dendritic cells (DCs) in initiating adaptive immunity. Synthetic HIV proteins are fused to a monoclonal antibody that binds to an uptake receptor, DEC-205, that is primarily expressed on dendritic cells. In order to elicit immune responses, dendritic cells need to be in a mature state when antigen is delivered within the anti- DEC-205 antibody. A key component of our protein vaccine platform is the use of a vaccine adjuvant, poly ICLC, in combination with the anti-DEC-205 fusion antibody in order to induce maturation of dendritic cells.

Dr. Caskey has worked closely with other members of the laboratory to characterize the immunogenicity of the anti-DEC-205 p24 mAb vaccine construct in mice. When compared with other vaccine strategies in mice, anti-DEC205 HIV gag fusion antibody in combination with poly ICLC, as an adjuvant, induced stronger T cell immunity both in quantity and quality. These preclinical studies helped design the first-in-human concept study to test this novel dentritic cell-targeted HIV vaccine.

She is a key member of the clinical team to bring this vaccine candidate to the clinic. The first proof-of-concept trial of anti-DEC-205 p24 vaccine candidate is currently enrolling healthy volunteers at the Heilbrunn Outpatient Research Center of the Rockefeller University Hospital. Together with Dr. Schlesinger, Dr. Caskey evaluates and follows volunteers as they enroll in the trial. In the laboratory, Dr. Caskey will study the immune responses generated by this DEC-targeted HIV gag vaccine. If successful, this vaccine approach will add to the current arsenal of HIV vaccine strategies.

In order to understand, in humans, the mechanism whereby poly ICLC enhances T and B cell immunity, Dr. Caskey and colleagues carried on a phase I study to test the safety and early immune responses induced by poly ICLC. She found that poly ICLC reliably induces a systemic type-I IFN response when administered subcutaneously to healthy volunteers. This early IFN signature might correlate with the effectiveness of poly ICLC as a vaccine adjuvant. Future studies will continue to address the mechanism whereby poly ICLC and other adjuvants exert their immunomodulatory efffects in humans.

Prior to coming to the Rockefeller University, Dr. Caskey attended medical school at the Federal University of Sergipe in Brazil, she then completed her internal medicine residency at Saint-Lukes Roosevelt Hospital in New York, followed by fellowship training in Infectious Diseases at New-York Presbyterian Hospital (Cornell). Upon completion of medical training she joined the Laboratory of Cellular Physiology and Immunology, headed by Dr. Ralph Steinman, as a clinical scholar from 2006-2009. In 2009 she was awarded a Master.s degree in Clinical and Translational Research. She is now an Instructor in Clinical Investigation at the Rockefeller University. Dr. Caskey is funded through a Career Development Award from the National Institutes of Health.

Publications:

1. S. Vasan, S. J. Schlesinger, Z. Chen, A. Hurley, A. Lombardo, S. Than, P. Adesanya, C. Bunce, M. Boaz, R. Boyle, E. Sayeed, L. Clark, D. Dugin, M. Boente-Carrera, C. Schmidt, Q. Fang, L. Ba, Y. Huang, G.J. Zaharatos, D.F. Gardiner, M. Caskey, L. Seamons, M. Ho, L. Dally, C. Smith, J. Cox, D.K. Gill, J. Gilmour, M.C. Keefer, P. Fast, D. D. Ho. Phase 1 Safety and Immunogenicity Evaluation of ADMVA, a Multigenic, Modified Vaccinia Ankara-HIV-1 B./C Candidate Vaccine. PLoS One. 2010 Jan 25;5(1):e8816. PMID: 20111599

2. Longhi, M.P., Trumpfheller, C., Idoyaga, J., Caskey, M., Matos, I., Kluger, C., Salazar, A.M>, Colonna, M., and Steinman, R.M. Dendritic cells require a systemic type 1 interferon response to mature and induce CD4+ Th1 immunity with poly IC as adjuvant. J Exp Med 2009. 206:1589-1602. PMID: 19564349

3. Trumpfheller C, Caskey M, Nchinda G, Longhi MP, Mizenina O, Huang Y, Schlesinger SJ, Colonna M, Steinman RM. The microbial mimic poly IC induces durable and protective CD4+ T cell immunity together with a dendritic cell targeted vaccine. Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2574-9. PMID: 18256187

4. Morgan DJ, Caskey MF, Abbehusen C, Oliveira-Filho J, Araujo C, Porto AF, Santos SB, Orge GO, Joia MJ, Muniz AL, Siqueira I, Glesby MJ, Carvalho E. Brain magnetic resonance imaging white matter lesions are frequent in HTLV-I carriers and do not discriminate from HAM/TSP. AIDS Res Hum Retroviruses. 2007 Dec;23(12):1499-504. PMID: 18160007

5. Caskey MF; Morgan DJ; Giozza SP; Muniz AL; Carvalho EM; Glesby MJ. Clinical Manifestations of HTLV-I infection: a Case-Control study. AIDS Res Hum Retroviruses. 2007 Mar;23(3):365-71. PMID: 17411369