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Program Director/Principal Investigator (Last, First, Middle):
Kirken, Robert A.
BIOGRAPHICAL SKETCH
Provide the following information for the Senior/key personnel and other significant contributors in the order listed on Form Page 2.
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NAME
POSITION TITLE
June Kan-Mitchell
Professor, Biological Sciences
The University of Texas at El Paso
eRA COMMONS USER NAME (credential, e.g., agency login)
ag1671
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and
residency training if applicable.)
DEGREE
INSTITUTION AND LOCATION
MM/YY
FIELD OF STUDY
(if applicable)
Smith College, Northampton, MA
BA cum laude
1971
Biochemistry
Yale University School of Medicine
Ph.D.
1977
Yale University School of Medicine
Postdoctoral
fellow
1979
Pharmacology
(Dr. William H. Prusoff)
Pharmacology
(Dr. Malcolm S. Mitchell)
A. PERSONAL STATEMENT
My interest in human immunology, immunological therapies such as infusional IL-2, adoptive T cell therapy,
and experimental T cell-based vaccines dates back to my postdoctoral and junior faculty years. Working in the
laboratory of Dr. Malcolm S. Mitchell, I helped to develop the first melanoma vaccine (Melacine™) approved for
clinical use in Canada. Central to these investigations was the monitoring and culture of cancer-specific human
T cells and identification of novel tumor-associated antigens that are immunogenic to humans. For the latter, I
generated human monoclonal antibodies to melanoma-associated and breast cancer-associated antigens from
spontaneously immunized draining node B lymphocytes. My interest in HIV began with a collaboration with Dr.
Flossie Wong-Staal at UCSD to investigate the immunogenicity of human dendritic cells (DC) transduced to
express HIV antigens with novel lentiviral vectors. Gene delivery by lentiviral vectors has the major advantage
of not inducing vector-specific immunity. I have since used transduced DC to map dominant and subdominant
CD8+ T cell epitopes presented by HLA-A*0201 and HLA-B*57 in HIV proteins. These novel epitopes
recognized by the human T cell repertoire are processed and presented naturally. Moreover, we showed
immunodominance of N epitopes based on the frequency of recognition at the population level and the
magnitude of the in vitro immunized responses.
In terms of HIV vaccines, I am exploring the natural hierarchy of key CTL epitopes restricted by the “neutral”
HLA-A2, to allow alteration of this hierarchy through the design of synthetic immunogens to focus onto potent
driver CTL responses. Another program aims to identify and recruit naturally protective by subdominant CTL
reactivities restricted by the “protective” HLA-B*57 allele for more effective and durable CTL protection.
My laboratory continues to refine protocols to generate stable and homogeneous antigen-specific CD8+ T cells
from healthy seronegative donors and from patients, to provide insights into human immune responses that
may be relevant to successful vaccination. We then attempt to validate insights from cultured CD8+ T cells
with in vivo responses of T cells from HIV patients. For example, our observation that CTLs primed from
healthy donors to the chronic immunodominant Gag SL9 epitope were sensitive to IL-2-induced cell death was
confirmed with patient samples. This led us to caution that over-activation may lead to CTL elimination in the
highly proinflammatory milieu during early HIV infection, at a time when HIV vaccinologists were intent on
enhancing the immunogenicity of HIV antigens or vaccine preparations. My laboratory is well positioned to
carry out the proposed studies, because we have extensive experience with DC-, B- and T-cell cultures,
characterization of the CD8+ clonotypes by polychromatic flow cytometry, in vitro HIV suppression assays,
positional scanning combinatorial peptide libraries to examine TCR degeneracy, and gene expression by rtPCR. I have also had long-standing productive collaborations with all but two of our proposed investigative
team. Overall, my demonstrated interest and expertise are directly relevant to this study and will allow me to
serve effectively as the Principal Investigator, to oversee the utilization of resources and to insure that the
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Program Director/Principal Investigator (Last, First, Middle):
Kirken, Robert A.
project aims are addressed in a timely manner. Moreover, I will ensure that appropriate go/no-go decisions are
made expeditiously, to optimize scientific productivity.
B. POSITIONS AND HONORS
Positions and Employment
1978-1981
NIH NCI Individual Postdoctoral Fellow, University of Southern California School of
Medicine, Los Angeles
1981-1989
Assistant Professor, Department of Microbiology, USC School of Medicine
1990-1994
Associate Professor, Department of Pathology, USC School of Medicine
1994-1999
Associate Adjunct Professor, Department of Pathology, University of California San
Diego, San Diego
1999-2004
Associate Professor, Karmanos Cancer Institute and Microbiology and Immunology,
Wayne State University School of Medicine, Detroit
2004-2006
Professor with tenure, WSU School of Medicine
2007-present
Professor with tenure, Biological Sciences, The University of Texas at El Paso, El Paso
Other Experience and Recent Professional Memberships
2012
NIAID Special Emphasis Panel (SEP) (Center for HIV Vaccine Immunology and
Immunogen Discovery (CHAVI-ID) (UM1))
2012
NIAID SEP (Partnerships for Development of Vaccine Technologies (R01))
2011, 2012
NIH SEP (Center for AIDS Research (P30))
2009-2012
NIAID SEP (HIV Vaccine Research and Design Program (HIVRAD) (P01))
2012
NIAID SEP (Partnerships for Development of Vaccine Technologies (R01))
2012
NIAID SEP (Member Conflict: HIV/AIDS Immune Response and Vaccines (R01))
2011-2012
NIAID SEP (Fellowships for Training in AIDS and AIDS-related Research (F30, F31,
F32, F33))
2011
NIAID SEP (Innate and Adaptive Responses as Guide to HIV Vaccine Design (P01))
2010
NIDCR SEP (Oral Mucosal Vaccination against HIV Infections (R01))
2008-2010
DOD Congressionally Directed Breast Cancer Research Study Section
2008-2010
DOD Congressionally Directed Prostate Cancer Research Study Section
2004-2007
NIAID Study Section (Vaccines for Infectious Diseases, VACC (R01))
2004-2007
Susan G. Komen Breast Cancer Foundation, Tumor Cell Biology III Study Section
1987-2005
NCI Special Review Committees for Cancer Therapeutics Program Project, Cancer
Center Core Support, and Cancer Immunology Program Project
Editorial Boards: Journal of Clinical Laboratory Analysis; Human Antibodies and Hybridomas; Vaccine
Research; Cancer Immunology and Immunotherapy, and HIV/AIDS - Research and Palliative Care.
Organizing Committees: Viruses from Nature, 2012 McLaughlin Symposium, University of Texas Medical
Branch and the Western Regional Center of Excellence for Biodefense and Emerging Infectious Diseases
Research (WRCE), Galveston, TX
C. SELECTED PEER-REVIEWED PUBLICATIONS
Most relevant to the current application
1. Gruber A, Kan-Mitchell J, Kuhen KL, Mukai T, Wong-Staal F. Efficient and non-disturbing transduction of
dendritic cells by HIV-1 vectors to elicit HIV specific T-lymphocytes in vitro. Blood. 96:1327-33, 2000.
PMID: 10942374.
2. Kan-Mitchell J and Wong-Staal F. Pseudotyped nonreplicative lentiviral vectors to elicit virus-specific T cell
responses. In AIDS Vaccine Research in Perspective, eds. F. Wong-Staal and R.C. Gallo, Marcel Dekker,
Inc., New York (2002).
3. Kan-Mitchell J, Bisikirska B, Wong-Staal F, Schaubert KL, Bajcz M, Bereta M. The HIV-1 HLA-A2SLYNTVATL is a help-independent CTL epitope. J Immunol. 172:5249-5261, 2004. PMID: 15100263
4. Kan-Mitchell J, Bajcz M, Schaubert KL, Price DA, Brenchley JM, Asher TE, Douek DC, Ng HL, Yang OO,
Rinaldo CR, Benito JM, Bisikirska B, Hegde R, Marincola FM, Boggiano C, Wilson D, Abrams J, Blondelle
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Program Director/Principal Investigator (Last, First, Middle):
5.
6.
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Kirken, Robert A.
SE, Wilson DB. Degeneracy and repertoire of the human HIV-1 Gag p1777-85 CTL response. J Immunol.
176:6690-701, 2006. PMID: 16709828
Mitchell MS, Lund TA, Sewell AK, Paul E, Wilson DB, Kan-Mitchell J. The cytotoxic T cell response to
agonistic peptide analogs of the HLA-A*0201-restricted MUC1 signal sequence epitope, M1.2 Cancer
Immunol Immunother. 56:287-301, 2007. PMID: 16874487
Schaubert KL, Price DA, Frahm N, Li J, Ng HL, Joseph A, Paul E, Majumder B, Ayyavoo V, Gostick E,
Adams S, Marincola FM, Sewell AK, Altfeld M, Brenchley JM, Douek DC, Yang OO, Brander C, Goldstein
H, Kan-Mitchell J. Availability of a diversely avid CD8+ T cell repertoire specific for the subdominant HLAA2-restricted HIV-1 Gag p2419-27 epitope. J Immunol. 178:7756-66, 2007. PMCID: PMC2365726.
Schaubert KL, Price DA, Li J, Salkowitz JR, Sewell AK, Sydney J, Asher TE, Blondelle SE, Adams S,
Marincola FM, Joseph A, Sette A, Douek DC, Ayyavoo V, Storkus W, Ng HL, Yang OO, Goldstein H,
Wilson DB, and Kan-Mitchell J. Repertoire modulation with mimotopes: an approach to the generation of
robust CD8+ T cell responses specific for subdominant epitopes derived from conserved regions of human
immunodeficiency virus. Eur J Immunol. 40:1950-62, 2010.
Subramanya S, Armant M, Salkowitz JR, Nyakeriga AM, Haridas V, Hasan M, Bansal A, Goepfert PA,
Wynn KK, Ladell K, Price DA, N M, Kan-Mitchell J, Shankar P. Enhanced induction of HIV-specific
cytotoxic T lymphocytes by dendritic cell-targeted delivery of SOCS-1 siRNA. Mol Ther. 18(11):2028-37;
2010. PMCID: PMC2990509.
Additional publications of importance to the field (in chronological order)
9. Kan-Mitchell J, White WL, Mitchell MS. Tumor-reactive human IgG monoclonal antibody from a melanoma
patient. Cancer Res. 49:4536-41, 1989. PMID: 2472881
10. Hutchins JT, Deans RJ, Mitchell MS, Kan-Mitchell J. Novel gene sequences expressed by human
melanoma cells identified by molecular subtraction. Cancer Res. 51:1418-25, 1991. PMID: 1997180
11. Kan-Mitchell J, Huang X-Q, Steinman L, Oksenberg JR, Harel W, Parker JW, Goedegebuure PS, Darrow
TL, Mitchell MS. Clonal analysis of in vivo-activated CD8+ cytotoxic T lymphocytes from a melanoma
patient responsive to active-specific immunotherapy. Cancer Immunol Immunother. 37:15-25, 1993. PMID:
8513449
12. Kan-Mitchell J, Liggett PE, Taylor CR, Rao N, Granada ESV, Danenberg KS, White WL, Van Eldik LJ,
Korikoshi T, Danenberg PV. Differential expression of S100 by choroidal and skin melanomas: quantitation
by the polymerase chain reaction. Invest Ophthalmol Vis Sci. 34:3366-3375, 1993. PMID: 8225871
13. Huang X-Q, Mitchell MS, Liggett PE, Murphree AL, Kan-Mitchell J. Non-fastidious, melanoma-specific
CD8+ cytotoxic T lymphocytes from choroidal melanoma patients. Cancer Immunol Immunother. 38:399405, 1994. PMID: 8205561
14. Mitchell, MS, Darrah D, Yeung D, Halpern S, Wallace A, Voland J, Jones V, and Kan-Mitchell J. Phase I
trial of adoptive immunotherapy with cytolytic T lymphocytes immunized against a tyrosinase epitope. J
Clin Oncol. 20:1075-1086, 2002. PMID: 11844833
15. Mitchell MS, Kan-Mitchell J, Morrow PR, Darrah D, Jones VE, Mescher MF. Phase I trial of Large
Multivalent Immunogen (LMI) derived from melanoma lysates, in patients with disseminated melanoma.
Clin Cancer Research. Clin Cancer Res. 10:76-83, 2004. PMID: 14734454
C. RESEARCH SUPPORT
Active
1 R01 AI 102663 – 01 Kan-Mitchell J (PI)
8/01/2012  7/30/2016
NIAID/NIH
Effector and Regulatory Activities of HLA-E-restricted HIV-specific αβCD8 T Cells
This project will explore the novel HIV-specific CD8 T cell immunity restricted by class Ib HLA-E molecules,
specifically to map conserved epitopes and assess the character of these reactivities within the HLA-E based
antigen presentation system in HIV infection.
R01AI077413-01 Kan-Mitchell J (PI)
9/1/2008 – 8/31/2012
NIAID/NIH
Mapping Novel Subdominant B*5701 Epitopes in Conserved Regions of the HIV Proteome
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Program Director/Principal Investigator (Last, First, Middle):
Kirken, Robert A.
This project will explore a new HIV vaccine strategy aimed to redirect the CTL response exclusively to “driver”
targets embedded in the most conserved regions of the HIV proteome. We will map epitopes presented by the
“protective” B*5701 allele and assess their recognition by B*57 progressor and controller patients to correlate
these reactivities to protection.
Completed
1R01 AI064069-01 Kan-Mitchell J (PI)
5/01/2006  4/30/2012 (no cost extension)
NIAID/NIH
Optimizing Gag CTL Epitopes to Improve Immunogenicity
This project will analyze immunodominant hierarchy of HLA-A2-restricted CTL epitopes to aid in the design of
a genetically improved HIV Gag protein as vaccine immunogen.
1 U54 AI 057156 Walker DH (PI)
04/23/2009 – 09/04/2014
NIH/NIAID
Region VI Center for Biodefense and Emerging Infections
The major goals of this project are to conduct multidisciplinary, multifaceted research to develop biodefense
countermeasures for Category A – C infectious agents.
Subproject: Kan-Mitchell (PI)
09/01/2009 – 08/31/2011
Toward Defining Protective Human T-cell Epitopes in Rift Valley Fever Virus
This subproject will show that the RVFV N protein is a human CD8 T cell antigen and identified HLA-A*0201restricted epitopes that are immunodominant based on the magnitude of the CD8 responses immunized in vitro
and the frequency of responders among healthy donors.
Role: PI
R01AI077413-01S1 Kan-Mitchell J (PI)
4/20/2010 – 8/31/2012
NIAID/NIH
Mapping Novel Subdominant B*5701 Epitopes in Conserved Regions of the HIV Proteome
Support for a doctoral candidate (Luis Rodriguez Valdes).
1R01 AI064069-01S1 Kan-Mitchell J (PI)
NIAID/NIH
Optimizing Gag CTL Epitopes to Improve Immunogenicity, Diversity Supplement
Support for a doctoral candidate (Margaret C. Costanzo).
1 U54 AI 057156S1 Walker DH (PI)
NIH/NIAID
Region VI Center for Biodefense and Emerging Infections
Subproject: Kan-Mitchell (PI)
WRCE Toward a Universal Rickettsial Subunit T Cell-Based Vaccine
Support for post baccalaureate research scholar (Stacey Moreno).
0925-0001/0002 (Rev. 08/12)
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5/16/2008  8/30/2011
04/23/2009 – 09/04/2014
04/01/2011 – 10/31/2011
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