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Masoud H. Manjili ,
D.V. M., Ph.D.
Assistant Professor

Phone: (804) 828-8779
Dept. Fax: (804) 828-8453
e-mail:
mmanjili@vcu.edu
Address:
Department of Microbiology & Immunology
Virginia Commonwealth University
Massey Cancer Center Goodwin Research Laboratory Room 286
PO Box 980035
401 College Street
Richmond, VA 23298-0035
Professional Experience
- D.V.M.,
1990, University of Tehran
- Ph.D.,
1996, University of Sydney
- Research
Scientist, 1997-1999, Razi Vaccine & Serum Institute, Pasteur Institute
-
Postdoctoral, 1999-2002, Roswell Park Cancer Institute
-
Instructor, 2003-2004, Roswell Park Cancer Institute, State University
of New York at Buffalo
Research Interests:
Research
projects in our laboratory are focused on understanding mechanisms of tumor
cell-immune cell interactions that lead to: i) immunosurveillance and tumor
regression; ii) tumor immunoediting and cancer recurrence; iii) immune
suppression by increasing myeloid-derived suppressor cells (MDSC) and/or
Tregs. We believe that all these three mechanisms are interrelated and must
be investigated systematically in order to develop an effective
immunotherapeutic approach for breast cancer.
Project I) Adoptive T cell therapy (AIT) and development of a highly
tailored humoral breast cancer vaccine
We have developed an ex vivo protocol for the expansion of low affinity
tumor-specific central memory CD8+ T cells. AIT by using these T cells
resulted in the regression of breast cancer and produced long-lasting
memory, leading to the prevention of spontaneous mammary carcinoma. Very
recently, we have identified distinct sub-domains of the extracellular
domain (ECD) of HER-2/neu towards which humoral immune responses are
associated with either tumor progression or tumor rejection and relapse-free
survival. Identification of these sub-domains resulted in designing a highly
tailored antigen target for development of a humoral vaccine against breast
cancer.

Project II) Tumor
immunoediting
While
immune responses are induced against variety of cancers resulting in the
inhibition of tumor development, molecular alterations in tumors can occur
under immune pressure resulting in tumor escape. In other words, anti-tumor
immune response is a “double-edged” sword exerting both host-protective and
tumor-sculpting effects on developing tumors. Such tumor immunoediting
process could induce epigenetic changes in tumors resulting in tumor antigen
loss and recurrence of primary or metastatic tumors.
Therefore, one of the challenges in the immunotherapy of cancers is how to
overcome tumor escape.
In
project I, we meet the challenge of developing immunotherapeutic approaches
to overcome tumor escape. We have shown that a
subset of HER-2/neu-specific IFN-γ
producing CD8+ T cells participate in HER-2/neu antigen loss, tumor
recurrence, epithelial to mesenchymal transition (EMT) and generation of
breast cancer stem cells (BCSC). Similar mechanisms have been extrapolated
to the clinic by the observation that some patients with HER-2/neu negative
breast cancer had pre-existing HER-2/neu-specific IFN-γ
producing T cell responses, suggesting that these patients might have had
HER-2/neu positive premalignant lesions in the past that had lost HER-2/neu
expression under the influence of HER-2/neu-specific IFN-γ
producing CD8+ T cells and progressed to HER-2/neu negative invasive breast
cancer. This hypothesis is being evaluated in cancer patients. Microarray
analysis of the tumor lesions identified signatures of immune function genes
associated with tumor progression, tumor escape and recurrence, or tumor
rejection and relapse-free survival in mouse model of breast carcinoma.
Clinical validity of these signatures is being investigated in patients with
breast cancer and neuroblastoma.
Project III) Immune suppression
We demonstrated that premalignant events in FVBN202 mouse model of
spontaneous breast carcinoma not only break tolerance to the neu protein but
also increase MDSC. MDSC, but not Tregs, were found to be the major cells
involved in the suppression of anti-tumor immune responses against breast
cancer such that elimination of MDSC in vivo by means of anti-Gr1 antibody
or gemcitabine resulted in successful adoptive immunotherapy. Microarray
analysis of mammary tumor lesions revealed that failure of FVBN202
transgenic mice in rejecting neu positive breast tumors was not merely due
to the immune tolerance but rather due to the induction of immune
suppression pathways.
We investigate tumor-derived chemokines that drive differentiation of MDSC
from bone marrow progenitor cells and compromise cancer immunosurveillance.
Selected Publications:
Morales JK, Kmieciak M, Knutson KL, Bear HD, Manjili MH. GM-CSF is
one of the main breast tumor-derived soluble factors involved in the
differentiation of CD11b-Gr1- bone marrow progenitor cells into
myeloid-derived suppressor cells. Breast Cancer
Res Treat.
2009 Nov 8. [Epub ahead of print]
Kmieciak M, Gowda M, Graham L, Godder K, Bear HD, Marincola FM, Manjili
MH. Human T cells express CD25 and FoxP3 upon activation and exhibit
effector/memory phenotypes without regulatory/suppressor function. J
Transl Med
7(1):89, 2009.
Cha E, Graham L, Manjili MH, Bear HD.
IL-7 + IL-15 are superior to IL-2 for the ex vivo
expansion of 4T1 mammary carcinoma-specific T cells with greater efficacy
against tumors in vivo. Breast
Cancer Res Treat 2009 Oct 14. [Epub ahead of print]
Le HK,
Graham L, Miller CHT, Kmieciak M, Manjili MH, Bear HD. Incubation of
antigen-sensitized T lymphocytes activated with Brayostatin-1 + Ionomycin in
IL-7 + IL-15 increases yield of cells capable of inducing regression of
melanoma metastasis compared to culture in IL-2. Cancer Immunol
Immunother
58(10):1565-76,
2009
Le HK, Graham L, Cha E, Morales JK, Manjili MH, Bear HD. Gemcitabine
directly inhibits myeloid-derived suppressor cells in Balb/c mice bearing
4T1 mammary carcinoma and augments expansion of T cells from tumor-bearing
mice. Int Immunopharmacol 9(7-8):900-9, 2009
Santisteban M, Reiman JM, Asiedu M, Nassar A, Kalli KR, Haluska P, Ingle JN,
Hartmann LC, Manjili MH, Radisky D, Ferrone S, Knutson KL.
Immune-induced epithelial to mesenchymal transition in vivo generates breast
cancer stem cells. Cancer Res 69(7):2887-95, 2009
Morales JK, Kmieciak M, Graham L, Feldmesser M, Bear HD, Manjili MH.
Adoptive transfer of HER-2/neu specific T cells expanded with alternating
gamma chain cytokines mediate tumor regression when combined with the
depletion of myeloid-derived suppressor cells. Cancer Immunol Immunother
58(6):941-53, 2009
Habibi M, Kmieciak M, Morales JK, Graham L, Bear HD, Manjili MH.
Radiofrequency thermal ablation of breast tumors combined with intralesional
administration of IL-7 and IL-15 augments anti-tumor immune responses and
inhibits tumor relapse and metastasis. Breast Cancer Res Treat
114(3):423-31, 2009
Worschech A, Kmieciak M, Knutson KL, Bear HD, Szalay AA, Wang E, Marincola
FM, Manjili MH. Signatures associated with rejection or recurrence in
HER-2/neu positive mammary tumors. Cancer Res 68(7):2436-46, 2008
Manjili MH
and Kmieciak M.
Immunotherapy of cancer using
heat shock protein vaccines: A retreat from bedside to bench. In F. Columbus
(Eds. Emma Morel and Camille Vincent), Heat shock proteins: new research, 1st
edition, pp. 89-110. New York, NY: Nova Science Publishers, Inc. 2008
Ghadersohi A, Odunsi k, Zhang s, Azrak RG, Bundy BN, Manjili MH, Li
F. Prostate-derived
Ets
transcription factor (PDEF) as a favorable prognostic marker in ovarian
cancer patients. Int J Cancer
15;123(6):1376-84,
2008
Kmieciak M, Morales JK, Morales J, Bolesta E, Grimes M, Manjili MH.
Danger signal and nonself entity of tumor antigen are both required for
eliciting effective immune responses against HER-2/neu positive mammary
carcinoma: implications for vaccine design. Cancer Immunol Immunother
57(9):1391-8,
2008
Manjili MH,
Kmieciak M. Does HER-2/neu antigen loss in metastatic breast tumors occur
under immune pressure? Int J Cancer 15;123(6):1476-7,
2008
Kmieciak M, Knutson KL, Dumur C, Manjili MH.
HER-2/neu antigen loss and relapse of mammary
carcinoma are actively induced by T cell-mediated anti-tumor immune
responses. Eur J Immunol 37:675-85,
2007
Manjili MH.
Come forth 1E10 anti-idiotype vaccine: delivering
the promise to immunotherapy of small cell lung cancer. Cancer Biol Ther
6:151-152, 2007
Reiman JM, Kmieciak M, Manjili MH, Knutson KL. Tumor immunoediting
and immunosculpting: pathways to immune escape and disease progression.
Semin Cancer Biol 17(4):275-87, 2007
Manjili MH,
Arnouk H, Knutson KL, Kmieciak M, Disis ML, Subjeck JR, Kazim AL. Emergence
of immune escape variant of mammary tumors that has distinct proteomic
profile and a reduced ability to induce “danger signals”. Breast Cancer
Res Treat 96:233-41, 2006
Manjili MH,
Park J, Facciponte JG, Wang X-Y, Subjeck JR. Immunoadjuvant chaperone,
GRP170, induces “danger signals” upon interaction with dendritic cells.
Immunol and Cell Biol 84: 203-8, 2006
Park J, Facciponte JG, Chen X, MacDonald I, Repasky EA, Manjili MH,
Wang X-Y, Subjeck JR. Chaperoning function of stress protein grp170, a
member of the hsp70 superfamily, is responsible for its immunoadjuvant
activity. Cancer Res 66:1161-8, 2006
Zhao YL,
Murthy SN, Manjili MH, Guan LJ, Sen A, Hui SW. Induction of cytotoxic
T lymphocytes by electroporation enhanced needle-free skin immunization.
Vaccine
24(9):1282-9, 2006
Facciponte JG, MacDonald I, Wang X-Y, Park JE, Arnouk H, Grimm MJ, Li Y, Kim
H, Manjili MH, Easton DP, Subjeck JR. Heat shock proteins HSP70 and
GP96: structural insights. Cancer Immunol Immunother
255:339-46, 2006
Segal BH, Wang X-Y, Carly GD, Youn R, Repasky EA, Manjili MH, Subjeck
JR. Heat shock proteins as vaccine adjuvants in infections and cancer.
Drug Discov Today 11:534-40, 2006
Manjili MH,
Kmieciak M, Keeler J. Comment on “Tumor progression can occur despite the
induction of very high levels of self/tumor antigen-specific CD8+ T cells in
patients with melanoma”. J Immunol 176:4511, 2006
Manjili MH,
Park J, Facciponte JG, Subjeck JR. HSP110 induces “danger signals” upon
interaction with antigen presenting cells and mouse mammary carcinoma.
Immunobiology 210: 295-303, 2005
Facciponte JG, MacDonald I, Wang X-Y, Kim H, Manjili MH, Subjeck JR.
Heat shock proteins and scavenger receptors: role in adaptive immune
responses. Immunol Invest 34: 325-342, 2005
Wang X-Y, Manjili MH, Park J, Chen X, Repasky E, Subjeck JR.
Development of cancer vaccines using autologous and recombinant high
molecular weight stress proteins. Methods 32:13-20, 2004
Manjili MH,
Wang X-Y, Macdonald IJ, Arnouk H, Yang GY, Pritchard MT, Subjeck JR. Cancer
Immunotherapy and Heat Shock Proteins: promises and challenges. Expert
Opin Biol Ther 4(3): 363-373, 2004
Manjili MH,
Wang X-Y, Chen X, Martin T, Repasky EA, Henderson R, Subjeck JR.
HSP110-HER-2/neu chaperone complex vaccine induces protective immunity
against spontaneous mammary tumors in HER-2/neu transgenic mice. J
Immunol 171:4054-4061, 2003
Wang X-Y, Chen X, Manjili MH, Repasky EA, Henderson R, Subjeck JR.
Targeted immunotherapy using in vitro reconstituted chaperon complex of
HSP110 and melanoma associated antigen gp100. Cancer Res
63:2553-2560, 2003
Wang X-Y, Li Y, Manjili MH, Repasky EA, Pardoll DM, Subjeck
JR. HSP110 overexpression increases the immunogenicity of the murine CT26
colon tumor. Cancer Immunol Immunother 51: 311-319, 2002
Manjili MH,
Henderson R, Wang X-Y, Repasky E, Kazim L, Subjeck JR. Development of a
recombinant HSP110-HER-2/neu vaccine using the chaperoning properties of
HSP110. Cancer Res 62: 1737-1742, 2002
Manjili MH,
Wang X-Y, Park J, MacDonald I., Li Y, van Schie R, Subjeck JR. Cancer
immunotherapy: stress proteins and hyperthermia. Int J Hyperthermia
18: 506-521, 2002
Manjili MH,
Wang X-Y, Park J, Facciponte J, Subjeck JR. Immunotherapy of cancer using
heat shock proteins. Front Biosci 7: 43-52, 2002
Manjili MH,
Sangster NC, Rothwell TLW. In vitro leucocyte proliferative responses and
lymphocyte sub-types in guinea pigs with genetically determined high- and
low-level responsiveness to Trichostrongylus colubriformis. Parasitol Res
86: 311-317, 2000
Manjili MH,
Sangster NC, Rothwell TLW. Antibody production in guinea pigs with
genetically-determined high and low responsiveness to Trichostrongylus
colubriformis. Int J Parasitol 29: 225-261, 1999
Manjili MH,
France MP, Sangster NC, Rothwell TLW. Quantitative and qualitative changes
in intestinal goblet cells during primary infection of Trichostrongylus
colubriformis high and low responder guinea pigs. Int J Parasitol
28: 761-765, 1998 |