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, 1^st 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

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