The Witebsky Center :: Richard B. Bankert

My research focuses on immunity and immunotherapy of human cancer. To study the immune response of patients to their tumors and to evaluate ways to enhance this immunity (by tumor vaccination or cytokines delivered by gene therapy or biodegradable microspheres), mouse models have been developed in which we can engraft patient tumors and their immunocompetent cells. Students and postdoctoral fellows in this laboratory were the first to show that human tumors grow and metastasize when inoculated into the severe combined immunodeficient (SCID) mice. Subsequently, our research team showed that non-disrupted pieces of tumor biopsy tissues implanted into SCID mice resulted in the co-engraftment of patient tumors and their tumor infiltrating lymphocytes (TIL). The tumor/TIL SCID model was used to establish that TIL within the tumor graft remain functional and respond to lymphocyte growth factors (cytokines). This model is being exploited to monitor immunotherapeutic anti-cancer strategies including three methods of cytokine delivery to tumors: bolus injections, biodegradable microspheres and gene therapy. An attempt is being made to correlate specific changes in gene expression patterns following immunotherapy with tumor suppression, and thereby define the panoply of molecular events associated with the anti-cancer immune response. We have determined that peripheral blood lymphocytes of cancer patients also remain functional when injected subcutaneously into SCID mice with tumor cells. These cells mount an immune response that can be monitored and studied for up to 22 weeks. This model was used to demonstrate that T cell and NK cell dependent antitumor responses are enhanced with cytokines. Ways to augment this tumor immunity by enhancing lymphocyte co-stimulatory molecules or by blocking negative signals, i.e., through CTLAa-4, are being explored. SCID models and in vitro immunoassays are being used to evaluate several dendritic cell-based vaccination strategies for lung cancer and B-cell lymphomas. Tumor-specific antigens defined on human and mouse B-cell lymphomas are being identified structurally (i.e., VH region peptides) and studied for their ability to provoke protective antitumor immunity. Some of these strategies are being tested in Phase I clinical trials at Roswell Park Cancer Institute. In addition to preclinical and clinical studies, this laboratory is involved with basic science issues involving the immune response to well-defined antigens. Interests include: (a) defining the role of cell adhesion molecules (particularly beta 1 integrins) in the induction and regulation of cognitive immune responses, and (b) exploring the mechanisms by which B-cell clones are selected and regulated during an immune response.

Recent Publications:

Egilmez, N. K., Jong, Y.S., Sabel, M. S., Jacob, J. S., Mathiowitz, E. and Bankert, R.B. In Situ Tumor Vaccination with Interleukin-12- encapsulated Biodegradable Microspheres: Induction of Tumor Regression and Potent Antitumor Immunity. Cancer Research 60:3832-3837, 2000.

Egilmez, N. K., Jong, Y. S., Hess, S. D., Jacob, J. S., Mathiowitz, E. and Bankert, R. B. Cytokines Delivered by Biodegradable Microspheres Promote Effective Suppression of Human Tumors by Human Peripheral Blood Lymphocytes in the SCID-Winn Model. Journal of Immunotherapy 23(2):190-195, 2000.

Sable, M. S., Conway, T. F., Chen, F. A. and Bankert, R. B. Monoclonal Antibodies Directed Against the T-Cell Activation Molecule CD137 (Interleukin-A or 4-1BB) Block Human Lymphocyte-Mediated Suppression of Tumor Xenografts in Severe Combined Immunodeficient Mice. Journal of Immunotherapy 23(3):362-368, 2000.

Sugano, M., Egilmez, N. K., Yokota, S. J., Chen, F. A., Harding, J., Huang, S. K. and Bankert, R. B. Antibody Targeting of Doxorubicin-loaded Liposomes Suppresses the Growth and Metastatic Spread of Established Human Lung Tumor Xenografts in Severe Combined Immunodeficient Mice. Cancer Research 60:6942-6949, 2000.

Conway, Jr, T. F., Sabel, M. S., Sugano, M., Frelinger, J. G., Egilmez, N. K., Chen, F. A., Bankert, R. B. Growth of human tumor xenografts in SCID mice quantified using an immunoassay for tumor marker protein in serum. Journal of Immunological Methods 233:57-65, 2000.

Sugiyama, Y., Kato, M., Chen, F. A., Williams, S. S., Kawaguchi, Y., Miya, K., Jong, Y. S., Mathiowitz, E., Egilmez, N. K. and Bankert, R. B. Human Inflammatory Cells Within the Tumor Microenvironment of Lung Tumor Xenografts Mediate Tumor Growth Suppression in Situ that Depends on and Is Augmented by Interleukin-12. J. Immunotherapy 24: 37-45,2001.

Yamada, M., Shiroko, T., Kawagucki, Y., Sugiyama, Y., Egilmez, N. K., Chen, F. A. and Bankert, R. B. CD40-CD40 Ligand (CD154) Engagement Is Required But Not Sufficient For Modulating MHC Class I, ICAM-1 and FAS Expression And Proliferation Of Human Non-small Cell Lung Tumors. Int. J. Cancer 92:589-599, 2001.

Hess, S. D., Egilmez, N. K., Shiroko, J. and Bankert, R. B. Antitumor Efficacy of a Human Interleukin-12 Expression Plasmid Demonstrated in a Human Peripheral Blood Leukocyte/Human Lung Tumor Xenograft SCID Mouse Model. Cancer Gene Therapy 9: 371-377, 2001.

Bankert, R. B., Egilmez, N. K. and Hess, S. D. Human/SCID Mouse Chemeric Models for Pre-Clonical Evaluation of Anti-Cancer Therapies: Applications, Limitations, and Future Directions Trends in Immunology 22: 386-393, 2001.

Sugano, M., Conway, T.F., Kelleher, R., Sugiyama, Y., Chen, F-A, Bankert, R.B., and Bernstein, S. Human dendritic cells pulsed with autologous Epstein-Barr virus transformed B-cell lymphoblastoid cell (BCL) lystate elicit a BCL specific MHC-class II restricted T-cell response. J. Exptl. and Clin. Cancer Res. 20(2): 175-183, 2001.

Egilmez, N.K., Jong, Y.S., Mathiowitz, E. and Bankert, R.B. Tumor vaccination with cytokine-encapsulated microspheres. In: Methods in Molecular Medicine. In press, 2001.

Sabel, M.S., Hill, H., Jong, Y.S., Mathiowitz, E., Bankert, R.B., and Egilmz, N.K. Neoadjuvant therapy with interleukin-12-loaded polylactic acid microspheres reduces local recurrence and distant metastases. Surgery 130: 470-478, 2001.

Eglimez, N.K., Hess, S.D., Chen, F-A, Takita, H., Conway, T. and Bankert R.B. Human CD4+ Effector T-Cells Medite an Indirect IL-12 and IFN-gamma-Dependent Suppression of Autologous Lung Tumor xenografts in SCID Mice. Cancer Res. 62: 2611-2617, 2002.

Bankert, R.B., Hess, S.D., and Egilmez, N.K. SCID mouse models to study human cancer pathogenesis and approaches to therapy: Potential, limitations, and future directions. Frontiers in Bioscience 7:44-62, 2002.

Hill, H.C., Conway, Jr., T.F., Sabel, M.S., Jong, Y.S., Mathiowitz, E., Bankert, R.B. and Egilmez, N.K. Cancer immunotherapy with interleukin-12 and granulocyte-machrophage colony-stimulating factor-encapsulated microspheres: Coinduction of innate and adaptive antitumor immunity and cure of disseminated disease. Cancer Res. 62: 7254-7263, 2002.

Albra, R.M., Bankert, R.B, Chen, F., Egilmez, N.K., Huang, K., Saville, R., Slater, J.L., Sugano, M. and Yokota, S.J. The next generation of liposome delivery systems: recent experience with tumor-targeted, sterically-stabilized immunoliposomes and active-leading gradients. J. Lip. Es. 12: 1-3, 2002.

Hess, S.D., Egilmez, N.K., Bailey, N., Anderson, T.M., Mathiowitz, E., Bernstein, S.H. and Bankert, R.B. Human CD4+ T cells present within the microenvironment of human lung tumors are mobilized by the local and sustained release of IL-12 to kill tumors in situ by indirect effects of IFN-γ. Immunol. 170: 400-412, 2003.

Egilmez, N.K., Jong, Y.S., Mathiowitz, E., and Bankert, R.B. Tumor vaccination with cytokine-encapsulated microspheres. Meth. In Molec. Med. 75: 687-696, 2003.

Anderson, T.M., Hess, S.D., Egilmez, N.K., Nwogu, C.E., Lenox, J.M.and Bankert, R.B. Comparison of human lung cancer/SCID mouse tumor xenografts and cell culture growth with patient clinical outcomes. J. Cancer Res. Clin. Oncol. 129: 565:568, 2003.

Lou, Qiang., Kelleher, R.J., Jr., Sette, A., Loyall, J. Southwood, S., Bankert, R.B. and Bernstein, S.H. Germline tumor-associated immunoglobin VH region peptides provoke a tumor specific immune response without altering the response potential of normal B cells. Blood. 104: 752-759, 2004.

Broderick, L., Yokota, S.J., , Reineke, J., Mathiowitz, E., Stewart, C.C., Barcos, M., Kelleher, R.J., Jr. and Bankert, R.B. Human CD4+ effector memory T cells persisting in the microenvironment of lung cancer xenografts are activiated by local delivery of IL-12 to proliferate, produce IFN-, and eradicate tumor cells. J. Immunol. 174: 898-906, 2005.

Lou Q. Conway TF Jr. Egilmez NK. Loall Jl. Bernstein SH. Kelleher RJ Jr. Bankert RB. B cell tumor vaccine enhanced by covalent attachment of immunoglobulin to surface proteins on dendritic cells. Clinical Immunology. 118(1):66-76, 2006 Jan.

Bernstein JM. Broderick L. Parsons RR. Bankert RB. Human nasal polyp microenvironment maintained in viable and functional states as xenografts in SCID mice. Annals of Otology, Rhinology & Laryngology. 115(1):65-73, 2006 Jan.

Broderick L. Brooks SP. Takita H. Baer AN. Bernstein JM. Bankert RB IL-12 reverses anergy to T cell receptor triggering in human lung tumor-associated memory T cells. Clinical Immunology. 118(2-3): 159-69, 2006 Feb-Mar.

Broderick L. Bankert RB. Memory T cells in human tumor and chronic inflammatory microenvironments: sleeping beauties re-awakened by a cytokine kiss. [Review] [68 refs] Immunological Investigations. 35(3-4):419-36, 2006.

Broderick L. Bankert RB. membrane-associated TGF-beta1 inhibits human memory T cell signaling in malignant and nonmalignant inflammatory microenvironments. Journal of Immunology. 177(5):3082-8, 2006 Sep 1.

Nazareth MR. Broderick L. Simpson-Abelson MR. Kelleher RJ Jr. Yokota SJ. Bankert RB. Characterization of human lung tumor-associated fibroblasts and their ability to modulate the activation of tumor-associated T cells. Journal of Immunology. 178(9):5552-62, 2007 May 1.

Hilchep SP. De A. Rimsza LM. Bankert RB. Bernstein SH. Follicular lymphoma intratumoral CD4+CD25+GITR+ regulatory T cells potently suppress CD3?CD28-costimulated autologous and allogeneic CD8+CD25- and CD4+CD25- T cells. Journal of Immunology. 178(7):4051-61, 2007 Apr 1.