University at Buffalo
The Witebsky Center

The Witebsky Center
University at Buffalo
Bacteriology Host-Microbe Interactions Immunology Parasitology Virology
The Witebsky Center The Witebsky Center
Richard B. Bankert, V.M.D., Ph.D.
Richard B. Bankert, V.M.D., Ph.D., Professor 
Department of Microbiology & Immunology
Phone: 829-2701
Fax: 829-2662
Email:
rbankert@buffalo.edu
bankert

Our work focuses upon the interaction between tumor cells and the inflammatory cells in the microenvironment of human tumors.  We have determined that the effector memory T cells within lung, ovarian and breast tumors are hypo-responsive to activation via the T cell receptor.  This failure of the tumor-associated T cells to respond to activation signals is due to an arrest or checkpoint in the T cell receptor signaling cascade and is thought to contribute to the failure of these cells to control tumor growth. We have determined that fibroblasts present within the tumor microenvironment produce soluble factors that prevent the full activation of T cells by inhibiting the translocation of NF-κB from the cytosol to the nucleus following the antibody cross-linking of CD3 and CD28. We discovered that the hypo-responsiveness of the tumor-associated T cells was reversed by IL-12.  Using a human tumor-xenograft model it was established that a local and sustained release of IL-12 into the tumor microenvironment re-activated quiescent memory T cells and that these re-activated T cells initiate a cascade of events that results in the eradication of the tumor cells in the xenograft.  Based upon these preclinical studies we are now embarking upon a Phase I clinical trial to evaluate the effect of low doses of IL-12 that is delivered directly into patients’ tumors by an irradiated IL-12 producing cell line.

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.

Nazareth, M.R., Broderick, L., Simpson-Abelson, M.R., Kelleher, R.J., Jr., Yokota, S.J. and Bankert, R.B.  Characterization of human lung tumor-associated fibroblasts and their ability to modulate the activation of tumor-associated T cells.  J. Immunol. 178: 5552-5562, 2007.  PMID: 17442937

Stanford, M.M., Barrett, J.W., Gilbert, P-A., Bankert, R. and McFadden, G.  Myxoma virus expressing human IL-12 does not induce myxomatosis in European rabbits.  J. Virol. 81: 12704-12708, 2007 .  PMID: 17728229

Simpson-Abelson, M. and Bankert, R.B.  Targeting the TCR signaling checkpoint: a therapeutic strategy to reactivate memory T cells in the tumor microenvironment.  Expert Opin Ther Targets. 12: 477-490, 2008.  PMID: 18348683

Simpson-Abelson, M.R., Sonnenberg, G.F., Takita, H., Yokota, S.J., Conway, T.J., Jr., Kelleher, R.J., Jr., Shultz, L.D., Barcos, M. and Bankert, R.B.  Long-term engraftment and expansion of tumor-derived memory T cells following the implantation of non-disrupted pieces of human lung tumor into NOD-scid IL2Rγnull mice.  J. Immunol. 180: 7009-7018, 2008.  PMID: 18453623

Hilchey, S.P., Hyrien, O., Mosmann, T.R., Livingstone, A.M., Friedberg, J.W., Young, F., Fisher, R.I., Kelleher, R.J., Jr., Bankert, R.B. and Bernstein, S.H.  Rituximab immunotherapy results in the induction of a lymphoma idiotype-specific T-cell response in patients with follicular lymphoma: support for a “vaccinal effect” of rituximab.  Blood 113: 3809-3812, 2009.  PMID: 19196657

Simpson-Abelson, M., Purohit; V.S., Pang, W.M., Iyer, V.; Odunsi, K., Demmy, T.L., Yokota, S.J., Loyall, J.L., Kelleher, Jr., R.J., Balu-Iyer, S. and Bankert, R.B.  IL-12 Delivered Intratumorally by Multilamellar Liposomes Reactivates Memory T Cells in Human Tumor Microenvironments.  J. Clin. Immunol. 132: 71-82, 2009.  PMID: 19395317

Bernstein, J.M., Brooks, S.P., Lehman, H.K., Pope, L., Sands, A., Shultz, L.D. and Bankert, R.B.  Human nasal polyp microenvironments maintained in a viable and functional state as xenografts in the NOD-scid IL2rγnull mouse.  Ann. Otology, Rhinology, Laryngology 118: 866-875, 2009.

Zou, W. and Bankert, R.B.  Use of SCID mice to assay immune responses to human tumors in situ and to assess the efficacy of immunotherapeutic strategies for cancer.  Curr. Proc. Immunol., in press, 2008.

Hilchey, S.P., Hyrien, O., Mosmann, T.R., Livingstone, A.M., Friedberg, J.W., Young, F., Fisher, R.I., Kelleher, R.J., Jr., Bankert, R.B. and Bernstein, S.H.  Rituximab immunotherapy results in the induction of a lymphoma idiotype-specific T-cell response in patients with follicular lymphoma: support for a “vaccinal effect” of rituximab.  Blood 113: 3809-3812, 2009.  PMID: 19196657; PMCID: PMC2670795

Simpson-Abelson, M., Purohit; V.S., Pang, W.M., Iyer, V.; Odunsi, K., Demmy, T.L., Yokota, S.J., Loyall, J.L., Kelleher, Jr., R.J., Balu-Iyer, S. and Bankert, R.B.  IL-12 Delivered Intratumorally by Multilamellar Liposomes Reactivates Memory T Cells in Human Tumor Microenvironments.  J. Clin. Immunol. 132: 71-82, 2009.  PMID: 19395317; PMCID: PMC2693480.

Bernstein, J.M., Brooks, S.P., Lehman, H.K., Pope, L., Sands, A., Shultz, L.D. and Bankert, R.B.  Human nasal polyp microenvironments maintained in a viable and functional state as xenografts in the NOD-scid IL2rγnull mouse.  Ann. Otology, Rhinology, Laryngology 118: 866-875, 2009.  PMID: 20112521

Barnas, J.L., Simpson-Abelson, M.R., Brooks, S.P., Kelleher, R.J. and Bankert, R.B.  T cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets.  Cancer Microenvironment 3: 29-47, 2010.

Barnas, J.L., Simpson-Abelson, M.R., Brooks, S.P., Kelleher, R.J. and Bankert, R.B.  Reciprocal functional modulation of the activation of T lymphocytes and fibroblasts derived from human solid tumors.  J. Immunol. 185: 2681-2692, 2010.  PMID:  20686130

 

 

 

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