Ivan Borrello, M.D.
Phone: (410) 955-8964
Fax: (410)614-9705
Titles
Associate Professor of Oncology
Schools/Degrees
M.D., Medical College of Virginia School of Medicine, Richmond, VA
Training
Intern, University of Chicago, Chicago, IL Resident, Internal Medicine, University of Chicago, Chicago, IL Clinical Fellow, Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD
Certifications
Internal Medicine, Medical Oncology
Clinical Interests
Immunotherapy in Multiple Myeloma and Acute Myeloid Leukemia
Research Summary
Autologous transplantation has been typically viewed as a platform for the delivery of high-dose chemotherapy with stem-cell support but void of immune-mediated antitumor responses. In contrast, allogeneic transplantation has been shown to generate a measurable immune-mediated antitumor effect. Data generated in murine models has demonstrated that the peritransplant period is a time of heightened immune responsiveness that serves as an ideal platform for the integration of immunotherapeutic interventions. Specifically, Dr. Borrello's group has evidence of the development of an autologous graft vs. tumor effect early post-transplant that can be maintained by tumor-specific vaccinations. Explanations for these observations include evidence that T cell immune responsiveness is restored with transplantation through the reversal of T cell tolerance mediated through a variety of factors present in the transplanted host. A major focus of his work now is based on identifying the mechanisms mediating this enhanced antitumor activity, further enhancing immune-based therapies through in vitro and in vivo immune interventions, and developing a non-myeloablative platform in which these therapies can be delivered with similar efficacy but less toxicity. This work has direct applicability to the development of future clinical studies. Specifically, this work has established the importance of utilizing a lymphopenic host in the development of adoptive immunotherapeutic strategies. This preclinical model, coupled to the development of a universal bystander GM-CSF secreting vaccine developed by Dr, Borrello, has now been used in two currently ongoing clinical studies: one in patients with multiple myeloma and the second in patients with acute myeloid leukemia.
A major hurdle in tumor immunotherapy is how to deliver a cellular product with stringent tumor specificity. Evidence of the enhanced tumor specificity of activated marrow infiltrating lymphocytes (MILs) as compared with activated peripheral blood lymphocytes suggests a strategy of easily developing antigen-specific T cell adoptive immunotherapeutic strategies with minimal interventions and may well represent a significant advance in the development of a polyvalent, highly enriched tumor-specific population. The advantage of such an approach is to deliver immunotherapy marked by enhanced tumor-specificity and T cell responsiveness. His group has demonstrated that the T cells from the tumor/bone marrow microenvironment display evidence of marked tumor-specificity, yet are lacking endogenous tumor-specific reactivity. In contrast, the in vitro activation of these cells with beads containing anti-CD3/anti-CD28 is capable of activating these cells and expanding them while still maintaining marked antitumor specificity. This strategy is an approach that will hopefully represent a significant advance in the development of tumor-specific adoptive immunotherapeutic interventions starting with the treatment of multiple myeloma but with broad applicability to numerous other hematologic diseases.
Tumor vaccines have typically been utilized as an approach to enhance antigen specificity of T cells in an effort to impart a potent antitumor effect. GM-CSF-based vaccines have been utilized in several clinical trials. Until recently, an extensive body of literature existed to suggest the minimal amount of GM-CSF required to generate effective antitumor responses. Murine data is now emerging identifying a maximal threshold as well above which these vaccines induce myeloid suppressor cells capable of inhibiting a T cell response. This is the first such evidence to demonstrate a therapeutic ceiling for vaccines that will be important in designing subsequent clinical studies. Pharmacologic agents capable of inhibiting the function of the myeloid suppressor cells are also actively being investigated.
Journal Citations
Borrello, I. (2009). Lenalidomide in renal insufficiency - balancing the risks and benefits. Br J Haematol 144, 446-447.
Luznik, L., O'Donnell, P.V., Symons, H.J., Chen, A.R., Leffell, M.S., Zahurak, M., Gooley, T.A., Piantadosi, S., Kaup, M., Ambinder, R.F., Huff, C.A., Matsui, W., Bolanos-Meade, J., Borrello, I., Powell, J.D., Harrington, E., Warnock, S., Flowers, M., Brodsky, R.A., Sandmaier, B.M., Storb, R.F., Jones, R.J., and Fuchs, E.J. (2008). HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 14, 641-650.
Serafini, P., Mgebroff, S., Noonan, K., and Borrello, I. (2008). Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells. Cancer Res 68, 5439-5449.
Warlick, E.D., O'Donnell, P.V., Borowitz, M., Grupka, N., Decloe, L., Garrett-Mayer, E., Borrello, I., Brodsky, R., Fuchs, E., Huff, C.A., Luznik, L., Matsui, W., Ambinder, R., Jones, R.J., and Douglas Smith, B. (2008). Myeloablative allogeneic bone marrow transplant using T cell depleted allografts followed by post-transplant GM-CSF in high-risk myelodysplastic syndromes. Leuk Res 32, 1439-1447.
Huff, C. A., Fuchs, E. J., Smith, B. D., Blackford, A., Garrett-Mayer, E., Brodsky, R. A., Flinn, I. W., Ambinder, R. F., Borrello, I. M., Matsui, W. H., Vogelsang, G. B., Griffin, C. A., Luznik, L. & Jones, R. J. (2006). Graft-versus-host reactions and the effectiveness of donor lymphocyte infusions. Biol Blood Marrow Transplant 12, 414-21.
Serafini, P., Borrello, I. & Bronte, V. (2006). Myeloid suppressor cells in cancer: recruitment, phenotype, properties, and mechanisms of immune suppression. Semin Cancer Biol 16, 53-65.
Serafini, P., Meckel, K., Kelso, M., Noonan, K., Califano, J., Koch, W., Dolcetti, L., Bronte, V. & Borrello, I. (2006). Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J Exp Med 203, 2691-702.
Bolanos-Meade, J., E. Garrett-Mayer, L. Luznik, V. Anders, J. Webb, E. J. Fuchs, C. A. Huff, W. Matsui, I. M. Borrello, R. Brodsky, Y. L. Kasamon, L. J. Swinnen, I. W. Flinn, R. F. Ambinder, R. J. Jones, A. D. Hess, and G. B. Vogelsang. 2007. Induction of autologous graft-versus-host disease: results of a randomized prospective clinical trial in patients with poor risk lymphoma. Biol Blood Marrow Transplant 13:1185-91.
Matsui, W., Q. Wang, J. P. Barber, S. Brennan, B. D. Smith, I. Borrello, I. McNiece, L. Lin, R. F. Ambinder, C. Peacock, D. N. Watkins, C. A. Huff, and R. J. Jones. 2008. Clonogenic multiple myeloma progenitors, stem cell properties, and drug resistance. Cancer Res 68:190-7.
Mirmonsef, P., G. Tan, G. Zhou, T. Morino, K. Noonan, I. Borrello, and H. I. Levitsky. 2007. Escape from suppression: tumor-specific effector cells outcompete regulatory T cells following stem cell transplantation. Blood 111:2112-2121.
Caligiuri, M. A., Velardi, A., Scheinberg, D. A., & Borrello, I. M. 2004. Immunotherapeutic approaches for hematologic malignancies. [Review]. Hematology (Am. Soc. Hematol. Educ. Program). 337-353.
Noonan, K., Matsui, W., Serafini, P., Carbley, R., Tan, G., Khalili, J., et al. 2005. Anti-myeloma activity of activated marrow infiltrating lymphocytes: a novel approach to adoptive immunotherapy. Cancer Res. 65:2026-2034.
Serafini, P., Carbley, R., Noonan, K. A., Tan, G., Bronte, V., & Borrello, I. 2004. High-dose granulocyte-macrophage colony-stimulating factor-producing vaccines impair the immune response through the recruitment of myeloid suppressor cells. Cancer Res. 64:6337-6343.
EM 5/06
