Sylvester Comprehensive Cancer Center

Krishna Komanduri, M.D.

Krishna Komanduri, M.D.

Professor of Medicine and Microbiology & Immunology; Director, Sylvester Adult Stem Cell Transplant Program

Description of Research

Dr. Komanduri’s laboratory studies human T cell immune responses to pathogens and allogeneic antigens, with a primary goal of developing better clinical approaches to improve outcomes in the setting of allogeneic stem cell transplantation (SCT) in humans. Research areas include:

To better understand how immune reconstitution occurs after the administration of immunosuppressive chemotherapy and after allogeneic SCT in humans. Since delays in immune recovery are a major cause of death in the clinical SCT setting, development of improved clinical strategies requires a clear understanding of how immune reconstitution occurs after SCT. Dr. Komanduri’s laboratory contributed to one of two simultaneous studies which first demonstrated human thymic function could be measured using molecular approaches to detect recent thymic emigrants in the peripheral human circulation, and that the thymus continues to contribute to T cell homeostasis throughout adulthood. Among the first to apply cytokine flow cytometry to precisely quantitate antigen-specific human T cells in clinical studies, the laboratory has applied this approach to characterize human T cells responses to pathogens, including cytomegalovirus (CMV), Epstein-Barr virus (EBV) and Aspergillus fumigatus, in preclinical and clinical studies.

To better understand the process of graft-versus-host disease (GVHD) in humans, including the cellular populations that mediate GVHD, including T cells and dendritic cells. Dr. Komanduri and his colleagues have developed approaches to characterize the number and function of human alloreactive T cells using flow cytometry, and preclinical approaches that may selectively deplete human donor grafts of alloreactive T cells while preserving antigen-specific human T cells (e.g., specific for pathogens and cancer). They are actively investigating human regulatory T cell (Treg) immunology, including clinical strategies to isolate and expand human Tregs in the clinical setting, aiming to develop graft engineering strategies to decrease GVDH incidence while benefiting immune reconstitution. The group is collaborating with other experts in murine models of GVHD and immune function and those interested in clinical problems related to graft tolerance to develop multidisciplinary approaches to facilitate tolerance after SCT and solid organ/islet transplantation.

To better characterize fine T cell subsets in humans, including early and late memory T cells. Using recently developed methods allowing flow cytometric evaluation of 10+ simultaneous parameters, Dr. Komanduri’s laboratory has optimized approaches to characterize fine subsets of CD4+ and CD8+ T cells defined by the expression of surface markers of maturation (e.g., CCR7, CD27, CD45RA and CD57), cytokine and chemokine production following stimulation (including IFN&gamma, TNF&alpha, IL-2, MIP-1&beta) and activation of intracellular signaling cascades (e.g., the MAPK pathway, as assessed by detection of phospho-ERK). These studies demonstrated early and late memory T cells differ substantially and predictably in expression of surface markers of maturation, and in functional properties defined by cytokine/chemokine production and relative level of phosphoprotein expression following TCR-dependent and independent stimulation. With the laboratory’s demonstration that late memory T cells appear to predominate in the post-SCT setting, and others' findings that adoptive transfer of late-memory T cells appears to confer less protective advantage, it is critical to understand how fine T cell subsets may function in human disease states. This work should facilitate development of more selective strategies of immunosuppression and T cell targeting, critical for advancement in the setting of SCT and solid organ transplantation.

Highlights

  • Performed the first study demonstrating the recovery of cytomegalovirus-specific human T cells following the administration of highly active antiretroviral therapy in HIV-infected individuals. This study was also among the first to demonstrate the clinical utility of cytokine flow cytometry as a measure of antigen-specific T cell responses in humans (Komanduri, et al., Nature Medicine, 1998).
  • Participated in a collaborative effort developing the first quantitative approach to measure recent thymic emigrants in human peripheral blood. This was one of two parallel studies that first demonstrated that human thymic function could be measured and that thymopoiesis persists throughout life (Poulin, et al, J Exp Med, 1999).
  • Developed novel flow cytometric approaches to characterize human T cell responses to Aspergillus fumigatus (Stanzani, et al., Blood Plenary Paper, 2004) and alloantigens (Martins, et al., Blood Plenary Paper, 2005).
  • Demonstrated that immune reconstitution following unrelated donor cord blood transplantation in humans is markedly delayed, and characterized by the failure to recovery thymopoiesis, relative to other allogeneic stem cell transplant recipients (Komanduri, et al., Blood, 2007).

Selected Cancer-Related Publications

  • Díaz-Montero CM, Zidan AA, Pallin MF, Anagnostopoulos V, Salem ML, Wieder E, Komanduri K, Montero AJ, Lichtenheld MG. Understanding the biology of ex vivo-expanded CD8 T cells for adoptive cell therapy: role of CD62L. Immunol Res 57:23-33,2013 Read more »
  • Ross D, Jones M, Komanduri K, Levy RB. Antigen and lymphopenia-driven donor T cells are differentially diminished by post-transplantation administration of cyclophosphamide after hematopoietic cell transplantation. Biol Blood Marrow Transplant 19:1430-8,2013 Read more »
  • Newman RG, Ross DB, Barreras H, Herretes S, Podack ER, Komanduri KV, Perez VL, Levy RB. The allure and peril of hematopoietic stem cell transplantation: overcoming immune challenges to improve success. Immunol Res 57:125-39,2013 Read more »
  • Vence LM, Wang C, Pappu H, Anson RE, Patel TA, Miller P, Bassett R, Lizee G, Overwijk WW, Komanduri K, Benjamin C, Alvarado G, Patel SP, Kim K, Papadopoulos NE, Bedikian AY, Homsi J, Hwu WJ, Boyd R, Radvanyi L, Hwu P. Chemical Castration of Melanoma Patients Does Not Increase the Frequency of Tumor-specific CD4 and CD8 T Cells After Peptide Vaccination. J Immunother 36:276-86,2013 Read more »
  • Komanduri KV, Wieder ED, Benjamin CL, Levy RB. The evolving art of hematopoietic stem cell transplantation: translational research in post-transplant immune reconstitution and immunosuppression. Immunol Res 57:140-50,2013 Read more »
  • Khan S, Juckett MB, Komanduri KV, Krishnan A, Burns LJ. American society of blood and marrow transplantation guidelines for training in hematopoietic progenitor cell transplantation. Biol Blood Marrow Transplant 18:1322-8,2012 Read more »
  • de Lima M, Giralt S, Thall PF, de Padua Silva L, Jones RB, Komanduri K, Braun TM, Nguyen HQ, Champlin R, Garcia-Manero G. Maintenance therapy with low-dose azacitidine after allogeneic hematopoietic stem cell transplantation for recurrent acute myelogenous leukemia or myelodysplastic syndrome: A dose and schedule finding study. Cancer 116:5420-31,2011 [JIF 5.131] Read more »
  • Díaz-Montero CM, Naga O, Zidan AA, Salem ML, Pallin M, Parmigiani A, Walker G, Wieder E, Komanduri K, Cole DJ, Montero AJ, Lichtenheld MG. Synergy of brief activation of CD8 T-cells in the presence of IL-12 and adoptive transfer into lymphopenic hosts promotes tumor clearance and anti-tumor memory. Am J Cancer Res 1:882-896,2011 Read more »
  • Bayraktar UD, Kim TK, Drews-Elger K, Benjamin C, El-Ashry D, Wieder E, Komanduri KV. Simultaneous measurement of ER?,HER2,and PhosphoERK1/2 in breast cancer cell lines by flow cytometry. Breast Cancer Res Treat 129:623-8,2011 Read more »

Programs

Collaborating in the Multidisciplinary Research Program(s):

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