Laszlo G Radvanyi, Ph.D.
Present Title & Affiliation
The focus of the laboratory is on tumor immunology by addressing both and basic and clinical research questions on the role of human T cells in anti-tumor immune responses. We take an interdisciplinary approach by working together with a team of basic and clinical researchers in addressing these questions. There are two main research areas in the lab: 1) Adoptive T-cell therapy for metastatic melanoma using expanded tumor-infiltrating lymphocytes (TILs), including basic research projects on TIL biology, and 2) The function of CD4+, Foxp3+ T-regulatory cells (T-regs) in melanoma tumor progression and immunotherapy.
1. Adoptive T-cell Therapy (ACT) and Studies on TIL Dynamics and Function
Our first area of research is on ACT for metastatic melanoma. This area is sub-divided into two parts. The first part involves Phase I and Phase II ACT clinical trials for metastatic melanoma using ex vivo expanded TILs. The second part involves translational bench research studying the phenotype and function of TILs from melanoma using a number molecular approaches aimed at understanding how the tumor microenvironment affects anti-tumor T-cell activity and how the proliferation, lifespan, and anti-tumor effector function of TILs can be boosted by immunomodulatory agents. The knowledge gained from these laboratory studies are then applied clinically in the development of new methods for ACT for metastatic melanoma using TILs expanded from isolated patients’ tumors ex vivo.
Adoptive T-cell therapy clinical trials. Currently, we are conducting a number of Phase I and Phase II ACT clinical trials for metastatic (Stage IV) melanoma involving the expansion of TILs from isolated tumors ex vivo under different conditions followed by the infusion of these autologous, expanded TILs back into patients. We are tracking the fate of these TIL subsets after infusion into patients in our ACT clinical trials to identify which T-cell phenotypes in the expanded TIL infusion products are associated with the best clinical responses in patients. In addition, we are identifying immunomodulators that enhance TIL survival and function to improve the efficacy of ACT. These immunomodulators are being tested in new clinical trials. For example, we are currently testing a new ACT strategy involving TIL plus co-vaccination with autologous dendritic cells pulsed with an epitope from a major melanoma antigen, Melan/MART-1, in HLA-A2.1+ patients. In another new approach we have found that the costimulation of CD8+ TILs through the TNF-R family of costimulatory molecules (41BB and Ox40) greatly improves melanoma TIL survival function. A Phase I clinical trial testing a clinical-grade anti-41BB monoclonal antibody in patients together with expanded TILs will begin shortly.
Translational research on TILs. In parallel with our TIL ACT clinical trials, we run a translational research program aimed at a thorough characterization of the phenotype and function of CD8+ melanoma TIL subsets. The main source of research materials are TILs directly isolated and expanded from fresh melanoma metastatic surgical specimens. The tissues are collected in sterile containers and taken to the lab where small fragments of the tumors are cultured to expand the TIL for further analysis. We also directly isolate TIL sub-populations from the tumors using a variety of tissue digestion methods and study their phenotype and function in short-term and long-term culture. To study the function and phenotype of the isolated cells, we employ multi-color flow cytometry and effector cell assays using intracellular cytokine staining, ELISPOT, CTL assays, CFSE-based proliferation assays, multiplex cytokine analysis, as well as TCR clonotype analysis. A number of molecular biology approaches, including gene expression analysis by DNA microarray and real-time RT-PCR are also used to characterize TIL sub-populations. Using these approaches we have found that the differentiation of fully-mature CD8+ cytotoxic T-lymphocytes (CTL) is defective in melanoma tumors and that this disrupted differentiation process leads to the accumulation of some novel CD8+ T-cell subsets in melanoma patients. We are studying the function of these atypically-differentiated CTL and how they can be induced to mature into potent anti-tumor CTL. Another aspect of these studies is the identification and characterization of CD8+ TIL subsets exhibiting maximal anti-tumor killing activity and long-term effector-memory T-cell survival after expansion of TILs for ACT.
Other related projects on TILs are examining how TILs respond to antigenic re-stimulation under different conditions and how the state of differentiation of TILs affects their sensitivity to activation-induced cell death (AICD) and their proliferative capacity after antigenic re-stimulation. We have found that melanoma TILs expanded for use in clinical ACT lose their proliferative potential and many CD8+ TILs become AICD sensitive. This is due to the extensive expansion of TILs required for ACT and the increased state of differentiation associated with a gain of CTL activity, but loss of proliferative potential. Currently, we are examining methods to expand TILs for ACT while preventing further differentiation and loss of cell division potential.
2. Role of Specific T-reg Subsets in Modulating Melanoma Anti-tumor Immunity
The second main research area of the lab is studying the role of suppressive Foxp3+, CD4+ T-regulatory cells (T-regs) in melanoma immunotherapy. Here, we are characterizing how the numbers, phenotype, and function of T-regs changes during tumor progression in melanoma patients and how different forms of immunotherapy affect these T-reg parameters. We are particularly interested in how high-dose Interleukin-2 (IL-2) therapy for metastatic melanoma affects T-reg activity. In addition, we are also interested in how immunomodulatory molecules expressed by melanoma tumor cells, such the B7 family members and Wnt factors, regulate the survival and activation of Foxp3+ T-regs and the inhibition of CTL differentiation within tumors.
Role of T-regs in high-dose IL-2 therapy for melanoma. At present, high-dose IL-2 therapy is the only FDA-approved immunotherapy for melanoma and renal cell cancer that can shrink tumors in about 16% of patients. More importantly, high-dose IL-2 therapy can induce long-lasting disease remission (>10 year disease-free survival after therapy), in about 5-6% of melanoma patients. Although IL-2 is such a promising drug, little is known about its mechanism of action, how we can predict who will respond positively to IL-2, and how we can further improve the therapy. We have been extensively tracking how different lymphocyte subsets change in patients receiving high-dose IL-2 therapy and have found that T-regs are the T-cell subset most affected by IL-2, expanding more than any other lymphocyte population in response to IL-2. We are also characterizing the changes and function in a unique subset of T-regs that exhibit an exceptionally high response to IL-2, expanding far more than any other T-cell, NK cell or T-reg subset in high-dose IL-2 patients. In addition, we are also determining how changes in specific T-reg subsets may predict who will respond to high-dose IL-2 therapy and who will not. Our studies on T-regs involve isolation of patient PBMC and tracking the function of different T-reg subsets after different treatments ex vivo. We also perform gene expression analysis on sorted T-reg subsets using a novel technology that can quantity mRNA expression in single sorted cells. This allows us to characterize gene expression in small and discreet subsets of T-regs not possible before.
B7 family costimulatory molecules in melanoma and their effects on T-reg activity. As part of our studies on melanoma TIL, we are also interested in understanding how tumor-derived T-reg cells may interact with melanoma cells and how this is involved in modulating melanoma-specific CD8+ CTL responses and cytokine production. We have recently discovered that both cultured and fresh melanoma cells express B7 family costimulatory molecules on their surface that can promote T-cell immunosuppression by activating Foxp3+ T-reg cells. Both of these areas are being actively pursued in the laboratory with collaborators from the Immunology Dept. at M.D. Anderson Cancer Center (Dr. Natalia Martin-Orozco and Dr. Chen Dong). We have also found that these novel B7 family members are also expressed in murine B16 melanoma. The function of these molecules is being tested in B16 tumor models in mice where we look at T-cell function in vivo and in vitro and tumor growth following manipulation of these B7-induced signaling pathways.
Education & Training
|1996||University of Toronto, Toronto, Canada, PHD, Clinical Biochemistry/Immunology|
|1989||University of Toronto, Toronto, Canada, MS, Botany|
|1986||University of Toronto, Toronto, Canada, BS, Biology|
|1998-2000||Research Fellowship, Immunology, Joslin Diabetes Center, Harvard Medical School, Boston, MA|
|1997-1998||Postdoctoral Fellow, Immunology, Scripps Research Institute, La Jolla, CA|
|4/1996-9/1997||Research Associate, Ontario Cancer Institute/Princess Margaret Hospital, Toronto, Ontario, Canada|
Peer-Reviewed Original Research Articles
|1.||Hernandez-Chacon JA, Li Y, Wu RC, Bernatchez C, Wang Y, Weber JS, Hwu P, Radvanyi LG. Co-stimulation through the CD137/4-1BB pathway protects human melanoma tumor-infiltrating lymphocytes from activation-induced cell death and enhances anti-tumor effector function. J Immunother 34(3):236-50, 4/2011. PMCID: PMC3063939.|
|2.||Martin-Orozco N, Li Y, Wang Y, Liu S, Hwu P, Liu YJ, Dong C, Radvanyi L. Melanoma cells express ICOS ligand to promote the activation and expansion of T-regulatory cells. Cancer Res. e-Pub 11/2010. PMID: 21098714.|
|3.||Liu S, Etto T, Rodríguez-Cruz T, Li Y, Wu C, Fulbright OJ, Hwu P, Radvanyi L, Lizée G. TGF-beta1 induces preferential rapid expansion and persistence of tumor antigen-specific CD8+ T-cells for adoptive immunotherapy. J Immunother 33(4):371-81, 5/2010. PMID: 20386469.|
|4.||Li Y, Liu S, Hernandez J, Vence L, Hwu P, Radvanyi L. MART-1-specific melanoma tumor-infiltrating lymphocytes maintaining CD28 expression have improved survival and expansion capability following antigenic restimulation in vitro. J Immunol 184(1):452-65, 1/2010. e-Pub 11/2009. PMID: 19949105.|
|5.||Chen J.Q., Litton J., Xiao L., Zhang H.Z., Warneke C.L., Wu Y., Shen X., Wu S., Sahin A., Katz R., Bondy M., Hortobagyi G., Berinstein N.L., Murray J.L., and Radvanyi L. Quantitative immunohistochemical analysis and prognostic significance of TRPS-1, a new GATA transcription factor family member, in breast cancer. Hormones and Cancer 1(DOI 10.1007/s12672-010-0008-8.):21-33, 1/2010.|
|6.||Wang-Johanning F, Radvanyi L, Rycaj K, Plummer JB, Yan P, Sastry KJ, Piyathilake CJ, Hunt KK, Johanning GL. Human endogenous retrovirus K triggers an antigen-specific immune response in breast cancer patients. Cancer Res 68(14):5869-77, 7/2008. PMID: 18632641.|
|7.||Campbell-Anson RE, Kentor D, Wang YJ, Bushnell KM, Li Y, Vence LM, Radvanyi LG. A new approach for the large-scale generation of mature dendritic cells from adherent PBMC using roller bottle technology. J Immune Based Ther Vaccines 6(1):1, Jan-Feb, 3/2008. PMID: 18321390.|
|8.||Lee ST, Liu S, Radvanyi L, Sukhumalchandra P, Molldrem JJ, Wieder ED, Hwu P, Liu YJ, Kwak LW, Lizée G, Neelapu SS. A novel strategy for rapid and efficient isolation of human tumor-specific CD4(+) and CD8(+) T-cell clones. J Immunol Methods 331(1-2):13-26, Jan-Feb, 2/2008. PMID: 17959194.|
|9.||Lizée G, Radvanyi LG, Overwijk WW, Hwu P. Improving antitumor immune responses by circumventing immunoregulatory cells and mechanisms. Clin Cancer Res 12(16):4794-803, Jan-Feb, 8/2006. PMID: 16914564.|
|10.||Lizée G, Radvanyi LG, Overwijk WW, Hwu P. Immune suppression in melanoma: an obstacle to effective immunotherapy. Clin Cancer Res 12(7 Pt 2):2359s-2365s, Jan-Feb, 4/2006. PMID: 16609059.|
|11.||He L, Hakimi J, Salha D, Miron I, Dunn P, Radvanyi L. A sensitive flow cytometry-based cytotoxic T-lymphocyte assay through detection of cleaved caspase 3 in target cells. J Immunol Methods 304(1-2):43-59, Jan-Feb, 9/2005. PMID: 16076473.|
|12.||Radvanyi L, Singh-Sandhu D, Gallichan S, Lovitt C, Pedyczak A, Mallo G, Gish K, Kwok K, Hanna W, Zubovits J, Armes J, Venter D, Hakimi J, Shortreed J, Donovan M, Parrington M, Dunn P, Oomen R, Tartaglia J, Berinstein NL. The gene associated with trichorhinophalangeal syndrome in humans is overexpressed in breast cancer. Proc Natl Acad Sci U S A 102(31):11005-10, Jan-Feb, 8/2005. PMID: 16043716.|
|1.||Wu S, Jin L, Vence L, Radvanyi LG. Development and application of "phosphoflow" as a tool for immunomonitoring. Expert Rev Vaccines 9(6):631-43, 6/2010. PMCID: PMC2933839.|
|2.||Radvanyi L. Discovery and immunologic validation of new antigens for therapeutic cancer vaccines. Int Arch Allergy Immunol 133(2):179-197, 2004. PMID: 14764946.|
|1.||Radvanyi LG, Hennessy B, Gish K, Mills GB, Berinstein N. Chapter 9: Towards a unified approach to new target discovery in breast cancer: Combining the power of genomics, proteomics and immunology. In: Immunogenomics and Human Disease. 1, 167-207, 2005.|
Last updated: 5/8/2013
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