Robert B. Levy, Ph.D.
Professor of Microbiology & Immunology
Description of Research
The research in Dr. Levy’s laboratory employs pre-clinical models of HSCT to generate and test strategies to block GVHD and garner transplanted donor T cells for use in anti-tumor immunity. Current approaches in the laboratory are exploring eliminating donor anti-host reactive T cells following allogeneic HSCT can be performed such that it is possible to: 1) "take advantage" of their anti-tumor reactivity prior to removal and subsequently 2) "take advantage" of surviving non-anti host reactive donor T cells via their expansion using tumor vaccination strategies in recipients post-transplant. Pre-clinical transplant models are investigating how alkylating agents post-transplant may be used to reduce anti-host alloreactive "GVHD" T cell component while sparing donor T cells which do not respond to recipient allogeneic histocompatibility antigens. These latter cells are crucial for immune responsiveness and include anti-pathogen (i.e. viral and bacterial) as well as anti-tumor reactive T cells. Studies are examining how this strategy impacts immune reconstitution post-transplant via the thymic and peripheral immune compartments. Dr. Levy and his laboratory propose following elimination of donor anti-host alloreactive T cells to employ effective vaccines to elicit anti-tumor responses without accompanying graft vs. host reactivity. Studies are underway comparing the effectiveness of two multi-antigen vaccine strategies, one involving a heat shock protein based tumor cell vaccine and the second employing tumor cells which can be targeted in vivo to express new antigens following elimination of donor anti-host reactive T cells. Dr. Levy is also developing immunotherapy strategies to employ immediately following autologous HSCT utilizing tumor cell based vaccines together with the directed delivery of interleukin 2. Studies are designed to assess "individualized" vs. allogeneic off the shelf vaccines.
The laboratory is also interested in the process of engraftment following BM. These studies examine the presence of defined donor progenitor cell populations (lineage committed and more primitive multi-lineage stem cells) and peripheral chimerism in recipients post-transplant. They are interested in understanding the mechanisms used by: (a) donor lymphoid cells for their facilitation and support of progenitor cells and engraftment after transplant, and (b) barrier cells in the host which inhibit progenitor cells annd engraftment. Strategies applying the administration of T regulatory cells or the expansion of residual Treg cells which survive the transplant via targeting CD25 in vivo are being used to inhibit the resistance response and facilitate engraftment and tolerance. Dr. Levy's studies involve collaborative interactions with Drs. Podack, Malek, Bayer, Gilboa, Komanduri, Barredo and the Perez and Bhattacharya laboratories (Department of Opthalmology) involving eye disorders.
Highlights
- Demostrated that combination of vaccination using hsp transfected tumor cells together with IL-2 delivered as a complex with anti-IL-2 mAb elicits rapid and potent anti-tumor immunity in mice administered following autogous HSCT.
- Discovery that after allogeneic bone marrow transplant, the recipient can resist the engraftment of transplanted donor stem cells by using immune responses, which do not involve the two major pathways of T lymphocyte mediated killing. This is a surprising finding and demonstrates that it is likely that for some transplants, different pathways in the recipient must be blocked to help the transplanted bone marrow engraft.
- Learned that lymphocytes added to donor stem cells before transplant to help or facilitate the engraftment by these stem cells after transplant use different functions for the purposes of (a) helping to 'seed' the stem cells in the recipient and (b) helping to maintain their permanent presence.
- Identified survival and expansion of non-host reactive donor cells following ameliorization of GVHD after administration of post-transplant cyclophosphamide
- Combined vaccination using a tumor cell vaccine with IL-2 delivered as a complex with anti-IL-2 mAb to elicit rapid and potent anti-tumor immunity in mice administered autologous HSTC.
Selected Cancer-Related Publications
- Kutlesa S, Zayas J, Valle A, Levy RB, Jurecic R. T-cell differentiation of multipotent hematopoietic cell line EML in the OP9-DL1 coculture system. Exp Hematol 37:909-23, 2009. Read more »
- Shatry A, Levy RB. In situ activation and expansion of host tregs: a new approach to enhance donor chimerism and stable engraftment in major histocompatibility complex-matched allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 15:785-94, 2009. Read more »
- Shatry A, Chirinos J, Gorin MA, Jones M, Levy RB. Targeting Treg cells in situ: emerging expansion strategies for (CD4(+)CD25(+)) regulatory T cells. Biol Blood Marrow Transplant 15:1239-43,2009. Read more »
Programs
Collaborating in the Multidisciplinary Research Program(s):