Robert B. Levy, Ph.D.
Professor of Microbiology & Immunology
Description of Research
The research in Dr. Levy’s laboratory employs pre-clinical animal models to develop strategies to regulate the immune responses necessary for the success of allogeneic and autologous hematopoietic stem cell transplants (HSCT). These responses include those by T cell populations with donor anti-host (“GVH”), host versus donor (“HVG”), anti-tumor and anti-pathogen reactivity. The key objective regarding allo-HSCT is a clinically translatable strategy which can prevent GVHD – a systemic and lethal complication of allo-HSCT while maintaining effective use of transplanted donor T cells for protective anti-tumor / pathogen immunity. In the last 12 months Dr. Levy and his lab have discovered a new pre-clinical strategy to ameliorate GVHD which involves expansion of T regulatory cells in both the donor and recipient of an allo-HSCT. They have identified distinct protocols in donors before - and recipients - after transplant involving signaling via CD25 and TNFRS25. Historically, strategies to ameliorate GVHD by depleting donor anti-recipient reactive T cells prior to transplant have not translated to clinical value due to the loss of anti-tumor (GVL) and anti-stem cell engraftment promoting activity. They recently developed a new approach to this conundrum, by asking the question: “Is it possible to program - immediately prior to transplant - GVHD inducing donor anti-host T cells to undergo death following their transplant into the recipient?
To begin addressing this hypothesis, Dr. Levy and his lab developed a strategy involving short-term (~ 24hrs) ex-vivo stimulation of donor T cells against recipient allo-antigens followed by brief exposure to a DNA alkylating agent. Following transplant of such treated (but not control) cells into complete genetically mismatched recipients, the onset of GVHD has been remarkably diminished, i.e. prolonged or abrogated. They hypothesize that due to the amelioration of GVHD, tumor vaccines– including heat shock protein and aptamer based which are unique to the Sylvester Cancer Center - can be employed immediately post-transplant to eliminate minimal residual disease and generate long-term anti-tumor immunity. They are also developing immunotherapy strategies to employ in the immediate period following autologous HSCT. These studies have utilized tumor cell based vaccines together with the directed delivery of interleukin 2. Studies investigate "individualized" vs. allogeneic off the shelf vaccines.
In total, from an immunological perspective, “turning allo-HSCT into an auto-HSCT” would enable the application of vaccine strategies which are limited to auto-HSCT transplant recipients. 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. The objective is to understand the mechanisms used by: (a) donor lymphoid cells in their facilitation and support of progenitor cell engraftment, and (b) barrier cells in the host which inhibit such engraftment. Dr. Levy's studies involve collaborative interactions with Drs. Podack, Malek and Gilboa (Microbiology and Immunology), Komanduri, Wolf, Benjamin, Wieder (Medicine) and Perez (Ophthalmology).
- During 2013-14, Dr. Levy’s laboratory discovered a new protocol to ameliorate GVHD through the use of in situ manipulation of donor regulatory T cells through signaling via TNFRSF25 followed by CD25 in T cell donors in conjunction with the reverse targeting of these receptors in recipients post-transplant.
- Developed a novel strategy to prevent GVHD by treating donor T cells prior to transplant with recipient antigen presenting cells and a DNA alkylating reagent. This protocol differs from all previous attempts in the field based on its objective not to pre-delete donor anti-host allo-reactive (GVHD inducing) T cells prior to transplant - but to transiently employ their benefits prior to their subsequent death in recipients.
- The first laboratory to demonstrate survival and expansion of non-host (allo) reactive donor cells following administration of post-transplant cyclophosphamide for amelioration of GVHD.
- Demonstrated that a combined vaccination strategy using a tumor cell heat shock protein vaccine with IL-2 delivered as a complex with anti-IL-2 mAb can elicit rapid and potent anti-tumor immunity in mice following autologous HSCT.
- Discovered that after allogeneic bone marrow transplant, the recipient could resist the engraftment of transplanted donor stem cells by using immune responses, which does not involve the two major pathways of T lymphocyte mediated killing. This was 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.
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 »
Collaborating in the Multidisciplinary Research Program(s):