Advances in Hematologic Malignancies Issue 3, Spring 2014
Hematopoietic stem cell transplantation (HSCT) is undergoing a transformation through the development of novel strategies to manipulate cellular products in order to combat recurrent malignancy, treat persistent infection, prevent or treat graft-versus-host disease (GVHD), and accelerate hematopoietic recovery.
For patients with active, advanced acute myeloid leukemia (AML) and chronic lymphoid leukemia (CLL) who are undergoing HSCT, our Adult Stem Cell Transplantation Program team here at Dana-Farber/Brigham and Women’s Cancer Center (DF/BWCC) is exploring vaccination shortly after transplant, using radiation-inactivated patient-derived malignant cells engineered to secrete GM-CSF.
Analyses from earlier published trials indicated induction of potent anti-tumor immunity with encouraging long term remission rates. We are also planning to participate in trials of chimeric antigen receptor-expressing T (CAR-T) cells capable of recognizing CD19-expressing malignancies such as CLL, acute lymphoblastic leukemia (ALL), and diffuse large B cell lymphoma (DLBCL).
In CD19 directed CAR-T cells, genetic constructs encoding antibody against CD19 — a costimulatory molecule — and the CD3 zeta chain of the T cell receptor are transduced into T cells, thus delivering a powerful stimulatory signal to any T cell bearing this construct that encounters a CD19+ cell. CAR-T cells enhanced in this way can be generated in the autologous setting for refractory disease to enable curative HSCT, or in the allogeneic setting for relapse of a CD19+ malignancy after HSCT.
Both our center and others are currently developing CAR-T cells directed at myeloma and myeloid leukemia antigens, and we plan to use this technology to better harness the anti-tumor effects of T lymphocytes and natural killer cells.
Cytomegalovirus (CMV), Epstein-Barr virus (EBV), and adenoviral infections can be deadly after HSCT. These dangerous infections can now be prevented and treated by adoptive transfer of autologous, HSCT donor-derived, or unrelated donor-derived "third-party" T cells that specifically recognize these viruses.
Troublesome technological aspects in the generation of these cytotoxic T cells that have been problematic in the past — such as multiple months required for preparation, difficulty in harnessing naive T cells in umbilical cord grafts, and necessity for full HLA matching — have all recently been overcome. These virally directed, cytotoxic T lymphocytes are now broadly applicative to viral infections and virally-driven post-transplant lymphomas after HSCT, as well as in the treatment of refractory infections and viral-associated lymphomas prior to transplant.
To improve stem cell homing and decrease the prolonged neutropenia that is associated with umbilical cord transplants, a number of strategies to accelerate engraftment are being developed. Two such strategies are being studied: one at DF/BWCC (in adults) and one at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center (in children).
Prompted by laboratory findings in zebrafish, we have developed a promising program utilizing Prostaglandin E2 (PGE2) treatment of one umbilical cord unit prior to double cord transplantation. PGE2 enhances stem cell homing, proliferation, and survival, and can also accelerate neutrophil recovery. In addition, we are collaborating on a project examining cord expansion via Notch ligand to enhance engraftment.
New strategies to prevent and treat chronic GVHD are also needed. We are currently exploiting our ability to enrich and deplete individual cell subsets using antibody-conjugated magnetic beads to select for CD4+CD25+regulatory T cells (Treg) that suppressive allo-reactivity. Lack of Tregs — a subtype of T lymphocytes known to play a critical suppressive role in immune homeostasis — contributes to GvHD. We are now conducting trials delivering exogenous CD25+ Tregs cells, freshly isolated from the original HSCT donor and expanded in vivo with low dose interleukin-2 (IL-2), to treat established chronic GVHD symptoms.
In summary, stem cell transplant is increasingly becoming an initial platform for further immunotherapy targeting complications that arise after HSCT, such as relapse, infection, and GvHD. (Figure 1)
As researchers here and elsewhere push the boundaries of what is possible with HSCT through ongoing clinical trials, we are simultaneously collecting immunologic and genetic data to better understand the mechanisms of these immunotherapeutic tools and further advance our modulation of immune reconstitution after HSCT.
Robert Soiffer, MD
Sarah Nikiforow, MD, PhD
— Sarah Nikiforow, MD, PhD, of the Adult Stem Cell Transplantation Program and Robert Soiffer, MD, Chief of the Division of Hematologic Malignancies and Co-Chief of the Adult Stem Cell Transplantation Program