Contact the Group
ccapitini [at] pediatrics [dot] wisc [dot] edu
1111 Highland Avenue
Madison, WI 53705
Our group focuses on using preclinical mouse models of allogeneic blood and marrow transplant (alloBMT) to cure pediatric leukemias and solid tumors with tumor-directed immunotherapeutic therapies such as dendritic cell vaccines, adoptive NK cell and T cell-based infusions. The goal of this research is to both improve presently used biological therapies in clinical alloBMT, such as donor lymphocyte infusion (DLI), as well as develop novel immune-based therapies that have potential to be translated into the clinic.
While alloBMT has been used to treat a variety of malignant (and nonmalignant) disorders in children and adults for the last 50 years, the field has struggled with the same major complications: 1. Tumor relapse, 2. Graft-versus-host-disease (GVHD), 3. Infections, and 4. Graft rejection. In particular, relapse remains the largest contributor to mortality after alloBMT, and we still do not have adequate therapies to treat relapsed disease. Immune-based therapies are attractive because relapsed tumors are resistant to chemoradiotherapy, and these traditional therapies have deleterious side effects that can be lifelong.
One component of the Immunotherapy & Hematopoietic Stem Cell Transplant Research Group is exploring methods to improve the efficacy of DLI, which is used clinically to treat viruses like CMV or EBV, or treat relapsed leukemia (particularly CML). Allogeneic T cells present in the DLI can potentially recognize the tumor as foreign, treating relapse (termed the graft-versus-tumor or GVT effect), infections or even host T and NK cells to help prevent graft rejection. But all of these benefits come with the potential of inducing GVHD, which is caused by donor T cells attacking normal host tissues such as the liver, skin or gut. Dr. Capitini has previously demonstrated that even subclinical GVHD can have deleterious effects on the efficacy of tumor vaccines as well as promote tumor growth. He also showed a novel approach of modulating GVHD with preservation of anti-tumor responses by DLI and vaccine through usage of T cell depleted bone marrow deficient in gamma interferon receptor signaling. By using this platform, one can give high doses of T cells via DLI without inducing GVHD. Ongoing studies in this laboratory are exploring the mechanism of this effect in donor-derived antigen presenting cells.
Tumor Vaccines After Allogeneic Hematopoietic Stem Cell Transplantation - A Lost Hope?
UW Pediatrics Grand Rounds - Christian M. Capitini, MD
While T cells are one element of DLI that have been well studied, there are other populations of lymphocytes that contribute to the GVT effect, such as NK cells. Over the last 10 years, allogeneic NK cells have been shown to play a role in GVT after T cell depleted killer immunoglobulin-like receptors (KIR)-mismatched alloBMT was shown by others to enhance survival in adults with AML. One question is whether infusion of KIR-mismatched allogeneic NK cells as an adoptive cell therapy could replicate this effect, and whether there is benefit in using allogeneic NK cells to target other tumors as well.
Thus another component of the Immunotherapy & Hematopoietic Stem Cell Transplant Research Group is exploring the biology of expanding allogeneic NK cells ex vivo for treating pediatric tumors after alloBMT. Because of prior studies by others with IL-2, as well as recent efforts to bring other gamma (c) cytokines like IL-15 and IL-21 to the clinic, artificial antigen presenting cells that express costimulatory molecules are being combined with gamma (c) cytokines to stimulate NK cell proliferation and activation ex vivo. Ongoing work is comparing NK cells expanded with a variety of agents against several pediatric tumors in the alloBMT setting.
Additional Research Activities
- Basic, translational and clinical research of pediatric cancers
- Cancer vaccines
- Adoptive cell therapies (T and NK cell infusions)
- Models of bone marrow transplant
- Extracorporeal photopheresis