Graft-versus-host disease (GVHD)
Patients undergoing bone marrow or stem cell transplant from a sibling or unrelated person receive an immunologically active product in bone marrow or stem cells. As a result of this, lymphocytes in the stem cell/bone marrow product can react against tissue proteins in the recipient which mediates a pro-inflammatory response termed GVHD. If not prevented or left untreated GVHD can be lethal. For this reason, bone marrow/stem cell transplants are only offered to individuals that are a perfect or very close HLA match with their donor. The HLA proteins are what the T cells recognize and activates this process. T cells are typically infused into the blood system as part of the transplant yet acute GVHD involves predominantly the skin, upper and lower GI tract and the liver. How donor T cells go from the bloodstream to these organs has been the focus of our laboratory. We have found that donor T cells initially go to lymphoid tissue where they are activated by host antigen presenting cells. Blocking this process completely by targeting the chemokine receptor CCR7 which is critically important for the migration of naïve and central memory T cells, prevented GVHD. Once activated, donor T cells express a new subset of proteins important for the migration to the organs in which GVHD occurs. This in part is mediated by the generation locally of chemokine ligands as shown by our group which recruit particular subsets of T cells to these sites.
Additionally, there are a subgroup of donor immune cells that can naturally inhibit GVHD which are termed regulatory T cells. We have found that the migration of these cells is critically important for their function. Most recently, we have used multiphoton laser scanning microscopy to evaluate the interaction between donor T cells, regulatory T cells and host APCs. This has shown that donor regulatory T cells use multiple different mechanisms to prevent GVHD. Finally, our group has focused on the function of different subsets of T cells in the biology of GVHD. This work has shown that Th1 and Th17 cells can mediate inflammation in specific organs during GVHD and revealed a complex interaction between these cell types and epigenetic modifications after transplant of genetic loci critical for the generation of each subtype.
Our data and that from a large number of other laboratories indicates that individuals can generate immune responses to tumors but that in most instances this is not effective. Our laboratory has been working on trying to understand this finding and has focused on the function of adaptive immune cells to tumor antigens and the ability of tumors to generate proteins that generate a local immunosuppressive environment. We have focused on specific subtypes of breast cancer that are associated with a poor outcome in women. Using human tissues and mouse models we can show that these subtypes generate a very immunosuppressive local environment. Active work in the laboratory is seeking to understand the mechanism for this finding and the consequences of this on the growth of tumors locally and during metastasis.
Our laboratory has been at the forefront of generating tumor vaccines for the treatment of breast cancer as well as vaccines for melanoma. We have investigated a number of properties for those vaccines to function in tumor models including the activity of the adaptive immune cells in the tumor environment, enhancing vaccination by removing immunosuppressive cells post vaccine, using vaccine approaches that stimulate broad-based immunity and most recently focusing on methods to predict which subjects will respond to active or passive vaccination. These studies have informed the three clinical trials that we have run using vaccine therapy for the treatment of women with breast cancer.
We have generated 3 different tumor vaccines in which we hold the FDA IND that have been used for the treatment of women with metastatic breast cancer whose tumors express HER-2/neu. The most recent treatment is combined with trastuzumab and vinorelbine. Here we have early preliminary data suggesting an improvement in survival in individuals that mount a robust immune response to the vaccine.