Adjuvant immunotherapy for non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is the biggest cancer killer in the United States and worldwide. In 2011, there are estimated to be 221,130 new cases of lung cancer in the United States. Over a million people will die of lung cancer worldwide this year alone. When possible, surgery to remove the tumor is the best treatment strategy for patients with NSCLC. However, even with adjuvant (postoperative) chemotherapy and radiation, more than 40% of patients will develop recurrences locally or systemically and ultimately succumb to their disease. Thus, there is an urgent need for developing superior approaches to treat patients who undergo surgery for NSCLC to eliminate residual disease that is likely responsible for these recurrences. Our group and others have been interested in using immunotherapy to augment the efficacy of current treatment strategies. Immunotherapy is very effective against minimal disease burden and small deposits of tumor cells that are accessible by the circulating immune cells. Therefore, this strategy may be ideally suited as an adjunct to surgery to seek and destroy microscopic tumor deposits that remain after surgery. This review describes the mechanistic underpinnings of immunotherapy and how it is currently being used to target residual disease and prevent postoperative recurrences after pulmonary resection in NSCLC.

T-cell immune responses to Wilms tumor 1 protein in myelodysplasia responsive to immunosuppressive therapy.

Clinical observations and laboratory evidence link bone marrow failure in myelodysplastic syndrome (MDS) to a T cell-mediated immune process that is responsive to immunosuppressive treatment (IST) in some patients. Previously, we showed that trisomy 8 MDS patients had clonally expanded CD8(+) T-cell populations that recognized aneuploid hematopoietic progenitor cells (HPC). Furthermore, microarray analyses showed that Wilms tumor 1 (WT1) gene was overexpressed by trisomy 8 hematopoietic progenitor (CD34(+)) cells compared with CD34(+) cells from healthy donors. Here, we show that WT1 mRNA expression is up-regulated in the bone marrow mononuclear cells of MDS patients with trisomy 8 relative to healthy controls and non-trisomy 8 MDS; WT1 protein levels were also significantly elevated. In addition, using a combination of physical and functional assays to detect the presence and reactivity of specific T cells, respectively, we demonstrate that IST-responsive MDS patients exhibit significant CD4(+) and CD8(+) T-cell responses directed against WT1. Finally, WT1-specific CD8(+) T cells were present within expanded T-cell receptor Vß subfamilies and inhibited hematopoiesis when added to autologous patient bone marrow cells in culture. Thus, our results suggest that WT1 is one of the antigens that triggers T cell-mediated myelosuppression in MDS.

Graft-versus-host disease: role of inflammation in the development of chromosomal abnormalities of keratinocytes.

Graft-versus-host disease (GVHD) is a major risk factor for secondary malignancy after hematopoietic stem cell transplantation. Squamous cell carcinoma (SCC) of the skin and mucous membranes are especially frequent in this setting where aneuploidy and tetraploidy are associated with aggressive disease. The current study is directed at the mechanism of neoplasia in this setting. Unmanipulated keratinocytes from areas of oral GVHD in 9 patients showed tetraploidy in 10% to 46% of cells when examined by florescein in situ hybridization (FISH). Keratinocytes isolated from biopsy sites of GVHD but not from normal tissue showed even greater numbers of tetraploid cells (mean = 78%, range: 15%-85%; N = 9) after culture. To mimic the inflammatory process in GVHD, allogeneic HLA-mismatched lymphocytes were mixed with normal keratinocytes. After 2 weeks, substantial numbers of aneuploid and tetraploid cells were evident in cultures with lymphocytes and with purified CD8 but not CD4 cells. Telomere length was substantially decreased in the lymphocyte-treated sample. No mutations were present in the p53 gene, although haploinsufficiency for p53 due to the loss of chromosome 17 was common in cells exposed to lymphocytes. These findings suggest that in GVHD, inflammation and repeated cell division correlate with the development of karyotypic abnormalities.