Immune system marker tied to improved bone marrow transplant outcomes

Sep. 16, 2013 — The risk of death following bone marrow transplantation can be reduced about 60 percent using a new technique to identify bone marrow donors who make the most potent cancer-fighting immune cells, according to research from St. Jude Children's Research Hospital. The findings appear in the September 16 online issue of the Journal of Clinical Oncology.

The research builds on an earlier St. Jude discovery that specialized immune cells called natural killer (NK) cells dispatched cancer cells more efficiently when the NK cells carried a particular version of a KIR protein on their surface. KIR is short for killer-cell immunoglobulin-like receptor. KIR proteins regulate NK cells.

For this study, researchers reviewed the outcomes of the 313 bone marrow transplants performed at St. Jude during the decade ending in January 2010. Investigators found that patients were far more likely to have survived the transplant and far less likely to had their disease progress if their new bone marrow came from donors whose NK cells included the same version of the protein, rather than the alternative form.

"This approach should dramatically improve the outcome for patients undergoing bone marrow transplantation, regardless of their age or underlying condition," said Wing Leung, M.D., Ph.D., the paper's corresponding author and chair of the St. Jude Department of Bone Marrow Transplantation and Cellular Therapy. "NK cells also play an important role in autoimmune disorders, chronic infections and other conditions, so these results will likely have an impact beyond cancer."

Transplant patients benefited regardless of their disease, previous treatment, completeness of the genetic match or other donor characteristics, including whether the donor was a relative. Leung said screening for the NK cell variation uses blood collected for the current donor screening process and will not slow donor selection.

NK cells account for less than 15 percent of white blood cells, but play a major role in defending against cancer and viral infections. This research focused on a protein named KIR2DL1, which belongs to the KIR family of proteins. The KIR2DL1 protein is found on NK cells of nearly all healthy individuals.

Proteins are made up of long chains of amino acids. Due to natural genetic variation, there are 25 versions of KIR2DL1, each with a slightly different amino acid sequence.

In an earlier study, Leung and his colleagues discovered that NK cells with one of the KIR2DL1 variations killed cancer cells growing in the laboratory more efficiently than NK cells with a different version of the protein. The potent NK cells featured the amino acid arginine at position 245 of KIR2DL1 rather than the amino acid cysteine in that spot. That discovery led to this study, which offers the first proof that the amino acid difference impacts patient outcomes.

Researchers checked the outcomes of all bone marrow transplants performed at St. Jude during the 10-year period. They found that donor bone marrow with two copies of the gene for the arginine 245 version of KIR2DL1 was associated with a 60 percent decreased risk of death following transplantation and a 62 percent reduced risk of disease progression compared to transplants with donor bone marrow that carried instructions for making just the cysteine version. The transplants involved patients battling both acute lymphoblastic and acute myeloid leukemia as well as other conditions.

St. Jude has patented and licensed a test to identify potential donors with the preferred amino acid. The goal is to make the screening test widely available to other transplant centers as soon as possible, officials said.

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New marker identified for early diagnosis of lung cancer

Sep. 17, 2013 — A protein called isocitrate dehydrogenase (IDH1) is present at high levels in lung cancers and can be detected in the blood, making it a noninvasive diagnostic marker for lung cancers, according to a study published in Clinical Cancer Research, a journal of the American Association for Cancer Research.

"This study is the first to report identification of IDH1 as a novel biomarker for the diagnosis of non-small cell lung cancers (NSCLC) using a large number of clinical samples," said Jie He, M.D., Ph.D., director of the Laboratory of Thoracic Surgery at the Peking Union Medical College and Chinese Academy of Medical Sciences in Beijing. "Lung cancer has a high mortality rate, mostly because of late diagnosis. With an increase in aging population, we are likely to see an increase in lung cancer incidence and a need for better biomarkers for early diagnosis. We have identified IDH1 as an effective plasma biomarker with high sensitivity and specificity in the diagnosis of NSCLC, especially lung adenocarcinoma."

Lung cancer is the leading cause of cancer deaths in both men and women in the United States and worldwide. To detect lung cancer in blood, currently certain biomarkers including CEA, Cyfra21-1 and CA125 are used, but these markers are not very sensitive, according to He.

He and colleagues found that IDH1 could be detected in the blood of lung cancer patients with 76 percent sensitivity and 77 percent specificity. When they used a mathematical model to combine the detection of IDH1 with the detection of existing markers CEA, Cyfra21-1, and CA125, the sensitivity increased to 86 percent.

"Based on the present data, IDH1 can be used to detect stage 1 lung cancer; however, it is also possible that IDH1 could be used to detect precancer but further studies are required to address that possibility," said He.

He and colleagues used blood samples collected from 943 patients with NSCLC and 479 healthy controls, enrolled between 2007 and 2011 in the Cancer Institute and Hospital of the Chinese Academy of Medical Sciences. None of the study participants had a cancer diagnosis, nor were they treated for cancer in the three years prior to the study. Using methods called ELISA and ECL, they measured the levels of IDH1, CEA, Cyfra21-1, and CA125 in the participants' blood.

The researchers then divided the samples into a training set and a test set to validate the detection efficiency of IDH1. They found the data obtained from the test set were as good as those from the training set, demonstrating the robustness of IDH1 as a biomarker for lung cancer diagnosis.

The median IDH1 levels in patients with two types of lung cancer, adenocarcinoma and squamous cell carcinoma, were 2.7-fold and 2.2-fold higher, respectively, compared with healthy controls.

The researchers also found that combining the detection of all four markers -- IDH1, CEA, Cyfra21-1, and CA125 -- helped to better classify different types of adenocarcinoma, compared with detection with IDH1 alone.

He and colleagues are planning to conduct a multicenter clinical trial for further validation of IDH1.

"Our research also suggests IDH1 may be involved in the development of lung cancer, and it may be a good target for the treatment of NSCLC," said He. His team is currently studying the molecular mechanisms that increase IDH1 in lung cancer patients and its clinical implications.

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