Preventing graft-versus-host disease disease after bone marrow transplant -- without toxicity

Trial will test a natural antibiotic depleted by pre-transplant chemotherapy

Unless the donor is an identical twin, patients undergoing bone-marrow transplant (also known as hematopoietic stem cell transplant, or HSCT) must first receive powerful chemotherapy drugs to wipe out their immune system and prevent their bodies from rejecting the donated cells. Research from Children’s Hospital Boston and the Dana-Farber Cancer Institute has helped demonstrate that this punishing regimen increases the risk of graft-versus-host disease (GVHD), in which the donor’s cells mount an immune response against the patient. But the most recent findings also suggest that the risk for GVHD can be reduced by replacing a natural antibiotic protein, known as bactericidal/permeability increasing protein (BPI), which is depleted when patients undergo chemotherapy.

Now, a multicenter study is about to test this idea in HSCT patients, using a manufactured form of BPI known as rBPI21 (XOMA Ltd.) Unlike other treatments to prevent GVHD, BPI does not suppress the immune system and has shown virtually no toxicity.

Researchers Ofer Levy, MD, PhD, of Children’s Hospital Boston, and Eva Guinan, MD, of Children’s Hospital Boston and Dana-Farber Cancer Institute, will present their most recent findings and discuss the new clinical trial on December 11 at the American Society of Hematology (ASH) Annual Meeting in Orlando, Fla. (abstract # 2856).

The new trial is the culmination of over five years of collaborative research by Levy and Guinan in human patients. "Many basic and translational studies, including our own, have provided a strong rationale for a trial of BPI in patients undergoing hematopoietic stem cell transplants," says Levy. "Replenishing a natural host defense factor that is deficient due to chemotherapy makes theoretical and practical sense, and we hope that bringing our bench work to patients will reduce the complications they suffer."

GVHD occurs when immune cells from donor attack the recipient, and can lead to multiple organ failure and death. It strikes some 30-60 percent of transplant patients, depending on how closely matched the donor is, and is kept in check only by eliminating otherwise useful donor immune cells or by using powerful immune-suppressing drugs.

Studies in mice had shown that the chemotherapy regimens used in HSCT not only wipe out white blood cells (with the intended effect of suppressing the immune system), but also damage the intestinal lining. This breach of the lining allows endotoxin, which is produced by bacteria living in the intestines, to enter the bloodstream. The endotoxin, in turn, provokes an inflammatory response that mobilizes donor immune cells, helping to trigger GVHD.

Levy, in Children’s Division of Infectious Diseases, had long been studying BPI, which naturally blocks and neutralizes endotoxin.(1) BPI is found in neutrophils, the very white blood cells that are virtually wiped out by pre-transplant chemotherapy. Studies in mice had shown that blocking endotoxin reduces the incidence of GVHD after chemotherapy and HSCT.(2)

Intrigued by these findings, Levy and Guinan began to study endotoxin and BPI in human patients undergoing HSCT with pre-transplant chemotherapy. In 2003 they showed, in a study of 57 children, that patients’ blood endotoxin levels rise markedly within a week of the transplant.(3) And now, in a study of 30 patient:donor pairs to be presented at the ASH meeting, they show that patients undergoing HSCT also have a sharp drop in BPI levels – just as their endotoxin levels are rising – and that BPI deficiency is associated with a greater likelihood of GVHD.

"BPI is markedly deficient – 100 to 1000-fold lower – in our transplant patients," says Guinan, associate director of the Center for Clinical and Translational Research at Dana-Farber. "If we can replenish this host defense factor, we might be able to moderate the damaging effects of GVHD."

The multicenter clinical trial, expected to begin within the next few months, will test rBPI21 (opebacan, NEUPREX® [Nasdaq: XOMA]). rBPI21 has been in phase I, II, and III human trials, with evidence of benefit in children and adolescents with serious meningococcal infections, but has not yet been approved by the Food and Drug Administration.

Levy and Guinan will first conduct a small safety trial, gradually increasing the amount of BPI given and the duration of treatment. If BPI appears safe, they will quickly mount a randomized, controlled trial in 30 to 40 patients who are undergoing HSCT for cancer or blood diseases. Children’s/Dana-Farber will be the lead center, with four to five additional pediatric and adult sites at prominent medical centers around the country.

"Our ultimate goal is to reduce the downstream complications of stem-cell transplant," says Guinan. "BPI would make these transplants significantly less toxic."

###

The study presented at the ASH meeting was supported by XOMA and private donations to Guinan’s laboratory.

Founded in 1869 as a 20-bed hospital for children, Children’s Hospital Boston today is the nation’s leading pediatric medical center, the largest provider of health care to Massachusetts children, and the primary pediatric teaching hospital of Harvard Medical School. In addition to 347 pediatric and adolescent inpatient beds and comprehensive outpatient programs, Children’s houses the world’s largest research enterprise based at a pediatric medical center, where its discoveries benefit both children and adults. More than 500 scientists, including eight members of the National Academy of Sciences, 11 members of the Institute of Medicine and 10 members of the Howard Hughes Medical Institute comprise Children’s research community. For more information about the hospital visit: www.childrenshospital.org/newsroom.

Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.

References

(1) Levy O. A neutrophil-derived anti-infective molecule: bactericidal/permeability-increasing protein. Antimicrob Agents Chemother. 2000 Nov; 44(11):2925-31.

(2) Cooke KR, Gerbitz A, Crawford JM, Teshima T, Hill GR, Tesolin A, Rossignol DP, Ferrara JL. LPS antagonism reduces graft-versus-host disease and preserves graft-versus-leukemia activity after experimental bone marrow transplantation. J Clin Invest 2001 Jun; 107(12):1581-9.

(3) Levy O, Teixeira-Pinto A, White ML, Carroll SF, Lehmann L, Wypij D, Guinan E. Endotoxemia and elevation of lipopolysaccharide-binding protein after hematopoietic stem cell transplantation. Pediatr Infect Dis J. 2003 Nov; 22(11):978-81.


Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
    Published on PsychCentral.com. All rights reserved.

 

 

If you find a path with no obstacles, it probably doesn't lead anywhere interesting.
~ Frank A. Clark