Curbing Graft v. Host Disease by Replacing Natural Antibiotic Protein

[Guest guest]

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. "