Tuesday, July 05, 2011

APRIL a new target for CLL

APRIL stands for a proliferation inducing ligand. It is a TNF family ligand and has a physiological role in B-cell immunity. It is also believed to have a role in several B-cell malignancies including CLL. High levels of APRIL are correlated with poor prognosis. A group in the Netherlands has developed a pair of monoclonal antibodies that block the binding of APRIL to its receptors.

They have shown that blocking APRIL binding to its receptors has an inhibitory effect on known effects of APRIL both in vitro and in vivo. Importantly, mice treated with APRIL antagonistic antibodies display significant reduction in APRIL serum levels after 2 injections and undetectable levels after 4 weeks of antibody treatment. To demonstrate therapeutic capacity, they extended their study to examine the effect of APRIL antagonism on the survival of lymphoma cells. They confirmed that APRIL binding and stimulation of lymphoma cells, as well as APRIL-induced survival of malignant CLL cells in vitro could be blocked by the antibodies. Their observations confirm the survival benefit APRIL provides to CLL cells, and illustrate the activity of the anti-APRIL antibodies in blocking this.

There has been a recent observation that megakaryocytes, which produce significant amounts of APRIL, are a crucial constituent of the bone marrow niche for plasma cells. Such a selective local production of APRIL may be crucial for the survival of lymphoid malignancies in the bone marrow too. A similar situation appears to exist for CLL where the role of the microenvironment is particularly well established. T-cells and Nurse-Like Cells are described to deliver important survival stimuli. In vitro APRIL, either produced by NLCs or delivered as recombinant proteins can promote survival of CLL cells. These data indicate a significant role for APRIL in the survival of CLL cells in patients and thus support therapeutic intervention with targeting this survival benefit. Similarly, diffuse large B-cell lymphoma patients also appear to have a poor prognosis when their serum level of APRIL is high. Perhaps there will be a role in Richter syndrome.

The toxicity of APRIL antagonistic antibodies should be relatively marginal and thus a valuable option in the selective blocking of lymphoma survival signals and thus the treatment of lymphoma patients. The mouse model for CLL provides evidence that this approach could work. Although this is clearly not a complete model for the disease CLL, they have previously provided compelling evidence that a CLL-like phenotype occurs in this mouse model and the selective B-cell expansion that is reminiscent of CLL is prevented by treatment with the antibody.

1 comment:

Barry B. said...

Unless the CLL clone is competely eliminated, there is a chance of further mutation (especially chemo related) that can kill.

So even if one controls the CLL, it may change into a terrible new disease such as Richter's Transformation or MDS, and kill you.

And I'm sure the underlying immune deficiency that accompanies CLL will remain, leaving patients at a much higher risk for melanoma, colon cancer, lung cancer and the like.

We should not be complacent in an era of hyperbole about CLL treatments.