CTLA-4 Inhibition in Hematological Malignancies

The stimulation of immunity against cancer has been demonstrated to some extent in conditions of hematopoietic malignancies.  For example, CML patients who are recipients of allogeneic stem cell grafts, after relapse, can be induced into remission by administration of donor specific lymphocytes.  Another method of stimulating immunity in transplant recipients would be to derepress a repressive element.  This can theoretically be accomplished by removal of suppressive agents from the patient's blood, such as exosomes, or alternatively by administration of an antibody that neutralizes a suppressive molecule.

Ipilimumab is a fully humanized monoclonal antibody that binds CTLA-4 and inactivates it.  Since CTLA-4 is a suppressive molecule that inhibits T cells, the inhibition of the inhibitor is believed to stimulate immunity.

In a recent study (Bashey et al. CTLA4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation. Blood. 2008 Oct 30) administration of ipilimumab was performed in a dose escalating manner in 29 patients with hematological malignancies recurring after allogeneic hematopoietic stem cell transplant.  There was no escalation of graft versus host, and response was seen in 3 patients.

These data support the feasibility of CTLA-4 inhibition in hematological malignancies and may open the door for immunotherapeutic interventions in larger studies using optimized dosing.