Grant Awarded in 2017

Functional Evaluation of Immunologic Checkpoint Blockade in the Therapy of Histiocytosis

Principal Investigator
Omar Abdel-Wahab
Memorial Sloan Kettering Cancer Center
New York, NY USA

*2017 William M. Keck, Jr. Foundation Scientific Excellence Grant Recipient

Date of Award

December 2017

Amount of Award

Layperson Summary

In recent years, immunotherapy has changed the outcome of many forms of adult and pediatric cancers. One of the most successful approaches has been the use of immune checkpoint inhibitors, which are drugs that promote the host’s immune system to attack tumor cells. The efficacy of these
drugs relies the presence of certain proteins on the tumor cell surface, particularly expression of PD-L1 (the "Programmed death-ligand 1"). In addition, response to inhibitors of PD-L1 are also correlated with the presence of immune cells within the tumor and certain genetic alterations within the tumor.

We and others have detected abundant expression of PD-L1 in samples from patients with Langerhans Cell Histiocytosis (LCH), which, together with the dense immune infiltrates that exist in LCH tumors, leads us to suspect that LCH patients are likely to respond to anti-PD-L1 therapies. In this proposal, we
plan to test this hypothesis using newly created mouse models of histiocytosis which remarkably mimic LCH and non-Langherhans histiocytosis in humans. We plan to treat these mice with immune checkpoint inhibitors, alone and in combination with additional targeted therapies used already in
histiocytosis patients. Such studies have not been performed to date, largely because of the lack of models of histiocytosis previously.

In cancer types more common than histiocytosis, certain genetic features predict response to immune checkpoint inhibitors. Our group has previously discovered different causative genetic abnormalities in adults with histiocytosis which led to clinical trials using targeted drugs with promising results. Through a multi-institutional collaboration we now have access to a large cohort of pediatric LCH cases. We now, at a larger scale, want to determine what the correlation is between different genetic lesions and presence of PD-L1, both in pediatric and adult samples of histiocytic disorders.

Given that immune checkpoint inhibitors are becoming approved for cancer in pediatrics and adult patients, the results of our proposal could immediately be brought to the clinic. We therefore strongly believe that the studies we propose here may offer a new therapeutic approach to improve outcome of
children and adult histiocytosis patients.

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