The University of Texas MD Anderson Cancer Center
Project Term: July 1, 2022 - June 30, 2027
SIRPα+ macrophages mediate resistance to lenalidomide in B-cell lymphoma, limiting the activity of immunotherapy for these patients. Therefore, we propose a phase I/II study, investigating the safety and efficacy of ALX148, a novel fusion protein of the SIRPα binding domain, in combination with rituximab and lenalidomide in patients with B-cell lymphoma. We hypothesize that this combination will be safe and effective, providing a chemotherapy-free option for these patients.
Macrophages are scavenger cells belonging to our immune system, defending us from external and internal enemies, including cancer. Cancer cells try to defend themselves from macrophages by showing on their surface a protein, called CD47. The latter interacts with another protein on the surface of macrophages, called SIRPa, and provides them a “do-not-eat me signal”. ALX-148 is a drug able to interrupt the interaction between CD47 and SIRPa, increasing the ability of macrophages to kill cancer cells. Its combination with rituximab, an antibody targeting a cancer protein called CD20, has shown to be very safe and effective for patients with B-cell lymphoma, a type of cancer originating from lymph nodes. However, its efficacy is limited, because the number of macrophages inside the lymphoma can be low, some of them can help rather than attacking the lymphoma, and because ALX148 has limited benefit to other members of the immune system, like lymphocytes. Lenalidomide is a pill able to increase the number of macrophages that migrate inside the lymphoma, to induce them to only attack and not help the lymphoma cells, and able to strengthen all members of the immune system, including lymphocytes. Therefore, the combination of these 3 drugs may work better than the single drugs. We propose a clinical trial where patients with B-cell lymphoma will receive all 3 drugs. During the first phase of this study, we will identify the safest dose of ALX148 to combine with rituximab and lenalidomide in patients with relapsed indolent and aggressive B-cell lymphoma. During the second phase of this study, we will determine the efficacy of this combination in patients with previously untreated indolent B-cell lymphoma. We expect that its use will increase the number of patients who achieve a complete remission, as compared to standard treatments, including chemotherapy. We will also collect a limited amount of blood and tissue samples, to better understand who could benefit from this treatment and how to help those who do not. If successful, this study will give a chemotherapy-free option to patients with lymphoma, who are frequently elderly and frail, and will help develop new exciting clinical trials.