Evaluation of CD137 as a costimulatory receptor in multiple myeloma

Multiple Myeloma (MM) is a plasma cell malignancy characterized by terminally differentiated plasma cells residing in the bone marrow. It is the second most common hematological malignancy in the United States. Despite recent advances in treatment strategies for multiple myeloma, the disease is incurable. Next-generation MM therapies such as T-cell redirection involve the use of bi-specific antibodies to redirect T-cells against tumor cells. The activation of T-cells by these bi-specific antibodies, also induces expression of costimulatory receptors such as CD137, which is an attractive target for immunotherapy. CD137 agonists stimulate this by potentiating costimulatory pathways on T-cells, leading to enhanced proliferation, survival, persistence, and improved memory differentiation, which is hypothesized to lead to improved tumor efficacy. Here, we evaluated the expression of CD137 on T-cells after treatment with two MM bispecific antibodies, GPRC5DxCD3 and BCMAxCD3. In addition, CD137 expression was evaluated on NK cells after treatment with effector function active anti-CD38 and anti-SLAMF7 on MM cells. Antibody-mediated stimulation of T-cells and NK cells by the effector function antibodies resulted in the initial expression of CD137 after which it gradually decreased with time. To explore strategies for augmenting CD137 expression, we cultured T-cells or NK cells in the presence of human recombinant cytokines (IL-2, IL-15, IFN-y, or TNF-a). While cytokines alone did not induce CD137 expression, IL-15 treatment resulted in the upregulation of activation markers in T-cells (CD25) or NK cells (NKG2D). Subsequently, T-cells were stimulated with activation antibodies (anti-CD3, anti-CD3/anti-CD28, or anti-TCR) and treated with IL-15 to investigate the expression of CD137. This resulted in a significant increase in CD137 expression, indicating that the combination of IL-15 and effector function antibodies may serve as an effective strategy to boost CD137.