Hennessy et al. demonstrated the antitumor efficacy of Bempegaldesleukin (BEMPEG; a selective IL-2Rβγ agonist) alone and with checkpoint inhibitors in several murine models of osteosarcoma. Prophylactic and therapeutic BEMPEG regimens prolonged survival in the metastatic K7M2-WT model with increased infiltration of NK cells and T cells, and expansion of CD25+Foxp3− effector CD4+ T cells in the lungs. BEMPEG monotherapy inhibited primary tumor growth in tibia and lung metastasis of K7M3 tumors with increased T cell infiltration. In combination with anti-CTLA-4, BEMPEG inhibited tumor growth and improved survival in the subcutaneous DLM8 tumor model.
Contributed by Shishir Pant
ABSTRACT: Survival of patients with relapsed/refractory osteosarcoma has not improved in the last 30 years. Several immunotherapeutic approaches have shown benefit in murine osteosarcoma models, including the anti-programmed death-1 (anti-PD-1) and anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4) immune checkpoint inhibitors. Treatment with the T-cell growth factor interleukin-2 (IL-2) has shown some clinical benefit but has limitations due to poor tolerability. Therefore, we evaluated the efficacy of bempegaldesleukin (BEMPEG; NKTR-214), a first-in-class CD122-preferential IL-2 pathway agonist, alone and in combination with anti-PD-1 or anti-CTLA-4 immune checkpoint inhibitors in metastatic and orthotopic murine models of osteosarcoma. Treatment with BEMPEG delayed tumor growth and increased overall survival of mice with K7M2-WT osteosarcoma pulmonary metastases. BEMPEG also inhibited primary tumor growth and metastatic relapse in lungs and bone in the K7M3 orthotopic osteosarcoma mouse model. In addition, it enhanced therapeutic activity of anti-CTLA-4 and anti-PD-1 checkpoint blockade in the DLM8 subcutaneous murine osteosarcoma model. Lastly, BEMPEG strongly increased accumulation of intratumoral effector T cells and natural killer cells, but not T-regulatory cells, resulting in improved effector:inhibitory cell ratios. Collectively, these data in multiple murine models of osteosarcoma provide a path towards clinical evaluation of BEMPEG-based regimens in human osteosarcoma.