Bempegaldesleukin (BEMPEG; NKTR-214) efficacy as a single agent and in combination with checkpoint-inhibitor therapy in mouse models of osteosarcoma
Marlene Hennessy1, Andrew Wahba2, Kumar Felix3
1Nektar Therapeutics, San Francisco, California, USA.
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. Finally, 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 toward clinical evaluation of BEMPEG-based regimens in human osteosarcoma.
Insights
Bempegaldesleukin (BEMPEG), an IL-2 pathway agonist, improved survival and delayed tumor growth in osteosarcoma mouse models. BEMPEG also enhanced the effectiveness of immune checkpoint inhibitors, offering a promising new treatment strategy.
Area of Science:
- Immunotherapy
- Oncology
- Pharmacology
Background:
- Osteosarcoma survival rates have stagnated for decades.
- Existing immunotherapies like anti-PD-1 and anti-CTLA-4 show promise but have limitations.
- Interleukin-2 (IL-2) has shown clinical benefit but suffers from poor tolerability.
Purpose of the Study:
- To evaluate bempegaldesleukin (BEMPEG), a novel IL-2 pathway agonist, as a monotherapy and in combination with immune checkpoint inhibitors.
- To assess BEMPEG's efficacy in preclinical models of osteosarcoma.
Main Methods:
- Utilized metastatic and orthotopic murine models of osteosarcoma (K7M2-WT, K7M3, DLM8).
- Administered BEMPEG alone and in combination with anti-PD-1 or anti-CTLA-4 antibodies.
- Analyzed tumor growth, overall survival, and immune cell infiltration.
Main Results:
- BEMPEG treatment significantly delayed tumor growth and improved survival in pulmonary metastases models.
- BEMPEG inhibited primary tumor growth and prevented metastatic relapse in lung and bone.
- Combination therapy with BEMPEG and checkpoint inhibitors demonstrated enhanced anti-tumor activity.
- BEMPEG increased intratumoral effector T cells and NK cells while sparing regulatory T cells, improving the effector:inhibitory cell ratio.
Conclusions:
- Bempegaldesleukin shows significant anti-tumor efficacy in multiple osteosarcoma models.
- BEMPEG enhances the therapeutic potential of immune checkpoint inhibitors.
- These preclinical findings support the clinical evaluation of BEMPEG-based regimens for osteosarcoma treatment.
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