Abstract 3210: A potential immunotherapeutic approach for the treatment of osteosarcoma
Authors: Hennessy Marlene , Felix Souri , Wahba Andrew , Kivimae Saul , Miyama Takahiko , Cabrera Mariella , Segura Maria Gabriela , Zalevsky Jonathan , Overwijk Willem , Gordon Nancy 
Published: August 2019

Purpose: Survival of osteosarcoma (OS) patients has remained stagnant for the past 30 years thus the need for new therapeutic strategies.

NKTR-214 is a novel cytokine therapy that provides sustained activation of the IL-2 pathway with a bias to the IL-2 receptor CD122 (IL-2Rbeta gamma) so that it can selectively expand and proliferate CD8+ T cells. Compared to recombinant human IL-2, NKTR-214 demonstrated superior therapeutic benefit in a melanoma mouse model and was well-tolerated. Because systemic IL-2 has shown limited efficacy against OS, we hypothesize that NKTR-214 could potentially offer increased therapeutic benefit.

Methods: The K7M2/K7M3 disseminated and orthotopic OS mouse models were used. Three doses of NKTR-214 were given intravenously every 9 days. In the K7M2 disseminated model a prophylactic or therapeutic approach was taken where treatment was started right after tumor injection or when there was evidence of lung metastases. In the K7M3 orthotopic model, treatment was started once tumor was established (day 20) or 10 days after tumor injection. Bone tumor size was assessed by serial plain X-rays. Immunohistochemistry was performed to assess histologic tumor response (bone and lung) as well as evidence of immune cell infiltrate. Tumor immune infiltrate was analyzed by flow cytometry.

Results: We demonstrated therapeutic effect of NKTR-214 as a single agent. In the disseminated model, NKTR-214 administered every 9 days i.v. prophylactically resulted in an increase in the median survival of mice with OS lung metastases (21 days untreated vs. 51 days NKTR-214). Survival was similar when therapeutic treatment was started after tumor nodules were apparent in the lung and continued every 9 days (51 days vs 52.5 days). In the orthotopic model, we demonstrated NKTR-214 efficacy against K7M3 primary bone tumor and the development of pulmonary metastases. The total tibia tumor area in the NKTR-214-treated group was significantly lower than in the untreated group (p&lt;0.01). Likewise, the total lung metastases tumor area as well as the number of micrometastases was significantly lower in the treated as compared to the untreated group (p&lt;0.009). We also demonstrated increase in the number of CD8+ and CD4+ T cells in mice treated with NKTR-214 single agent as compared to the untreated group. This data provides rationale for the use of NKTR-214 alone or in combination with checkpoint inhibitors or adoptively transferred NK cells or T cells as a potential effective therapy for OS.

Conclusion: In conclusion, our findings demonstrate that NKTR-214 is effective in controlling the growth of primary OS, regrowth of tumor after amputation and inhibition of lung metastasis formation. These pre-clinical studies provide the basis for potential translation of NKTR-214-based immunotherapeutic regimens for OS into the clinic.

Citation Format: Marlene Hennessy, Souri Felix, Andrew Wahba, Saul Kivimae, Takahiko Miyama, Mariella Cabrera, Maria Gabriela Segura, Jonathan Zalevsky, Willem Overwijk, Nancy Gordon. A potential immunotherapeutic approach for the treatment of osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3210.