Intra-tumoral immune cell mobilization and anti-tumor activity after treatment with the engineered cytokine NKTR-214 in multiple preclinical mouse tumor models

• Published in: European journal of cancer (1990) 2016-12, Vol.69, p.S101-S101
• Main Authors: Charych, D, Hennessy, M, Langowski, J, Dixit, V, Rubas, W, Hoch, U, Pena, R, Quach, P, Doberstein, S.K, Zaleveky, J
• Format: Article
• Language: English
• Subjects: Animal models; Anticancer properties; Antitumor agents; Biocompatibility; Biomedical materials; CD122 antigen; CD25 antigen; CD4 antigen; Colon; CTLA-4 protein; Cytokines; Cytometry; Effector cells; Flow cytometry; Foxp3 protein; Harnesses; Hematology, Oncology and Palliative Medicine; Immune checkpoint; Infiltration; Inhibition; Liver; Lungs; Lymphocytes; Lymphocytes T; Melanoma; Metastases; Metastasis; Osteosarcoma; Pancreas; PD-1 protein; Pharmacodynamics; Pharmacokinetics; Pharmacology; Solid tumors; T cell receptors; Tumors
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/S0959-8049(16)32899-4

Background: NKTR-214 is an immune-stimulatory cytokine designed to provide a sustained CD122-biased activation signal through the heterodimeric lL2 receptor pathway (lL2Rbg) resulting in an intra-tumoral ratio of CD8T/Treg of >400 in mouse melanoma tumors as well as increased NK cells [1]. NKTR-214 is being evaluated in a Phase 1/2 clinical trial for treatment of patients with advanced solid tumors. We demonstrate that NKTR-214 promotes immune cell mobilization and anti-tumor activity in multiple mouse tumor types both as a single agent, and in combination with checkpoint blockade. Methods: Anti-tumor activity of NKTR-214 was evaluated in established subcutaneously implanted mouse models including colon CT26, melanoma B16F1O, liver H22, Lewis lung or pancreatic PanO2 tumors. Treatment was started when tumor volume was >100 mm3. NKTR-214 was dosed as a single agent, 0.8 mg/kg q9d x 3 or in combination with mouse anti- P01 or anti-CTLA4, each 10mg/kg q2w. The anti-metastatic potential of NKTR-214 was evaluated in IV-disseminated mouse osteosarcoma K7M2 that metastasizes to lung. Mobilization of T cells into primary tumors or metastatic lung tissue was measured by flow cytometry, T cell receptor sequencing (Adaptive Biotechnologies) and IHC. Results: In the liver, lung, melanoma, pancreatic and colon mouse tumor models, NKTR-214 single agent resulted in either tumor regressions or tumor growth inhibition. When compared to single agent anti-PD1 or anti- CTLA4, NKTR-214 demonstrated superior increases in tumor infiltrating lymphocytes after one dose. While NKTR-214 single agent resulted in tumor growth inhibition in the colon tumor model, the combination with anti- PD1 was synergistic, providing up to 90% tumor-free animals, superior to the combination of anti-POl + anti-CTLA4. NKTR-214 combined with anti- PD1 led to the highest increase in T cell tumor infiltration compared to all other checkpoint inhibitor combinations. In the metastatic osteosarcoma model, single agent NKTR-214 treatment led to a significant increase in CD4+CD25+FoxP3- effector T cells. Conclusions: NKTR-214 harnesses the immunologically potent lL2 pathway to increase CDB, CD4 effector I and NK cells in murine tumors. This mechanism leads to broad anti-tumor activity in a diverse set of tumor types both as a single agent and in combination with checkpoint inhibitors. NKTR-214 is currently in a Phase 1 clinical trial to evaluate the safety, pharmacokinetics, pharmacodynamics and activity in m