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• Interleukin-2 (IL-2) is a cytokine that activates and expands tumor killing lymphocytes, but also potently activates suppressive T regulatory cells (Tregs) by binding to the heterotrimeric IL-2Rαβγ.

• NKTR-214 is a CD122-biased cytokine agonist conjugated with multiple releasable chains of polyethylene glycol (PEG), designed to provide sustained signaling through the heterodimeric IL-2 receptor pathway (IL-2Rβγ) to preferentially activate and expand effector CD8+ T and NK cells over Tregs (1).

• NKTR-214 is being evaluated in an outpatient setting in a Phase I dose escalation trial. NKTR-214 has a favorable safety and tolerability profile.(2)

• NKTR-214 as a single agent demonstrated a substantial increase in CD8+ T cells in the tumor microenvironment even in subjects pretreated with multiple prior immunotherapeutic agents(3).

• The adoptive cell transfer (ACT) of genetically engineered T cells expressing cancer-specific (TCR) is able to induce effective anti-tumor response. However, tumors frequently relapse after an initial response. Our hypothesis was that NKTR-214, could enhance the efficacy of ACT, compared to IL-2 by recruiting tumor killing T-cells, increasing their persistence, and reducing immunosuppresive T-cells in the tumor microenvironment.

• Here we evaluated the tumor immunology, biodistribution and anti-tumor activity of NKTR-214 combined with adoptive cell transfer (ACT) in a pre-clinical melanoma model

1. Charych et al, Clinical Cancer Research, 2016

2. ClinicalTrials.gov NCT: NCT02869295

3. Hurwitz et al, ASCO-GU, February 2016, Orlando, FL

Hall A-C, Poster section 26. AACR, April 3rd 2017, Washington, D.C. Abstract # 2671

Introduction NKTR-214 triggers more pronounced immunological

changes in tumor than in the spleen NKTR-214 provides significant anti-tumor activity in combination with adoptive cell transfer (ACT) therapy

Spleen

• NKTR-214 + ACT is well tolerated and provides a robust anti-tumor response in the aggressive B16F10 model.

• NKTR-214 significantly increases the total number of pmel-1 CD8+ T cells but not regulatory T cells in tumor.

• Treatment with NKTR-214 + ACT robustly mobilizes T cells into the tumor where they durably persist.

• The robust and long-lasting effect of NKTR214 supports its potential use in combination with cell-based therapeutics.

Antitumor activity of NKTR-214 in combination with pmel-1 ACT in an aggressive murine melanoma model Giulia Parisi, Justin Saco, Siwen Hu-Lieskovan, Ruixue Zhang, Paige Krystofinski, Cristina Puig Saus, Deborah H. Charych1, Antoni Ribas

Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles (UCLA) Los Angeles, CA 90095 1Nektar Therapeutics, 455 Mission Bay Blvd South, San Francisco CA 94158

Results

Splenocyte counts at day 5 after treatment. NKTR-214 induced a rapid splenic cell repopulation after irradiation. Unpaired t test (**, p<0.0001 with bars indicating comparisons).

C57/BL6 mice were implanted subcutaneously with B16F10 (0.5X106 per animal) syngeneic murine melanoma cell line on D-7 and lymphodepleted with 500 cGy on D-1. On D0, mice were treated with the combination of ACT (pmel-1 gp100 TCR transgenic T lymphocytes activated in vitro with 1 μg/ml gp100) and NKTR-214 (0.8 mg/kg, q9dx3, i.v.) or with IL-2 (0.4 mg/kg, qdX3 every 9 days for 3 cycles, i.p.), or vehicle. The second and third treatment cycle did not include ACT.

Tumors and spleens were collected on day 5 after treatment (single dose NKTR-214 and qdx3 of IL-2). The effect of NKTR-214 on regulatory T cells and CD8+ T cells was assessed by flow cytometry. In the tumor the absolute number of immune cells was normalized to tumor weight (grams) and graphed. NKTR-214 treatment increased pmel-1 CD8 T cells and amplified the CD8/Treg ratio compared to IL-2 or vehicle. The CD8/Treg ratio was greater in the tumor than the spleen after NKTR-214. Unpaired t test (**, p<0.05 with bars indicating comparisons, n=3).

References

Increased T cell expansion in the spleen and homing to the tumor is associated with NKTR-214 treatment In vivo bioluminescence imaging (BLI) of adoptively transferred lymphocytes. Pmel-1 transgenic T cells were transduced with a retrovirus–firefly luciferase and used for ACT. Representative figures on days 5 and 14, five replicate mice per group. T cell expansion in spleen (upper panels); mobilization to and persistence in tumor (lower panels).

Conclusions

Tumor

Quantification of serial images in the region of interest (ROI) of spleen and tumor (counts per pixel) through day 19 after ACT of pmel-1 T cells expressing luciferase. A single NKTR-214+ACT treatment showed a statistically significant increase in T cell expansion in the spleen from day 5 to day 9 compared to 3 daily doses of IL-2+ACT or vehicle. The luciferase signal over time showed a stronger peak of tumor-infiltrating effector T cells in the NKTR-214 group compared to IL-2 or vehicle from day 5 to day 7. The second dose of NKTR-214 given at day 9 triggered a second expansion of effector T cells in the spleen and tumor from day 12 to day 17. In contrast, there was no expansion in spleen or tumor after the second IL-2 treatment. (** p<0.0001 compared to IL-2+ACT, # p<0.0001 compared to ACT+vehicle, pair-wise comparison using Tukey test, n =5, mean ± SE).

Left: NKTR-214 + ACT provides significant tumor growth delay compared to IL-2 + ACT with less frequent dosing. * p<0.0001 compared to ACT+IL-2; # p<0.0001 compared to vehicle (pair-wise comparison using Bonferroni test). Right: Tumor growth delay was assessed for each tumor growth curve by interpolating the time to achieve tumor volume of 1000 mm3. * p<0.0001 compared to ACT+IL-2; # p<0.0001 compared to vehicle (Log-Rank Mantel-Cox test). N=12/group

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Splenic cell recovery after irradiation is rapid after NKTR-214 compared to IL-2