Abstract A30: Modeling an immunotherapy of NK mechanism on a NSCLC patient derived xenograft
Authors: Henry Q. Li, Zhun Wang, Xiaoyu An, Jinping Liu, Likun Zhang, Jean-Pierre Wery, Yan Wu, James Tonra, Sam Waksal, Zhenping Zhu
Journal: Clinical Cancer Research (2016)

Abstract The recent clinical successes of immune checkpoint inhibitors have fueled the intense interest in novel immuno-oncology (I/O) therapeutics. The lack of relevant animal models remains a major hurdle in understanding the mechanism of action and evaluating the efficacy of such therapeutics. Patient derived xenograft (PDX), considered to most closely mimic patient tumors in both histo- and molecular pathology1,2, is however rarely used in I/O studies because it grow only in immune-compromised hosts. In reality, many PDXs grow well in nude mice where certain immune functions remain intact, excluding T-cells/T-cell functions. Therefore, PDX could still potentially be of practical use for studying T-cell independent I/O therapy. This study set out to evaluate a biologics for the treatment of a patient derived xenograft disease, by activating mouse natural killer (NK). NK and CD8 T cells are two major immune effector cell types that mediate cytotoxicity to tumor cells in vivo. One of the immunomodulatory agents, an anti-PD-L1 antibody-based IL-15 immunocytokine, was recently tested as a novel I/O treatment of cancer3. This molecule was engineered to be cross-species for both human and mouse PD-L1 and IL-15 that antagonize PD1/PD-L1 checkpoint-mediated immune suppression and also target the PD-L1-expressing tumor with IL-15 stimulated NK and CD8 T effector cells into local tumor sites, thus synergizing tumor-located anti-tumor immunity. In fact, our previous studies have demonstrated a greatly enhanced anti-tumor activity in the PDL-1-expressing syngeneic mouse tumor models via the mobilization of tumor infiltrating lymphocyte (TILs), over the PD-L1 antibody alone3. Since IL-15 also stimulates NKs in addition to T-cells, we reasoned that this bifunctional agent could also have potential activity against a PD-L1-expressing PDX in nude mice where NK remains functional. LU1901 is previously described NSCLC-PDX1, and was confirmed to express high level of PD-L1 by both RNAseq and flow analysis, after screening of a large panel of PDXs. We implanted LU1901 in Balb/c nude mice, and started to treat the mice by the bifunctional agent when the tumor reached to 150 mm3. Our result clearly demonstrated a significant inhibition of LU1901 growth by the bifunctional agent in nude mice, in the apparent absence of T-cells. When the treated tumors were examined at the termination, significantly infiltrate NK cells were found inside the treated tumors, as measured by both flow cytometry and immunohistochemistry (IHC). The number of infiltrating NK also statistically correlates to the amplitude of the tumor responses. Together, our data suggest that one of important mechanisms of action of this bifunctional agent relies on the tumor-targeting NK activation, and also that PDX could be a useful model suitable for in vivo efficacy analysis of T-cell independent immunotherapy. References 1. Yang, M., et al. Overcoming erlotinib resistance with tailored treatment regimen in patient-derived xenografts from naive Asian NSCLC patients. International journal of cancer. Journal international du cancer 132, E74-84 (2013). 2. Guo, S., Wubin Qian, Jie Cai, Likun Zhang, Jean-Pierre Wery, Qi-Xiang Li. Molecular pathology of patient tumors, patient derived xenografts and cancer cell lines EORTC-NCI-AACR. (2015). 3. Yan Wu, Zhaojing Zhong, Stella Martomo, Dan Lu, Zhanna Polonskaya, Xenia Luna, Haifan Zhang, Zhikai Zhang, Zhun Wang*, Leo Liu*, Jeegar Patel, James Tonra, Henry Li*, Larry Witte, Sam Waksal, Zhenping Zhu. Anti-PD-L1 antibody-based IL-15 immunocytokine has enhanced antitumor immunity. EORTC-NCI-AACR Abstract (2015). Citation Format: Henry Q. Li, Zhun Wang, Xiaoyu An, Jinping Liu, Likun Zhang, Jean-Pierre Wery, Yan Wu, James Tonra, Sam Waksal, Zhenping Zhu. Modeling an immunotherapy of NK mechanism on a NSCLC patient derived xenograft. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A30.