Poster: Drug/Disease modeling - Oncology

III-46 PK/PD modeling of new immunotherapeutic agents in cancer

Ana Margarita Contreras S. (1), Sara Zalba (1), Pedro Berraondo (2), María García-Cremades (1), Iñaki F. Trocóniz (1), María Jesús Garrido (1).

(1) School of Pharmacy. Department of Pharmacy and Pharmaceutical Technology. University of Navarra. 31008. Pamplona. Spain. (2) Division of Gene Therapy and Hepatology. Center for Medical Applied research (CIMA). University of Navarra. 31008. Pamplona. Spain.

Objectives: Immunotherapy is emerging as a new strategy in oncology to treat and cure tumors. Programmed death-1 ligand-1 (PD-L1 or B7-H1) is a co-stimulatory molecule which is expressed at high levels in tumor cells [1-4]. PD-1/PD-L1 binding interaction is able to down-regulate the immune response against tumor, inducing tolerance and enhancing tumor proliferation by inhibition of cytokines production such as interleukin (IL)-2 and interferon gamma (IFN-g) [2, 5]. According to this, PD-L1 and its receptor PD-1 at the activated lymphocytes, play a critical role in T-cell regulation to promote immune-inhibitory activity [2]. Thus, PDL-1 pathway had been proposed as a novel anti-tumor strategy, being possible to block the PD-1/PD-L1 interaction by a targeted molecule in order to increase tumor specific T-cell response [1, 2]. The development of anti-PD-L1 monoclonal antibodies (mAbs) arises as an effective approach for specific tumor immunotherapy [1], so that its pharmacokinetics and pharmacodynamics characterizations are essential.

Therefore, the aim of this work is to develop a PK-PD model able to be used as a platform for the characterization of these types of mAbs targeted to PD-L1, overexpressed on many solid tumors using a syngenic-tumor animal model.

Methods: C57BL/6 mice subcutaneously inoculated with B16F10 cells expressed ovalbumin (B16-OVA; melanoma) or MC38 (colorectal cancer) were treated with an Anti-PD-L1 mAb (clone 10F.9G2; BioXCell) at different dose schedules and/or initial tumor size. In control or saline and treated groups, tumor size and body weigh were monitored every two/three days for 50-60 days. The time profile of tumor growth will be described using a semi-mechanistic model where the impact of the schedules and the initial tumor size will also be evaluated [6]. The initial pharmacodynamics model tested to describe the control tumor growth will be based on the model previously described by Hahnfeldte et al [7].

On the other hand, additional assays are being optimized in order to quantify the anti-PD-L1 and CD8+ T cells in blood and tumor, respectively. The presence of these cytotoxic CD8 T cells is a relevant biomarker because they are required for an anticancer effective function of the immune system.

Results: The in-vivo experimentation is ongoing

Conclusions: Waiting for results

References: 
[1] Iwai Y, Ishida M, Tanaka Y, et al. Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12293-7.
[2] Li B, VanRoey M, Wang C, et al. Clin Cancer Res. 2009 Mar 1;15(5):1623-34.
[3] Yu P, Steel JC, Zhang M, et al. Clin Cancer Res. 2010 Dec 15;16(24):6019-28.
[4] Wu C, Zhu Y, Jiang J, et al. Acta Histochem. 2006;108(1):19-24.
[5] Dong H, Strome SE, Salomao DR, et al. Nat Med. 2002 Aug;8(8):793-800.
[6] Choo EF, Ng CM, Berry L, et al. Cancer Chemother Pharmacol. 2013 Jan;71(1):133-43.
[7] Hahnfeldt P, Panigrahy D, Folkman J, et al. Cancer Res. 1999 Oct 1;59(19):4770-5.