in vivo tumor models of anti-PD-1/PD-L1 immunotherapy

While targeting the PD1/PDL1 axis with therapeutic antibodies (eg. nivolumab / atezolizumab) offers unprecedented clinical benefit in metastatic melanoma and lung cancer, durable responses are observed only in a fraction of patients. To evaluate novel drugs capable of leveraging the efficacy of PD1/PD-L1 axis blockade, Explicyte has validated a series of in vivo tumor models of anti-PD-L1 and anti-PD1 antibody therapy. In these models, we propose to strengthen the preclinical efficacy data by ancillary mechanism of action (MOA) studies relying on the quantification of key immunological markers, within the tumor or in peripheral organs. These validated models can also support research of specific innovative biomarkers capable of identifying responding and non-responding subjects.

 

Preclinical Models Of Anti-PD-L1 Immune Checkpoint Inhibitor

 

  • Syngeneic tumor models: to keep tumor-immune system interactions intact, immunocompetent mice serve as host.
  • References: Explicyte only uses antibody clones which are well-described in the literature.
  • Anti-PD-L1 responding & non-responding tumor models, including a unique bioluminescent model of glioblastoma and a colon cancer model.

syngeneic mouse tumor model anti-pd1 pdl1 antibody cancer immunotherapy in vivo studies

In a GL261-Luc2 (glioma) tumor bearing mice model, benefit of PDL-1 blockade is optimized with a drug candidate. Mice were challenged intracerebrally with GL261-Luc2 tumor cells, and exposed to anti-PD-L1 antibody or to anti-PDL1 plus compound A. Tumor growth was followed over time and determined by bioimaging. PD-L1 blockade delayed partially survival while combination therapy with anti-PDL1 and compound A leaded in some mice to full tumor rejection.

Preclinical in vivo efficacy and anti-tumor immune response profiling

 

  • Standard package: Tumor growth, body weight and survival  are monitored 3 times per week in 4 experimental groups (N=10), including vehicle, anti-PD-L1 treatment, test compound, and anti-PD-L1 combotherapy.
  • Satellite mice: can be included in each experimental group and used to evaluate the effect of  treatment on tumor–host immune interactions at the tumor site & in peripheral compartments.
  • Multiplex & quantitative immunological analysis : validated immune markers (eg. CD4, CD8, FoxP3, CD11b, Gr1, …) can be tracked by FACS and/or RT-qPCR to decipher the in vivo mechanism of action of the test compound.

preclinical in vivo tumor model anti PD1 PDL1 cancer immunotherapy oncology CRO services

Immune cell profiling at the tumor site and within spleen of glioblastoma tumor-bearing mice. Tumors and spleens from glioblastoma tumor bearing mice were harvested, and stained for CD11b and Gr1 or CD4 followed by intracellular anti-FoxP3 staining. Flow cytometric analysis revealed the presence of CD11b+/Gr1+high myeloid cells and FoxP3+ cells (the majority being CD4 negative) within the tumor while splenocytes harbor a significant amount of CD4+/FoxP3+ Tregs.

Our added-value

 

  • Fast study initiation & weekly reports: tumor models are set up and ready for treatment in less than 1 month upon study proposal agreement. Study progress reports  are provided on a weekly basis.
  • Quantitative analysis of immunological markers: validated markers include CD4, CD8, CD25, FOXP3, CD11b, Gr1, CD11c, mPDCA1… among others.
  • A unique expertise in syngeneic tumor models of immune checkpoint inhibition: in addition to anti-PD-L1 immunotherapy, we offer a range of in vivo tumor models of CTLA-4 blockade & Immunization.
  • Expression of key immune-related genes: RT-qPCR data are available for some models. The panel includes Il6, Ifng, Il17, Tnfa, Tgfb, Il10, Foxp3, Rorgt, Cd274 (PD-L1), Pdcd1 (PD1), …
  • Longitudinal mice bleeding: blood samples can be collected on a weekly basis, which allows the evaluation of peripheral markers over time in responding and non-responding animals.

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Explicyte immuno-oncology offers preclinical in vivo models of PD-1/PD-L1 blockade. Our in vivo services are based on syngeneic mouse tumor models treated with anti-PD1/PDL1 antibodies, to mimic the efficacy and mechanism of action of FDA-approved PD-1/PD-L1 inhibitors, such as Nivolumab or pembrolizumab.