In Vivo Models of CTLA-4 blockade

CTLA-4 immune checkpoint blockade is known, as monotherapy, to install a long-lasting anti-tumor immunity in only a small fraction of patients. To assess new drugs for their capacity to improve the benefit of CTLA-4 modulators, Explicyte offers syngeneic tumor-bearing mouse models with well-characterized responses to an anti-CTLA-4 monoclonal antibody. Models include both CTLA-4 inhibition responding and non-responding models to deal with the evaluation of novel compounds capable of enhancing the efficacy of anti-CTLA-4 antibodies and with the study of predictive biomarkers for the selection of anti-CTLA-4 responders. Interestingly, our efficacy studies can be consolidated with immunological data of immune response profiling, to investigate the mechanism of action of test compounds.
 

Robust preclinical models of anti-CTLA-4 antibody therapy

  • A robust treatment protocol in line with published literature data.
  • Syngeneic tumor models - tumor cells are implanted into immunocompetent mice, to evaluate drug effects on the anti-tumor immune response in the presence of a functionally immunocompetent system.
  • Anti-CTLA-4 responding & non-responding tumor models, including colon, breast, and unique bioluminescent glioblastoma cancer models

Illustrative data

Differential CTLA4 blockade efficacy in different syngeneic mouse models
CTLA4 blockade enhances survival of CT26, slightly that of GL261, but not that of 4T1 tumor-bearing mice.

Mice are challenged with respective tumor cells and exposed to anti-CTLA4 antibody. In the CT26 responding model, anti-CTLA4 treatment significantly improves mouse survival. (sc, subcutaneous ; ot, orthotopic)

CTLA4 blockade enhances survival of CT26, slightly that of GL261, but not that of 4T1 tumor-bearing ...

Immune response profiling of CT26 tumor-bearing model to anti-CTLA4 therapy
RT-qPCR analysis of key immune markers encoding genes in CT26 tumor-bearing model of anti-CTLA4 therapy.

CTLA4 blockade modulates Th17-related encoding genes in TDLNs, including Rorc, Il17a and Il6.

RT-qPCR analysis of key immune markers encoding genes in CT26 tumor-bearing model of anti-CTLA4 ...

In vivo efficacy and profiling of anti-tumor immune response

  • Standard package: Tumor growth, body weight and survival are monitored 3 times per week in experimental groups of standardly 10 mice, including groups treated with test compound alone and with anti-CTLA4 combination therapy.
  • Immune profiling package: Satellite mice (N=4) can be added to each group to evaluate the immune cell response and study how cancer therapies perform in terms of tumor-host immune interactions, at the tumor site and in peripheral compartments.
  • Quantitative multiplex immunological analysis: validated immune markers (eg. CD4, CD8, FoxP3, CD11b, Gr1, …) can be analyzed appropriately using either flow cytometry, RT-qPCR, and/or immunohistology-based imaging, to delineate the in vivo mechanism(s) of action of drug candidates.

Our added value:

  • Weekly progress reports: the first report is sent within 10 days following study initiation. Weekly reports enable to follow the progressively achieved data, in conjunction with the Sponsor, and to adjust if necessary the study design.
  • Longitudinal mice bleeding: blood samples can be collected every week, allowing the monitoring of peripheral markers overtime in responding and non-responding animals.
  • A unique anti-CTLA-4 glioblastoma model, in which brain tumor progression is monitored in live animals by bioluminescence imaging.