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Martin O’Rourke, PhD, is senior director, Oncology In-Vitro Biosciences, Integrated Drug Discovery at Charles River Laboratories.
The combination of translatable in-vitro and in-vivo assays, coupled with expertise in immunology and oncology helps facilitate the progression of novel oncology therapeutics from hit identification to investigational new drug submission.
In early drug discovery, comprehensive characterization of compounds can provide insights that improve efficacy downstream. These early-stage platforms are a crucial bridge that support a candidate’s transition from the bench to clinic. This translational research generates information on compounds from each stage of the drug-discovery process to inform and progress therapies rapidly from in-vitro assays to in-vivo studies and, ultimately, successfully to patients.
Using in-vitro assays, researchers can establish a translational immuno-oncology platform with the capability of progressing biologics or small-molecule modulators of immune response from in-vitro to in-vivo. Immuno-oncology therapeutics embrace modulation of the immune system to recognize and target tumor cells for destruction, either by increasing the function of the immune system or preventing the evasion of tumor cells from it. The evolution of tumors to suppress the immune system, as well as maintaining a suppressive micro-environment, has hindered drug efficacy and restricted the regression of tumor masses. However, once these mechanisms are clearly understood, this complexity presents many known and novel targets for drug discovery.
Translational research typically starts by screening compounds in simple cell-based assays to determine the modulation of immune activity or responses: for example, the changes in the number of immune cells to fight immune evasion, or the amount of cytokines released by the immune cells, which raise immune reactivity to produce an anti-tumor response.
Through these simple assays, compounds are identified for further characterization in more complex co-culture assays, such as mixed lymphocyte reactions, T-cell invasion, antibody-dependent cellular cytotoxicity, and complement-dependent cytotoxicity. These multicellular in-vitro assays can bridge the gap from single cellular functional screening to in-vivo models by providing a predictive model to help compounds progress further in the pipeline. These multi-cellular assays, like the simpler immune cell assays, are validated with standard-of-care molecules, including checkpoint inhibitors and a selection of small-molecule inhibitors of targets known to modulate immune responses.
A translatable immuno-oncology platform enables oncology researchers to rapidly assess the immune modulatory function of therapeutic modalities in high-throughput platforms, and the use of in-vitro assays illustrates T-cell activation, increased proliferation, and cytokine release. The combination of translatable in-vitro and in-vivo assays, coupled with expertise in immunology and oncology helps facilitate the progression of novel oncology therapeutics from hit identification to investigational new drug submission.