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GEN: How has the area of immunotherapeutic research changed in the last five years?
Rose: The first five years of the last decade were the years of the checkpoint inhibitor, the cancer vaccine, and the oncolytic virus. The last five years have focused on the development of bispecific antibodies and chimeric antigen receptor cells. For example, the initial CAR-T cell therapeutics focused largely on disseminated tumors—engaging them directly in the bloodstream. Since then, we have seen an uptick in groups using their CAR-T cells to target solid-tumor, patient-derived xenograft—PDX—models in breathtaking proof-of-concept efficacy experiments. Drug developers are also expanding CAR’s beyond T cells and focusing on other cytotoxic cells like NK cells.
Furthermore, researchers have been exploring the combinatorial approaches using these biological therapeutics. For example, bispecific T-cell engagers, or BiTEs, have also shown immense promise. At The Jackson Laboratory (JAX), Dr. Jim Keck’s product development team showed that a CD3-EGFR BiTE can eliminate human cell line and PDX tumors in the context of both CD34+ hemopoietic stem cell and peripheral blood mononuclear cell, or PBMC, humanized mice. Plus, the CD3-EGFR BiTE was effective even after the mice had large tumors.
While these therapies have shown tremendous promise, their increased therapeutic potency can lead to adverse effects. With the Phase I failure of the TGN1412 CD28 superagonist, cytokine release syndrome (CRS) has become a significant consideration for biologics. Scientists want to minimize CRS in therapeutics, treat it when it arises, and use the right models to assess it earlier on in the drug development process.
GEN: How do animal models fit into immunotherapeutic development?
Rose: Many drugs, due to their biological nature, are difficult to assess in a common mouse model for several reasons: the target is not present, antibodies develop to the therapeutic, the mechanism of action is not relevant with mouse cells, etc. This has led many researchers to the human CD34+ and PBMC humanized immune system platforms. This allows researchers to target specific human immune cells more effectively.
A major development has been the humanized PBMC cytokine release syndrome platform at JAX. Drugs like TGN1412 can make it to clinical trials because the in vitro and primate models have proven unreliable in effectively identifying potential toxicity. Dr. Keck and his team have created a unique in vivo platform that evaluates biological therapeutics for efficacy and CRS-induced toxicity in 11 days. It allows for assessment of cytokine release in a biologically relevant context, allowing analysis of immune cell phenotype, tumor cell clearance measured by in vivo imaging, clinical scoring of toxicity in the mouse, and more. There is evidence that this platform would have preclinically detected the CRS-induced toxicity observed with TGN1412 and potentially other drugs currently moving toward clinical trials.
GEN: What services does JAX offer for the immunotherapeutic development pipeline?
Rose: In the discovery stage and lead identification, JAX offers genetically engineered mice to study a therapeutics’ mechanism of action, as well as syngeneic mouse cancer models for efficacy assessment. In lead selection, there’s humanized neonatal Fc receptor (or FcRn) models for pharmacokinetics, the CRS assay for combined efficacy and toxicity, and the PBMC humanized NSG-MHC I/II DKO mice for early-stage efficacy. Preclinical development products include CDX and PDX models, PBMC, CD34+ humanized mouse models and more. In short, we have drug developers covered.
GEN: What does the future have in store for this area and the role of animal models?
Rose: The most exciting thing is the possibility of using these platforms to catch potential toxicity from biologic therapeutics. Traditionally, the only other platforms are in vitro assays and nonhuman primates—both of which have significant downsides that a CRS mouse model might overcome or augment. Over the next few months, we will be working on refining and expanding on our product and service offerings to help the global research community bring more efficacious treatments to patients.
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