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David Grass
David Grass, PhD
The Jackson Laboratory

With the hope of uncovering the most efficacious and safe immunotherapeutics, scientists are working to understand the reasons for the observed patient-dependent successes. The discovery process is complicated by these fractional responses to approved therapeutics in this area. Because of this, most preclinical immuno-oncology studies lack real reference compounds.

Choosing the most optimal in vivo preclinical platform is vital for the development of antibody and other cellular therapies. GEN spoke to David S. Grass, PhD, General Manager, JAX Mice, Clinical & Research Services, at the Jackson Laboratory to get his perspective on the role preclinical in vivo models play in immunotherapy development.

How do in vivo models fit in with addressing the challenges in the field of oncology/immuno-oncology?

In reality, the challenge goes beyond oncology. Due to lack of efficacy or other reasons, 90% of potential therapeutic reagents fail in clinical trials. To develop more predictive platforms, we need to better understand how mice and humans differ in order to use genetic engineering in conjunction with cellular humanization to increase clinical translation. In vitro and in vivo models are complementary, and both have value. But in immunotherapy, the complex interactions between the immune system and the tumor make it difficult to simultaneously investigate all variables in a dish; in vivo systems can better model functionality to evaluate downstream results.

JAX’s ability to humanize components of the murine immune system allows assessment of both efficacy and safety. We are also genetically modifying models with intact immune systems to incorporate relevant human target molecules. Our direction is to create models more representative of affected subsets of the human population.

While the aim of drug development is to instigate tumor shrinkage, is there value in looking beyond just this one metric? How does JAX fit into this paradigm?

Tumor shrinkage is obviously the goal, but even if this does not occur, it is beneficial to assay for other aspects of success, such as tumor infiltration, any cellular activity, change, or effect that could point to future experimental design strategies as, for example, a combination approach. Imaging can also provide useful information about cells in the context of the tumor. JAX is working with collaborators to develop an immunophenotyping capability for evaluating our humanized mouse platform that allows deeper cellular characterization to tease out these effects.

There is a large variety of potential reagents, including checkpoint inhibitors, bispecific antibodies or reagents, and CAR-T cells with and without payloads. Our study directors seek to understand how compounds and biologics are designed and their mechanisms of action in order to develop optimized readouts for each preclinical study.

With the vast amount of information in this area growing rapidly, what does the future look like for oncology/immuno-oncology research?

At JAX, we want to provide improved tools and platforms to assist researchers and drug developers in evaluating their immunotherapy approaches. Many of our studies are performed with NSG mice humanized with CD34+ hematopoietic stem cells (HSCs). In general, this tends to be a T-cell-dependent model. By adding additional relevant transgenes on the NSG background, we have created models which amplify other diverse aspects of the immune system.

Each CD34+ HSC donor can only humanize a limited amount of animals. We are working to maximize this number to provide more flexibility in study designs. Human donor peripheral blood mononuclear cell (PBMC) batches are larger and can be used to produce more humanized mice, but may vary in response from one batch to another.

Another challenge with PBMCs, which are mature immune cells, is a much shorter window to see a therapeutic response due to a much quicker graft-versus-host response (GVHD). Using PBMCs to humanize a new genetically modified model from JAX (NSG MHC Class I/II KO) generally results in a longer therapeutic window prior to GVHD onset. In general, when we perform studies that require donor cell engraftment, we suggest the use of multiple HSC or PBMC donors to replicate human response variation.

 

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