Jen: There are many different assays and model systems, and it’s really hard to describe everything. Generally, you can model that cancer-immunity cycle or parts of it in vitro and in vivo, which depends on the biology of the target and the therapeutic being assessed. You have to kind of design your assays and investigations based on those key points.
When we are using in vivo systems, for example, then ideally a fully functional immune system would allow the whole cancer-immunity cycle to be assessed, and the endpoint would be tumor killing to demonstrate efficacy. These systems can include genetically engineered mouse models where tumors arise as a result of engineered oncogenic drivers, or syngeneic or homograft models. The tumor develops over time in these models, and so they can then grow and avoid immune surveillance.
“Any successful therapeutic intervention will result in that tumor reduction.”
Then, we can take samples at different stages from that study and look at tumor infiltration or cytokine release to see whether that response has worked or why it might not have worked. We do have to address the limitations of these systems. I think the biggest limitation is that we’re looking at murine-based biology with these models, so any hypothesis that we may generate from studying and using these models needs to then be translated into the human system.
“We still need to have further investigation into humanized systems.”
Again, this is possible with in vivo models, but is very complicated and time-consuming. We have to have alternatives. I think this is where in vitro systems really come into their own. We can do in vitro human systems as well, so you can overcome some of those limitations and really break down the cancer-immunity cycle so that you can look at different stages as well.
Gera: I totally agree with you, Jen. Indeed, you can really analyze more specific parts of the cancer-immunity cycle with in vitro assays instead of just looking at the overall complexity of the whole system in vivo. In vitro systems allow you to work with the human system, and you can incorporate the immune compartment in perhaps a better setup than within some of the mice models.
Additionally, in vitro models allow for higher throughput screening. If you would like to test combinational effects or different doses of your therapeutic compounds to optimize their efficacy, that’s really something that can be addressed with in vitro systems. For example, it can be done in 2D cell cultures, but those are just really high throughput solutions and can give you some simple answers, I would say. If you go to a more complex system with 3D cell cultures or incorporating organoids or patient tissue, that would really add a higher value for clinical translation.
“Assays can really bring [you] a step closer to clinical trials.”
Jen: These systems really work in concert, don’t they? They really do help support, so you can go back and forth as well and dive deeper into the different questions. Certainly, I think combinational effects is a very good example because you just can’t simulate all the different combinations in vivo as effectively as you can in vitro.
In vitro models really help reduce the number of animals we’re using in the end, and then also help us decide which ones to take forward and which to investigate further. Some of the technological advances as well, such as 3D modeling, have taken it a step closer to being more relevant.
“As technology and techniques improve and get better, we get better at modeling cancer.”