Researchers Are Developing Bispecific CAR Proteins to “Wake Up” the Immune Systems of Cancer Patients

Yvonne Chen, PhD, discusses some of the strategies that researchers are using to improve T-cell effectiveness and overcome immunosuppression in CAR T-cell therapy.

In an interview with Pharmacy Times at the Sixth International Cancer immunotherapy Conference (CICON) 2022, Yvonne Chen, PhD and Associate Professor at the University of California, Los Angeles, also breaks down the latest research from her laboratory, where she is engineering CAR proteins that can “wake up” the immune system.

Q: Have these next-generation CAR T-cells proven beneficial to targeting specific treatments?

Yvonne Chen, PhD: I think in recent months, we finally started seeing positive signal in solid tumors. So a very encouraging study had been published by a group at Stanford with Michelle Monje and Crystal Mackell, where they treated pediatric patients with the IPG diffuse midline glioma. They really have seen remarkable clinical response from the patients.

There's also emerging data on CAR T-cells targeting cloud in 6, cloud in 18.2. I think again, the responses are not quite as dramatic as we have seen in B-cell malignancies. But given that we're finally starting to see positive signals, I think there's a lot of room for both optimism and improvement.

I think some of the strategies that we have mentioned so far, as trying to improve T-cell effectiveness or effector function stemness, as well as ability to overcome immunosuppression, can likely be applied in combination so that we can engineer products that that can really be sufficiently potent to make a difference for our patients.

I think as we develop these different strategies, we tend to focus on one thing at a time, right? We develop CAR T-cells, and another group may decide to knock out, or knock in, this specific gene. But provided that one can implement these during the manufacturing process, there’s no reason why you couldn't combine these different strategies.

Of course, I think from a safety perspective, during clinical translation, we may have to do it one step at a time. But one can easily imagine the situation where you can combine a strategy that overcomes immunosuppression together with another strategy that promotes stemness and then generate a product, one that is both more capable of remaining functional in the tumor microenvironment as well as sustaining a prolonged, durable response.

I think it is important to keep in mind that a lot of these pathways are not fully orthogonal, as in they could have crosstalk and they could influence how each other functions. And so a combination is not always a straightforward thing like you know, like 1 plus 1 is 2. Sometimes they actually influence each other, sometimes synergistically sometimes in opposition. So I think the combination strategy requires a detailed investigation— but I imagine that will eventually be the path forward.

Q: Following the pandemic, what are you currently working on at your lab (Chen Laboratory)?

Yvonne Chen, PhD: My lab is, so far, primarily focused on CAR T-cell engineering, where my life is mostly biomolecular engineers. We really think about what's currently limiting the safety and/or efficacy of the CAR T-cell therapy, and what can we do to overcome these challenges.

A lot of our earlier efforts is focused on rational protein design on the CAR protein itself. We've engineered bispecific CARs that can hopefully reduce the probability of antigen escape because it can recognize two different antigens on the tumor. We focus on engineering CARs that can respond to soluble antigens like transforming growth factor beta (TGF beta). And now we're moving on to trying to find ways to engineer T-cells so that they don't have to do all the work themselves.

We talked about the problem of heterogeneity— tumor cells oftentimes don't uniformly express an antigen. And even though we can build bispecific CAR T-cells, one can even build trispecifics, or quads…I think these hardwired antigen specificities ultimately have a limit. And when you have highly heterogeneous tumors, I think the way to go is to engineer T-cells that can not only attack tumors themselves, but also engage endogenous immunity. And the idea is the T-cells go in, they do the frontline attack, but then at the same time send signals that pull in reinforcements from the endogenous immune system.

Now, the endogenous immune system naturally has a wide antigen repertoire. And the idea is if your T- cells can trigger the immune system to react against the tumor, we will have a better chance of attacking these highly heterogeneous tumors that are not all recognizable to our engineer T-cells. A lot of our ongoing effort is focused on figuring out how to engineer our T-cells to productively interact with endogenous immune.

CAR T-cells themselves still have limited antigen specificity. As I mentioned, we can build bispecifics, maybe even trispecifics and quads. But that's still 2 to 4 antigen recognition capabilities.

What we want to do is engineer these T-cells, even though they themselves have limited antigen specificity. Once they go into the patient, we want them to be able to induce immune response from the naturally occurring immune cells that we did not engineer.

The idea is you want to pull in this naturally occurring immune response with a much wider range of antigen specificities in order to make them reactive against the tumor. So, in a sense it’s waking the immune system up against a target that they don't normally recognize for a number of different reasons.