CTA: Is there anything else that you wanted to mention about CAR-T in solid tumors?
Dr Marasco: In general, I think this is an evolving technology, and it has a number of scientific hurdles, the most obvious being that these epithelial and related solid tumors, generally, have tumor-associated antigens that are overexpressed in tumor cells, but also [are] expressed at lower levels on healthy cells. So, the problem has been that if you go for a tumor — an antigen on the surface of the tumor cell that’s overexpressed — you’ve got to be very careful not to kill healthy cells.
The issue with CAR-T cells is they are very potent, which leads to some of the adverse side effects that are mentioned in one of the links that you [sent]3 on the nonrelapse mortality associated with some of these therapies. So, to be able to check that box to eliminate that toxicity is an important starting point that I think a number of companies are working on, including our laboratory, and we have certainly done a fair amount of designing CAR-T cells to able to have this in mind right out of the gate.
And, I will tell you, having been in this field for close to 30 years as a therapeutic human antibody drug developer, the technology and the benchmarks that we need to use to be able to achieve this are very different from that which is required for developing monoclonal antibody therapy. It’s taken some time to realize that, but with that realization, I think we’re now in position to really make headway [in] taking care of that particular problem, which is to decrease on-target/off-tumor toxicity. That’s point number one that I think is encouraging, and it will help propel the field further.
The second point is that we have, now, [technologies] that allow us multidimensional, or multiparameter facts analysis in invasive chemistry, to be able to look at the tumors in great detail at the molecular level; to find out exactly what they’re doing there. So, it’s clear to me, having done this both in patients and animal models, that the tumor microenvironment is different for different tumors.
So, if one understands that — and this is where our technology comes in — we can tailor the therapies to be able to target that tumor microenvironment. And, I don’t mean, necessarily, at the individual patient level, I mean at the tumor level.
Triple negative breast cancer has a particular public signature, which is different from other breast cancers, or other tumors, and if we can understand that in greater detail, we should be able to develop these CAR-T cell therapies that are highly effective at changing the tumor microenvironment in that particular tumor.
So, if one can do that, and then all these kinds of horns and whistles that are being developed, including the work in the Ma et al. paper as an example of, using the CAR-Ts for vaccine enhancement, I think we can go a long way to be able to get solid tumors under control.
We’re at a point now where I think that tumors are curable if we can be persistent in our efforts to understand this and improve the therapies, and I’m very excited about the CAR-T cells field for a number of reasons, not the least of which is, if you do this right, these cells can persist for years. And therefore, you’ve created an immune surveillance system against the tumor that helps keep them in check.
So, it’s not just a drug, it’s part of your immune system, and its result of that, I think we can get durable immunity, and that’s the reason I’m working on it, and the goal of our laboratory.