The dawn of chimeric antigen receptor (CAR) T-cell (CAR-T) therapies ushered in a period of intense medical innovation. Despite this, researchers are still struggling with translating the success seen with CAR-T in hematologic malignancies into the area of solid tumors.
Wayne Marasco, MD, PhD, professor in the department of cancer immunology at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School, is investigating the use of CAR-T in triple negative breast cancer (TNBC) and ovarian cancer. His lab, in collaboration with the Dana-Farber Cancer Institute, entered into an exclusive option with OncoSec for the company to license the product candidates and the associated intellectual property resulting from the research coming out of the Marasco lab “using engineered single-chain variable fragment (scFv) antibodies in a dual-targeted bispecific CAR T-cell approach.”1
His interests include marrying stimulatory cytokines and anti-inhibitory antibodies to break through the hostile tumor microenvironment that exists in solid tumors. To do this, he envisions using the local delivery of CAR-T cells to restore local antitumor immunity in the tumor microenvironment, and then allowing educated T cells to get out of the tumor cells so they can contribute to a systemic immune surveillance system that may help cells throughout the body persist against cancer for the long term.
Cancer Therapy Advisor sat down to speak to Dr Marasco to find out if he thinks CAR-T therapies should be categorized as cell or gene therapies, the feasibility of the approaches that can be used to deliver CAR-T payloads, and how dual-targeting CAR-Ts could be the one of the most durable options across adoptive cell therapy approaches.
This interview has been lightly condensed and edited for the purpose of clarity.
Cancer Therapy Advisor (CTA): I’m curious about the use of a vaccine boost with CAR-T — there’s new research that’s been out with other teams that combines the 2, and I was wondering how that works and if you could explain it.
Dr Marasco: So, first of all, I haven’t made it through the Ma et al. paper2 in great detail … Let’s just talk about the big picture, and that is that CAR-T cells can deliver payloads.
What may not be evident from what you’ve read from the press releases,1 and the internal information, is that we have designed CAR-T cell factories. So, they’re not just CAR-T cells, the whole basis of the work that we do is deliver payloads. So, the CAR-T cells not only get to the tumor in an antigen-specific way — and that’s where the dual targeting comes in — once they get there, they secrete molecules locally, at the tumor site, to change the tumor microenvironment.
In the case of the vaccine boost, it’s really that concept that you’re allowing molecules get to antigen-presenting cells to be able to boost the local immunity there. So, I haven’t been able to get through the paper in detail yet, but that’s, basically, the 64,000-foot view of what they’re trying to do.
So, the idea of using CAR-T cells to deliver payloads, and to change the tumor microenvironment is inherent in the approach that is now published in this vaccine paper, as well as the work that we do, which is to change the tumor microenvironment in a different way — the end result being restoration of immunities so that educated T cells that get to the tumor, that can’t do anything because they are suppressed, become unsuppressed, if you will, and restore local antitumor immunity.
CTA: Based on the press release that I read [about the partnership with OncoSec, The Marasco Laboratory, and the Dana-Farber Cancer Institute], some candidates were mentioned in that release. Could you share which ones they are?
Dr Marasco: We’re not releasing the targets yet because the work is still fairly early on, and we don’t want to disclose what the actual targets that we’re doing are. The diseases that we’re looking at, I think, are fair game, and to that question, that’s triple-negative breast cancer, as well as ovarian cancer, which was not mentioned in the press release, but that’s the other cancer that we’re working on for the team — so, 2 womens’ cancers.
CTA: There was a mention of the [use of OncoSec’s] intratumoral TAVO IL-12, that would help facilitate getting the actual engineered CAR-T cells into the tumor microenvironment. How does that work, and also, how does that keep them persistent in that microenvironment?
Dr Marasco: So, the data (OncoSec’s and the science that led to it) really show that IL-12 is a pretty potent cytokine to enhance T-cell stimulation, and I think the fact that they’re getting the clinical responses that they are shows that it’s working when injected locally — perhaps systemically, but certainly locally. So, the idea there is that that, in and of itself, is changing the tumor microenvironment.
The limitations of it, of course, are that it’s a plasma-based therapy, so that when you do your local electroporation, you’re getting the IL-12 gene taken up by the cells that are being electroporated, secreting that locally, that’s enhancing the entire local immune system, including recruitment of white blood cells. And to an extent that’s not totally worked out, because we just don’t have enough data yet to carve it in stone, is that they’re also changing the tumor microenvironment. So, the concept here is that whatever boost that we can get in the tumor microenvironment to be able to let those CAR-T cells work more potently, would be an added benefit.
So, for example, in our case, the work that we’ve published so far has looked at the PD-1/PD-L1 axis by secluding anti–PDL-1 locally at the tumor site. So, we know from many clinical trials now that that is certainly 1 of the keystones in the tumor microenvironment, that particular axis, but it doesn’t work 100% in patients, and it varies depending on the tumor, and a number of other factors. So, PD-L1/PD-1, and CTLA-4 are 2 of the cornerstones in that they, in themselves, may not be enough.
So, those 2 axes that have led to the whole breakthrough in the field, are really to put on the brakes of suppressive molecules. They’re not costimulatory; they’re blocking inhibitory pathways. So, when you look at the tumor microenvironment, and the whole way T cells get stimulated, there’s a number of molecules that suppress T-cell stimulation, and there’s a number of molecules that stimulate it. So, with therapy support, you only gain reverse in suppression. So, the idea of IL-12 is that it would be stimulatory.
If you combined a stimulatory cytokine, with the correct T cell that’s secreting anti-inhibitory antibodies, you may be able to get marked change in the tumor microenvironment, and therefore lead to a significant increase in T-cell simulation. So, that’s the idea between marrying the 2 therapies.