Jennifer Specht:

So I’m Dr. Jennifer Specht. I’m a breast medical oncologist and associate professor at the University of Washington and Fred Hutchinson Cancer Research Center, and I’m delighted to be here in Tampa this weekend to be talking about advances in CAR-T cell therapy, particularly for solid tumors. And we’ve had a super exciting morning, I think really a lot of very exciting data presented.

Jose Conejo-Garcia:

Exactly. My name is Jose Conejo-Garcia. I work here at Moffitt Cancer Center in Tampa. I am the chair of the Department of Immunology and co-leader of the Immuno-Oncology Program. I work on understanding and targeting mechanisms of immunosuppression in cancer, and developing novel immunotherapies, including CAR-T cells, with an emphasis on ovarian cancer. So very exciting events this morning, good advances, and very good discussions in this.

Jennifer Specht:

Yeah, so I was excited to hear about some newer techniques, particularly the idea of using not just a typical SCFE antigen targeting, but the idea of using the entire hormone. I was really impressed with this notion and the work that you presented with the follicular hormone receptor.

Jose Conejo-Garcia:

Many thanks.

Jennifer Specht:

Yeah, I was wondering what other uses may be relevant for the CER-T type of technology as opposed to a typical CAR-T cell?

Jose Conejo-Garcia:

Yeah, thank you. We came to this approach basically because we couldn’t find a good antibody motif to be used to direct our CAR-T against the receptor of the FSH hormone, and eventually, we came to the realization that we couldn’t be better than millions of years of evolution in terms of sensitivity, and we also think that the use of an endogenous molecule could be perhaps superior to an artificial antibody that could be at some point recognized by the immune system, perhaps not. So, we thought about other approaches. The low-hanging fruit, we think, is thyroid cancer, for which we can also use the TSH hormone as a targeting motif. We have been thinking about other hormones, but the pattern of expression is more complicated because as you know, fantastically well, there are receptors in the brain. So the good thing about the FSH hormone is that the negative feedback does not work through the hormone itself. The receptor is not expressed in the brain, what the brain senses are estrogens, so we want to leave the patient without a hypothesis or something.

Jennifer Specht:

No, it’s a very interesting and a novel approach, that one could imagine could be utilized for other types of CAR targeting, given the nature and the relative rarity of the antigens that we’re trying to identify for solid tumors.

Jose Conejo-Garcia:

I think that we need all hands on deck and all approaches to get to the goal of making CAR-T work against solid tumors. But I was very impressed about your trials and the approaches that you are following, and especially the fact that you are targeting breast cancer, which is, with the exception of triple-negative breast cancer, is quite resistant to immune checkpoint blockade, and is considered kind of a cold tumor, and I am very impressed with the results that you are getting, and I think that’s super promising.

Jennifer Specht:

Yeah. I think that the major thought has been that our work with CAR-T in solid tumors globally has been not that impressive yet, but I think that honestly, the data that we’re seeing in our session from Dr Shah is really suggesting that we’re making some strides, and so this sort of notion that it only works for CD19 or BCMA in terms of CAR-T therapy, I think is really starting to be overturned, and that’s very, very exciting.

Jose Conejo-Garcia:

Yeah.

Jennifer Specht:

Dr Alsdorf’s work as well, with the response rates, was very, very impressive.

Jose Conejo-Garcia:

It was very impressive to me too. Especially the fact that the most durable response that they found, was in ovarian cancer, and I was intrigued. I mean, we don’t have unlimited time, but I wanted to ask him about how he infused the cells, I assume, intravenously, and that’s something that is under discussion in the field. We are running this clinical trial with the FSH’s targeted care, and we are having two cohorts: one with intraperitoneal administered CAR-Ts, and one with intravenously administered CAR-Ts, precisely to sort that question, because as an immunologist, I thought, well, if you put the T-cells where the target is, they won’t go anywhere, right? And the relative concentration is going to be higher. But when you talk to the gynecological oncologist, they don’t see it that way, and it’s not only our local gynecological oncologists. Everywhere they think that intravenous could be more effective because the metastasis happens hematogenously interestingly, and that’s something that I am really, really curious about because…

Jennifer Specht:

No, and I think it’s going to depend not only on disease type, where obviously with ovarian, intraperitoneal or with mesothelioma, local administration makes a lot of sense. In breast, we always tend to think about it as being such a systemic disease that the idea of trying to target a tumor seems more difficult, technically and otherwise. However, it may really depend on where the tumor is located, and one can imagine strategies in the future for particularly cold tumors, where perhaps you give treatments or local treatments to try to prime the tumor prior to infusing adoptive T-cell therapy to try to enhance that response. And maybe we’ll be able to be more elegant to really sort out the question of the IP versus the IV, and what other ways can we augment that response to keep the persistence. I think that was one of the things that I found most interesting about Dr Alsdorf’s work is that they were showing evidence of CAR-T persistence months later, which was quite impressive, and something that I’m a little jealous of, but I mean, we haven’t been able to see for a variety of reasons, and so I think trying to understand the difference between their product and the microenvironment that it’s being used in to try to really help us hone in on how we can optimize these therapies.

Jose Conejo-Garcia:

Excellent. And the other interesting question to me, and we saw this mornings some approaches to target that is how we can make these T-cells, how we can engineer them to make them more resistant to immunosuppression, maybe to metabolic restrictions, right, by targeting for instance, mechanism of ER stress that are subsequent to metabolic restrictions, how we can favor a tissue-resident memory differentiation, how can we make them better? I think that’s where the field eventually will go, right, as long as we have a specific target.

Jennifer Specht:

No, I agree. And I think that with CD19, it was somewhat of a perfect storm and that you had a really optimal situation to show proof of principle, and we’ve seen such dramatic responses with CAR-T therapy. And I think for most, every other solid tumor and for other diseases, it’s going to take a more nuanced approach, and so it’s just very exciting to see how we can identify all the barriers. But I think that the sessions that we were chaired in, the sessions that we’re seeing today have just shown how each group is sort of chipping away at those barriers and figuring out ways to overcome them, and that is very optimistic and gives us a lot of promise. It’s going to be more complicated, but that’s okay.

Jose Conejo-Garcia:

Totally agree. Yeah. Thank you very much. I think that these kind of meetings are particularly important at this time and bringing together scientists, and clinicians, and companies working on these technologies will move the field further, absolutely.

Jennifer Specht:

Absolutely agree. It’s really a privilege to have the opportunity, number one to get together again, as well as to have our colleagues join us virtually, and really exciting sessions looking at, from everything from the basic science to really the clinical applications. So I’m privileged to be here today and thanks very much for the opportunity.

Jose Conejo-Garcia:

Thank you.

Jennifer Specht:

Thanks.