CAR T-cell therapies are the future of cancer treatment and Roswell Park Comprehensive Cancer Center is preparing to open a number of new trials based on research originating here and in partnership with the industry.
Marco Davila, Senior Vice President and Associate Director of Translational Research at Roswell Park, provides an overview of half a dozen new trials set to open in 2025, including a new treatment for patients with B-cell malignancies who have relapsed after an initial round of CAR T-cell therapy, targeting the CD19 antigen.
“What is interesting about this CAR, which is based on research from my laboratory, is it has a customized signaling domain in the chimeric antigen receptor,” Dr. Davila says. “My laboratory has demonstrated that this co-stimulator domain is more resistant to exhaustion inducting stimuli, so based on our research, we anticipate these CAR T cells will expand and persist longer in patients. We’re going to investigate that in a phase 1 clinical trial for patients at Roswell Park who have various B cell malignancies,” including patients who have relapsed or progressed after CAR T cell therapy or patients not eligible for other CAR T cell products.
This trial, along with one targeted the CD83 antigen, are first-in-human trials opening only at Roswell Park. Other trials expected to open this year will test treatments for solid tumor cancers, including ovarian cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, gastrointestinal malignancies and breast cancer, among others.
My name is Marco Davila. I'm the senior vice president of translational research. I'm also a physician scientist in the transplantation and cell therapy service at the Roswell Park Comprehensive Cancer Center in Buffalo, New York. Today I'm gonna be speaking about the innovative cell therapy trials, uh, that we are developing here at Roswell Park, uh, based on research from our investigators at Roswell Park or in partnership with pharmaceutical companies. Starting in malignant hematology, we have. A few cell therapy trials that aren't developed. The first is one that is being developed by Doctor Betts, uh, Brian Betts, who is our vice chair, um, in the department of medicine. Uh, he and I both developed a CAR targeting CDD3 which is expressed on acute myeloid leukemia. We're, uh, very excited that this should be open by summer of 2025. It's gonna be available for patients. With AML or high risk MDS, um, that has relapsed after initial treatment. A second cell therapy for malignant hematology that is developed based on our research is targeting the CD-19 antigen on B cell malignancies. What is interesting about this car, which has been, uh, based on research from my laboratory, is it has a customized signaling domain in the chimeric antigen receptor. So my laboratory has demonstrated that this co-stimulator domain is more resistant to exhaustion inducing stimuli. So based on our research, we anticipate that these CAR T cells will expand and persist longer in patients, and we're going to investigate that in a phase one clinical trial for patients at Roswell Park that have uh various B cell malignancies. This will include. Patients that have relapsed or progressed after CAR T cell therapies or those patients that are not eligible for a CAR T cell clinical trial or CAR T cell standard care product. The two clinical trials that um are targeting AML uh via CDA3 and CD-19 with the optimized cost inventory domain are essentially first in human trials. Um, CDD 3 has not been investigated as a cell therapy target or. Even an antibody-based target in clinical trials. So this is something that is really novel. They're gonna be open and available only at Roswell Park. The need for innovative and efficacious cell therapies is really in solid tum malignancies, and this includes uh technology that's based on research from Roswell Park, but also that is being developed, um, with our industry partners. So from the laboratory Doctor Brinins, we have a CAR T cell that he is developing that targets the MU 16 antigen on ovarian cancer, as well as some bladder cancer. Uh, this will be a phase one clinical trial for patients with uh relapsed refractory ovarian cancer. What is novel, um, about this technology is that the CAR T cell is also a gene engineered to express a cytokine. What this cytokine endows the T cells with is the is the ability to be able to resist a very hostile tumor microenvironment. The first iteration. CAR T cells and solid tumor malignancies really didn't work in looking at the clinical trials, the science behind this, we believe that's because the tumor microenvironment basically is suppressing the CAR T cells. So Doctor Brintons had a great idea to armor these T cells with a cytokine to make them counter, um, those suppressive measures, um, that are present in tumor microenvironment and this will. Another first in human uh phase one clinical trial that's available only at Rosa Park, and this is being developed in partnership with a company that has a very innovative technologies to be able to identify new binders very rapidly for tumor antigens. So this is one that we're hoping that will be open um by the end of the 2025 calendar year. Another similar co-developed car product that is spinning out of Roswell Park Labs is targeting the GPC-3 antigen on hepatoma or hepatocellular carcinoma. This is being done in collaboration with a company. This, um, antigenine targeted GPC-3. In the edit that's being introduced in the cell to enable it to resist the tumor micro environment is the deletion of the TNFR2 genes. The idea behind this technology is that the CAR T cells will not be able to bind the suppressive cytokines, so they'll essentially be able to ignore the signal from the tube from micro environment to be suppressed. We believe it will be open for patients with hepatocellular carcinoma. Summer of this year, a clinical trial that will be also available only at the Roswell Park Cancer Center. We are also opening clinical trials that have been developed by cell therapy companies. They're able to work with essentially some of the inventors of CAR T cell technology, as well as the robust cell therapy service that has been developed by Doctor Betts as well as myself. These include clinical trials. Targeting breast cancer, this is, um, innovative cell therapy technology, a protein that targets breast cancer that that protein when it buys a breast breast cancer is engaged by a car-like protein on a T cell, and that leads to activation of the of the T cell and killing of of the breast cancer. That's one that will be opening in 2025 for patients with relapsed refractory breast cancer. Um, that's gonna be a multi-center trial in Roswell Park be, um, one of the sites, uh, opening that clinical trial. Another, uh, clinical trial that we'll be opening is, uh, one that targets the CD70 antigen on renal cell cancer, and this is a multi-center uh clinical trial, and the reason we are interested in this technology is because it's called an. Off the shelf cell therapy product. So meaning that the T cells aren't extracted from patients and gene engineered off site, the cells are actually collected from a healthy donor and engineered to target CD70 antigen. They make a huge, um, volume of this product and basically ship allros of the products to the patients. So, the off the shelf cell therapy team being engineered here is a gamma-Delta T cell. So the gamma-Delta T cells are engineered to target CD70. So some benefits to gamma-Delta is that um they are not all reactive, so we don't have to engineer out the TCR. Um, to prevent alloy activity, also they have, um, inherent anti-tumor activity already, so we think that in addition to the CD70 target there's gonna be the ability for these T cells to be able to potentially kind of kill tumor cells independently of the CD70 car. So that's one that is currently going through our uh protocol review process and hopefully we will be opening in 2025 for patients with renal cell cancer. A clinical trial that we have open right now is for patients with um GI or gastrointestinal malignancies that express clot in 18.2. It is a second generation car that targets um this protein that's commonly expressed in GI malignancies such as gastric cancer. And so that is currently open and available for patients. It's a. Multi-unal trial. Arousal Park is one of those sites. We've already enrolled, um, a couple patients on this trial, um, and it is available for patients with GI malignancies such as gastric cancer that are clouded 18.2 positive. That's a small selection of cell therapy trials that are open now or soon to be open at Roswell Park. If you think you have a patient that's eligible for a trial, if you want to talk about potential trials for your patients, be very happy to discuss that with you and be partners in the care of your patient.
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