Enabling Wider Antigen Selection With Logic-Gated CAR T-Cell Therapy for Solid Tumors
Maria Pia Morelli, MD, PhD, assistant professor, MD Anderson Cancer Center, discussed her work on the EVEREST-1 trial of logic-gated CAR T-cell therapy currently being evaluated in colorectal and pancreatic cancers.
A2 Biotherapeutics has developed the A2B530 CAR T-cell therapy with its logic-gated T-cell therapy platform (Tmod) with the goal of addressing common safety issues that have largely barred the use of chimeric antigen receptor (CAR) T-cell therapy in solid tumors. In particular, antigen targeting is more difficult with solid tumors compared with hematological malignancies. A2B530 allows for the selective elimination of CEA-expressing cancer cells that have permanently lost the HLA-A*02 gene and is being evaluated in the phase 1 EVEREST-1 clinical trial (NCT05736731).
CGTLive spoke with Maria Pia Morelli, MD, PhD, assistant professor, department of gastrointestinal (GI) medical oncology, division of cancer medicine, MD Anderson Cancer Center, The University of Texas, who serves as a principal investigator in the EVEREST-1 trial, to learn more about her work on the trial and potential applications of Tmod technology.
What are some challenges when it comes to selecting targets for CAR T-cell therapy?
Maria Pia Morelli, MD, PhD: The first question when selecting a target is, is it safe and is it widely expressed to really trigger the response that you're looking for. Now, if we think about CAR, CARs are different than TCR because CAR is almost like an antibody construct that is binding a specific antigen that is expressed on the cancer cells, but these antigens are often also expressed on healthy normal tissue. So, one of the main concerns is that yes, we are targeting a valuable target, but what is the on-target off-cancer side effect?
What is a strategy you are working on to address these challenges?
Morelli: To answer this question, we have a clinical trial with a CAR-T that is targeting CEA, which is widely expressed in both colorectal and pancreatic cancers. In fact, we’ve used CEA as a tumor marker for those diseases.In the past, this target has been explored in another trial, but the main concern was that the highest dose started to show some kind of therapeutic effect, but we started to see side effects because CEA is also expressed on healthy tissue. Severe diarrhea was probably one of the most significant side effects that compromised the development of this type of product.
So to get around this issue, we have a product that actually has a logic gate that basically exploits a specific characteristic of the cancer, loss of heterozygosity (LOH). So basically, in the BASECAMP-1 and EVEREST-1 trials, we screen our patients for their HLA, which is something that is very specific to each person.Since cancer cells usually have LOH, A2 Bio has developed a beta blocker for it. So basically, you have a CAR-T that with one arm is able to bind the CEA that is expressed on the cancer cell, so recognizing the cancer cell and triggering all the activation of the T-cells, but at the same time as a blocker recognizes the HLA expression on the normal cells. So it will prevent those off-cancer, on-target side effects. And EVEREST-1 is a multicenter trial we have opened here; we’ve already treated several patients, so stay tuned for more data. It's enrolling in both colorectal and pancreatic cancer. So this is a very valuable technology because, eventually, it can apply to more different targets and become definitely like a wildly clinical application.
What are some potential future applications with logic-gating?
Morelli: The idea of having this blocker, this gate, this can help to expand the number of targets that you can actually use. Like CEA is widely expressed in colorectal, pancreatic cancer, lung cancer and ovarian as well. But now we're working on mesothelin which has always been very appealing as a target. Many groups have been working on mesothelin as a CAR, and unfortunately it has some side effects because mesothelin can also be expressed on pleural healthy tissue and peritoneal healthy tissue. In this case, because of the blocker, we can actually use it, and if you think about mesothelin expression of ovarian cancer, lung cancer, pancreatic cancer, mesothelioma, peritoneal malignancies- there is really a wide range of applications for that.
So, we've already opened EVEREST-1 which is targeting CEA, and we are in a process of opening EVEREST-2 that is targeting mesothelin. So, there’s more and more targets that we can use thanks to the presence of this blocker that really increases the therapeutic window, meaning we can give higher dose of cells to increase the activity without having to worry about severe side effects that can actually be life threatening in some situations. So, it’s very exciting.
We are definitely also expanding the HLA library, which is something very important. HLA-A*02 is one of the most expressed types in the population but definitely doesn't cover everyone. So, we’re definitely working on increasing that range.
