A recent study led by researchers from the University of Illinois Urbana-Champaign suggests that CAR-T immune therapies may be effective against solid tumors if the appropriate targets are identified. The researchers successfully utilized CAR-T in a mouse model of ovarian cancer, which is a type of aggressive solid-tumor cancer that has previously been resistant to such therapies.
According to Diana Rose Ranoa, the first author of the study published in the Journal of ImmunoTherapy for Cancer and a postdoctoral researcher at the Carl R. Woese Institute for Genomic Biology at Illinois, “Even with an advanced stage tumor model, even with a single dose, we saw strong anti-tumor effects.” She also stated that there are still unanswered questions, but this study demonstrates that CAR-T can effectively eliminate this type of cancer once it identifies the correct target.
T cells, which are white blood cells in the immune system, are responsible for recognizing and attacking specific foreign invaders in the body. CAR-T therapies utilize special molecular receptors known as chimeric antigen receptors, which attach themselves to cancer biomarkers. These CARs enable a patient’s own T cells to target and attack the cancer within their body as if it were an external invader.
While CAR-T immune therapies have proven effective against blood cancers like leukemia and lymphoma, they have struggled to treat cancers that produce solid tumors, as explained by study leader David Kranz. Kranz, who is a professor emeritus of biochemistry at Illinois and associated with the Carl R. Woese Institute for Genomic Biology and the Cancer Center at Illinois, highlighted the difficulty in finding suitable targets for these receptors in solid tumors that do not exist in healthy tissues. Additionally, solid tumor cells have their own mechanisms to suppress the immune response and evade recognition by immune cells, making treatment even more challenging. The research community is actively working to overcome these barriers by identifying target candidates for CAR-T therapy and developing CARs capable of recognizing these specific targets.
In this study, the researchers focused on a carbohydrate found exclusively on the surface of solid tumor cells, but not healthy cells. They designed CAR molecules with varying affinities for this carbohydrate and evaluated their effectiveness first in ovarian cancer cell cultures and then in live mice with ovarian cancer tumors.
The researchers discovered that the receptors with the highest affinity for the carbohydrate were exceptionally effective in assisting T cells to locate and destroy the cancer. After administering only one intravenous or injected dose, these receptors were able to shrink or even eliminate tumors. Furthermore, their effects continued for months or even over a year after the initial dose, resulting in an extended lifespan for the mice involved in the study.
David Kranz noted, “We were surprised that the CAR-T treatment was able to do such a good job at regressing the cancer, not just because it did it for a long period of time, but because we administered the treatment at a late stage of cancer.” He mentioned that most studies in mouse models typically administer treatment shortly after introducing the tumor, while their study began treatment at a later stage similar to when it is typically diagnosed in human patients.
The researchers believe that these unique aspects of their study design could enhance the potential for clinical application in humans. Unlike conventional cancer trials in mice where human cancer cells are introduced into mice with compromised immune systems to facilitate the growth of foreign cancer cells, the study conducted in Illinois used mice with fully functional immune systems. Instead, they targeted a marker present in both mouse and human ovarian cancers.
Ranoa stated, “Setting up our model in immunocompetent mice allowed us to show how the CAR-T cells behave in the presence of an intact host immune system and to demonstrate that these CARs do not have toxic effects against healthy tissues. The treatment is very specific to the tumor.” She added, “And now we have this CAR that we’ve demonstrated can kill mouse ovarian cancer — and it has been engineered to recognize the same target in human cancers. So human studies are the logical next step for this line of research.”
The researchers plan to further test their CAR-T therapy on human cancer cell cultures and continue searching for other potential targets for solid-tumor cancers and the corresponding CARs that can identify them.
Kranz expressed his hopes for the future, saying, “In this mouse model, there was such potency that it can hopefully be translated to human patients. To have something so specifically targeting the tumor without major side effects for the patients is the holy grail.”