Researchers at the UPMC Hillman Cancer Center Tumor Microenvironment Center developed a new model that can be used by immunologists to further the understanding of CAR-T cell biology and identified a new possible human CAR-T cell target.
The model published in the journal OncoImmunology, is a fully murine CAR, or chimeric antigen receptor, which has been scarce despite its significance in cancer therapies. Due to the similar genomic and physiological characteristics of tumor biology in mice and humans, murine models for human cancer research are extremely useful.
In the field of immunotherapy, the modeling of CAR-T cell therapies has traditionally focused on immunodeficient models. Most of the field uses human CAR-T cells in immunodeficient mice, but there are advantages in studying CAR-T in an immune-competent setting.
“CAR-T cells interact with other immune cells in the microenvironment so studying them in isolation in an immunodeficient animal is not similar to what happens in a patient,” says Konstantinos Lontos, MD, a hematology/oncology fellow at Pitt at the time of publication (now at MD Anderson Cancer Center).
The most widely used tumor model in immunology research is B16 melanoma — a murine tumor cell line. Prior to this work, there were no available fully murine CAR-T cell models that targeted B-16 melanoma directly. The lab sought to find a suitable target in a fully murine model.
“We were inspired by the fact that we had been using antibodies to endoglin, or CD105, to magnetically deplete B16 cells from our tumor preparations,” says Greg Delgoffe, PhD, senior author of the study. “Could this be a decent target?”
CD105 is a component of the TGFb receptor on the surface of solid tumors and acute leukemias. CD105-targeted CAR-T cells can be grown from murine backgrounds, tracked in vivo, and be activated by CD105 in isolation or expressed by tumor cells.
While CD105 is a decent tumor target, it is not without fault. In lymphodepleted animals, large doses of T cells can lead to toxicity consistent with cytokine release syndrome — a potentially life-threatening toxicity associated with elevated levels of cytokines. To alleviate the toxicity problem, researchers reduced the doses and found that decreasing the CAR-T cell dose by nearly 150%, the mice no longer suffered from toxicity.
After determining the safety of the dose, researchers evaluated the efficacy of CD105-targeted CAR-T cells. They observed a significant reduction in tumor growth after injecting the mice with the lower dose of CAR-T cells, doubling survival.
These promising results pave the way toward a human CAR-T product. There are several solid tumor and leukemia cell lines that express CD105, and other research supports that CD105 is frequently expressed in acute myeloid and lymphocytic leukemias as well as in solid tumors and tumor vasculature.
NSG mice cohorts with melanoma tumors or acute myeloid leukemia were treated with 10 million human CD105-targeted CAR-T cells or mock-transduced human T cells. The human CAR-T cells slowed the growth of both cancers, leading to prolonged survival in both groups. This suggests that not only is CD105 a useful target for understanding the function of CAR-T cells in murine models, but also a potential target for human CAR-T cell treatment.
“While there’s so much left to do, we are thrilled to have a model CAR that can help to answer existing questions in the field of immunotherapy and ultimately help to develop more effective cancer treatments,” says Dr. Delgoffe.
Learn more about the Tumor Microenvironment Center at UPMC Hillman Cancer Center.
Reference
Lontos K, Wang Y, Colbert M, Kumar A, Joshi S, Philbin M, Wang Y, Frisch A, Lohmueller J, Rivadeneira DB, Delgoffe GM. Fully murine CD105-targeted CAR-T cells provide an immunocompetent model for CAR-T cell biology. Oncoimmunology. 2022 Oct 18;11(1):2131229.
Written By: Annaliese Daniels
Reviewed By: Greg Delgoffe and Konstantinos Lontos
