A recent preclinical study suggests that enhancing CAR T cell therapy against various cancers, including solid tumors, could be achieved by using CRISPR-Cas9 technology to eliminate the CD5 protein found on the surface of T cells. This study was conducted by researchers at the University of Pennsylvania’s Perelman School of Medicine and Abramson Cancer Center.
CAR T cells are specialized T cells designed to target specific markers on cancer cells. While these cells have shown success in treating blood cancers, they have been less effective against solid tumor cancers like pancreatic cancer, prostate cancer, and melanoma. Scientists have been exploring ways to enhance the performance of CAR T cell therapy.
The study, published in Science Immunology, indicates that removing CD5 could be a promising strategy. Researchers revealed that CD5 functions as a potent immune checkpoint, limiting the effectiveness of T cells. Eliminating CD5 significantly improved the anticancer activity of CAR T cells in various preclinical cancer models.
According to senior author Marco Ruella, MD, deleting CD5 enhanced the function of CAR T cells against multiple cancer types in preclinical models. This suggests that CD5 knockout could be a universal approach to boost CAR T cell function.
Understanding Immune Checkpoints
Immune checkpoint mechanisms regulate immune responses to prevent excessive reactions that could harm healthy tissues. Cancer cells often exploit these mechanisms to evade the immune system.
Scientists have identified key immune checkpoint proteins such as PD-1 and CTLA-4, which have been targets for successful immune checkpoint inhibitor therapies. While ongoing research explores deleting these proteins to enhance CAR T cell therapies, other undiscovered immune checkpoint mechanisms exploited by cancers are also being investigated.
Targeting CD5
Initially focusing on CD5 as a potential tumor target, researchers discovered that CD5 is highly expressed on cancerous T cells in specific blood cancers without effective immunotherapy options. Creating CAR T cells that targeted CD5-bearing cancer cells led to the realization that deleting CD5 in CAR T cells was crucial to prevent internal cell destruction. By using CRISPR-Cas9 technology to delete the CD5 gene, researchers observed a significant improvement in CAR T cell effectiveness against various T-cell cancers in lab experiments.
Furthermore, CD5 deletion not only enhanced CAR T cells’ impact on liquid cancers but also on solid tumors. When tested on non-CD5-bearing cancer types like B-cell leukemias, lymphomas, pancreatic cancer, and prostate cancer, the CD5-knockout strategy resulted in increased proliferation, survival, and cancer-killing activity of CAR T cells, surpassing the effects seen with PD-1 deletion. The study demonstrated that CD5 knockout could enhance the anticancer activity of other T cells, underscoring its importance as an immune checkpoint protein.
The research detailed how CD5 deletion enhances genes related to T cell activation and cancer cell killing, with low CD5 expression in T cells associated with better patient outcomes according to tumor biopsy data analysis.
Upcoming Clinical Trials
A Phase I clinical trial involving CD5-knockout CAR T cells will soon enroll patients with CD5-bearing T-cell lymphomas. If proven safe and effective, this strategy could be extended to a wider range of cancers. Researchers are eager to transition this work from the laboratory to clinical settings.
For additional information about cancer clinical trials at Penn Medicine, visit the Abramson Cancer Center Clinical Trial Information Service website or call 1-855-216-0098 to connect with a clinical trial navigator.
The research received support from various organizations, including the National Institutes of Health, National Cancer Institute, and other foundations and institutes dedicated to cancer research.
Editor’s Note: The lead author has affiliations with ViTToria Biotherapeutics, and the University of Pennsylvania has financial interests in the company related to the study.
