CAR T-Cell Therapy: Boosting Activity Against Antigen-Low Disease | Healio
The challenge of treating cancers with low levels of target antigens – often called ‘antigen-low’ disease – may be addressed by strengthening the signal of CAR T-cell therapy, according to research presented this week. This approach aims to improve the effectiveness of these powerful immune therapies in patients where initial responses have been limited. The findings, shared at the Tandem Meetings | Transplantation &. Cellular Therapy Meetings of ASTCT and CIBMTR, offer a potential pathway to broaden the applicability of CAR T-cell therapy, a treatment that has shown remarkable success in certain blood cancers but can falter when tumor cells express insufficient levels of the target antigen.
Chimeric antigen receptor (CAR) T-cell therapy involves engineering a patient’s own T cells to recognize and attack cancer cells. However, a significant hurdle has emerged: relapse can occur when tumor cells reduce the expression of the antigen that the CAR T-cells are designed to target. This “antigen escape” phenomenon has prompted researchers to explore strategies to overcome this resistance.
Engineering a Boost for CAR T-cells
Maria Caterina Rotiroti, PhD, a postdoctoral fellow at Dana-Farber Cancer Institute, explained that her team focused on enhancing the intracellular signaling within the CAR T-cells themselves. “Relapse with antigen-low [disease] has emerged in the clinic after CAR T-cell therapy,” Rotiroti told Healio. “In our lab, we decided to address this challenge by engineering the intracellular machinery and providing CAR T-cells with a boost to enhance their activity when challenged with tumor cells expressing low levels of antigens.”
Specifically, the research involved a membrane-tethered version of SLP-76, a signaling molecule crucial for T-cell activation. By enhancing this signaling pathway, the engineered CAR T-cells demonstrated improved activity even against tumor cells with low antigen expression. This approach, detailed in a presentation at the recent conference, suggests a way to overcome a key limitation of current CAR T-cell therapies.
Dr. Rotiroti’s work builds on her broader research interests in preventing tumor immune escape following CAR T-cell adoption, as highlighted on her Majzner Lab profile. She previously obtained her PhD in Molecular and Translational Medicine from the University of Milano-Bicocca, Italy, focusing on immunology and CAR engineering at the Fondazione Tettamanti in Monza.
Understanding Antigen-Low Disease and CAR T-cell Therapy
CAR T-cell therapy has revolutionized the treatment of certain blood cancers, particularly B-cell lymphomas and acute lymphoblastic leukemia. However, its success hinges on the presence of a specific antigen on the surface of cancer cells. Common targets include CD19, a protein found on many B-cells. When these cancer cells downregulate or lose expression of the target antigen, the CAR T-cells are no longer able to effectively recognize and destroy them, leading to relapse.
Antigen-low disease represents a particularly challenging scenario. Whereas not a complete loss of the target antigen, the reduced expression levels can be insufficient to trigger a robust response from standard CAR T-cells. This is where strategies like the one developed by Dr. Rotiroti’s team become crucial. By amplifying the signaling within the T-cells, they can overcome the weaker signal from the low-level antigen and maintain their anti-cancer activity.
Implications for Future Treatment Strategies
The findings presented at the Tandem Meetings suggest a promising avenue for improving the durability of CAR T-cell therapy responses. While the research is still in its early stages, the concept of “boosting” CAR T-cell activity to overcome antigen-low resistance holds significant potential. Further research will be needed to validate these findings in larger studies and to assess the safety and efficacy of this approach in patients.
Dr. Rotiroti has consulting ties and equity in Link Cell Therapies, as disclosed in the Healio report, highlighting the growing commercial interest in innovative CAR T-cell engineering strategies. You can find her professional profile on LinkedIn.
What’s Next for CAR T-cell Research?
The development of strategies to address antigen-low disease is just one aspect of the ongoing evolution of CAR T-cell therapy. Researchers are also exploring ways to improve CAR T-cell persistence, reduce toxicity (such as cytokine release syndrome and neurotoxicity), and expand the applicability of CAR T-cells to solid tumors, which have proven more resistant to this type of immunotherapy.
The field is rapidly advancing, with ongoing clinical trials evaluating novel CAR designs, combination therapies, and strategies to overcome the immunosuppressive tumor microenvironment. The ultimate goal is to build CAR T-cell therapy a safe, effective, and widely accessible treatment option for a broader range of cancers. The Healio video featuring Dr. Rotiroti provides a concise overview of this emerging research area.
As research progresses, continued monitoring of clinical trial results and updates from organizations like the American Society of Transplantation and Cellular Therapy (ASTCT) will be essential for healthcare professionals and patients alike.