Although the immunotherapy axicabtagene ciloleucel has significantly improved treatment outcomes for some patients with large B-cell lymphoma, not all patients benefit. In a new study presented by Robbie G. Majzner, MD, and colleagues at the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract 556), investigators reported that CD58 status may be an important biomarker of durable response to chimeric antigen receptor (CAR) T-cell therapy in these patients. The team used this information to create a modified version of the treatment that may make the therapy effective for more patients.
Robbie G. Majzner, MD
Role of CD58 in Response to Axicabtagene Ciloleucel
Axicabtagene ciloleucel achieves a complete and lasting response in about 40% to 50% of patients treated with the therapy. The treatment involves removing a patient’s T cells and engineering them to express a certain receptor. These engineered cells, called CAR T cells, are then re-infused into the patient, where they use the receptor to seek and destroy cancer cells.
The new study focused on the role of a protein called CD58 in this process. Analyzing genetic samples from 51 patients treated with axicabtagene ciloleucel, the researchers discovered that the tumors of about 25% of the patients lacked a fully functioning version of this protein. In all but one of these patients, the therapy had no lasting effect. The researchers then created a mouse model that lacked CD58 and tested three different CAR T-cell therapies in the mice, and found none worked.
Probing the biologic mechanisms further, the researchers determined that CD58 helps activate the engineered T cells and assists with the process of killing cancer cells. Without a functional CD58 protein, CAR T cells are less effective. To overcome this problem, the researchers altered the engineering process by adding another protein, called CD2, to fill the role of CD58. Experiments in mice suggest these modified CAR T cells are capable of functioning well without CD58 present.
The researchers said they believe the approach could lead to clinical trials in the next 1 to 2 years. If successful, the modified treatment could significantly expand the pool of patients who are likely to benefit from therapy with axicabtagene ciloleucel.
“CD58 is an emerging biomarker. Endowing immunotherapeutics with the ability to get around CD58 loss may emerge as important for other cancers as well.”— Robbie G. Majzner, MD
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“Achieving an uptick of 20% to 25% in the complete response rate would really bring cures to a large number of additional patients,” said senior study author Dr. Majzner, of Stanford University School of Medicine, at an ASH press briefing. “Ultimately, we could potentially screen patients for CD58 status and provide a more precision approach to this therapy.”
In addition to leading to a next-generation therapy for large B-cell lymphoma, the work could have relevance for immunotherapy research more broadly.
“CD58 is an emerging biomarker,” concluded Dr. Majzner. “Endowing immunotherapeutics with the ability to get around CD58 loss may emerge as important for other cancers as well.”
Disclosure: For full disclosures of the study authors, visit ash.confex.com.
