CD58 aberrations limit durable responses to CD19 CAR in large B cell lymphoma patients treated with Axicabtagene Ciloleucel but can be overcome through novel CAR engineering

While the immunotherapy axi-cel has revolutionised treatment for large B cell lymphoma, it does not work for everyone.

In a new study, researchers uncovered a likely explanation for why about one-quarter of patients do not respond well to this therapy.

The researchers used this information to create a modified version of the treatment that may overcome the problem and make the therapy effective for more patients.

Axi-cel achieves a complete and lasting response in about 40-50% of patients treated.

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 focuses on the role of a protein called CD58 in this process.

Analysing genetic samples from 51 patients treated with axi-cel, the researchers discovered that the tumours 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 therapies in the mice.

None worked.

Probing the biological 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 one to two years.

If successful, the modified treatment could significantly expand the pool of patients who are likely to benefit from axi-cel therapy.

“Achieving an uptick of 20-25% in the complete response rate would really bring cures to a large number of additional patients,” said senior study author Robbie G. Majzner, MD, of Stanford University School of Medicine.

“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,” said Dr. Majzner. “Endowing immunotherapeutics with the ability to get around CD58 loss may emerge as important for other cancers, as well.”

Robbie G. Majzner, MD, Stanford University School of Medicine, will present this study in an oral presentation on Monday, December 7, at 7:30 a.m. Pacific time on the ASH annual meeting virtual platform.

Source: American society of hematology