For third-line follicular lymphoma, where both CAR-T and bispecifics are approved, experts are leaning towards CAR-T. The long-term follow-up data for CAR-T suggests a potential for cure, making it a more compelling option for eligible patients despite logistical challenges.

CELMoDs are being actively trialed as a maintenance therapy after CAR T-cell treatment. The strategy is to leverage the CELMoDs' ability to enhance T-cell function and upregulate effector T-cells to boost the activity and persistence of the CAR-T product, potentially leading to more durable responses and preventing relapse.

In follicular lymphoma, the treatment goal is durable remission with manageable toxicity, not necessarily a cure. Therefore, clinicians frequently prefer using a bispecific antibody first, reserving the more complex and toxic CAR-T cell therapy for transformed disease or after a bispecific fails.

Unlike some targeted therapies that lead to antigen loss, treatment with the CD19-directed antibody tafasitamab does not appear to eliminate CD19 expression on lymphoma cells. This is a critical finding, as it preserves the target for subsequent potent therapies like CD19-directed CAR T-cells.

Clinicians should not be deterred from using CD19 CAR T-cell therapy in patients who have previously received other CD19-targeting agents like tafasitamab. Preclinical and retrospective clinical data suggest prior exposure does not impair CAR T efficacy, and therefore re-testing for CD19 expression is unnecessary.

In the IN-MIND trial for relapsed follicular lymphoma, the tafasitamab-lenalidomide-rituximab arm had zero cases of histologic transformation to a more aggressive lymphoma. This contrasts with nine cases in the control arm, suggesting the CD19-targeting antibody may eradicate precursor cells responsible for this dreaded complication.

Quell's CEO suggests a competitor's transient target may limit long-term efficacy. He notes that for a CAR-Treg to persist, it needs a stable antigen for activation. By targeting CD19 on B-cells which are not depleted, Quell ensures its therapy has a durable target, aiming for sustained, long-term disease control.

The first successful CAR T-cells targeted CD19, a protein on leukemia cells but also on healthy B-cells. The therapy worked because humans can live without B-cells. This "tolerable collateral damage" was serendipitous and highlights the primary challenge for other cancers: finding targets that won't cause fatal damage to healthy organs.

Before initiating a CD20-targeting bispecific antibody in patients who have failed CAR-T therapy, a new biopsy is mandatory. Up to 30% of these patients experience CD20 antigen loss, which would render the bispecific therapy ineffective and necessitates choosing a drug with a different target.