More Than Just the Dose: Why Timing and Bridging Therapy are a Game-Changer for CAR-T

In a presentation at the IMS 2025 conference, Dr. Surbhi Sidana explained that the effectiveness and safety of "living drugs" like CAR-T cell therapy are not just about the initial dose. Instead, optimal outcomes depend on a delicate balance of dose, the quality of the patient's own T-cells, and, most critically, the timing and effectiveness of the therapies given before the CAR-T cells are infused.

New data now strongly suggests that properly managing a patient's disease while their CAR-T cells are being manufactured is one of the most powerful tools available to prevent severe and life-threatening toxicities.

The "Living Drug": Dose, expansion, and toxicity

CAR-T therapy is unique because the infused cells multiply inside the patient. This expansion is what drives the anti-cancer effect, but it's also linked to side effects. Dr. Sidana presented compelling new evidence showing a direct link between extremely high CAR-T expansion and a rare but severe side effect: delayed neurotoxicity, including Parkinsonism.

Because directly measuring CAR-T levels with tools like flow cytometry is difficult in most clinics, her research group identified a simple, widely available blood test—the absolute lymphocyte count (ALC)—as a reliable surrogate. They discovered that patients who developed Parkinsonism after CAR-T infusion showed a rapid and dramatic spike in their ALC. This groundbreaking observation has led to a new clinical study to see if giving immune-suppressing drugs in response to a rising ALC can prevent this dangerous side effect.

The critical role of bridging therapy

Dr. Sidana argued that one of the most important factors for a safe and effective CAR-T outcome is bridging therapy—the treatment given to control a patient's myeloma during the weeks or months it takes to manufacture their personalized CAR-T product.

Drawing from a massive real-world dataset of over 750 patients, she revealed a stunning correlation: The risk of developing Parkinsonism was ten times higher in patients who did not respond to their bridging therapy.

An astonishing 21 out of 22 patients who developed Parkinsonism had failed to respond to their bridging therapy.

This powerful evidence suggests that an uncontrolled, rapidly growing tumor at the time of CAR-T infusion can lead to a dangerously explosive and poorly controlled expansion of the CAR-T cells. Dr. Sidana argued that, whenever possible, CAR-T infusion should be delayed until a patient has responded to bridging therapy, even if it means trying a different bridging regimen. For heavily pre-treated patients, the bispecific antibody teclistamab is emerging as a highly effective and safe bridging option.

Earlier is better: The biology of T-cell quality

CAR-T therapy is now being used in earlier lines of treatment, and the results are superior. Dr. Sidana explained this isn't just because patients are healthier, but because their T-cells are of better quality. T-cells collected from patients who have not been exposed to as much chemotherapy are more "naive" and robust. Data from the CARTITUDE-1 trial showed that long-term survivors had CAR-T products made from these higher-quality T-cells, which led to a more effective expansion and durable response.

Less is more: Optimizing bispecific antibody dosing

Finally, the same principle of optimizing treatment applies to bispecific antibodies like teclistamab and talquetamab. Continuous, frequent dosing can lead to T-cell exhaustion, where the immune cells become tired and less effective.

New data shows that once a patient has responded, reducing the dosing frequency from weekly to every other week or even monthly can improve T-cell health. This "less is more" approach not only maintains the treatment's effectiveness but also dramatically reduces the risk of side effects, particularly infections. While the exact timing for this transition is still being studied, it represents a major step toward making these powerful therapies safer and more sustainable for patients.