Beyond Bispecifics: Costimulatory Antibodies Poised to Reshape Multiple Myeloma Treatment
For patients battling relapsed or refractory multiple myeloma (RRMM), the landscape of treatment options is rapidly evolving. But even with the advent of CAR T-cell therapy and existing bispecific antibodies, a significant need remains for therapies that deliver deeper, more durable responses. Now, a new generation of immunotherapies – costimulatory bispecific antibodies – is emerging, promising to overcome current limitations and potentially redefine the treatment paradigm. These aren’t just incremental improvements; they represent a fundamental shift in how we approach stimulating the immune system to fight this challenging cancer.
The Limitations of First-Generation Bispecifics
Current bispecific antibodies, like linvoseltamab, function by bringing T cells into close proximity with myeloma cells, triggering T-cell activation and subsequent cancer cell killing. This “signal one” activation is effective, but often insufficient to sustain a robust and long-lasting response. As Dr. Karen Rodriguez-Lorenc, therapeutic area lead of hemato-oncology at Regeneron, explained at the International Myeloma Society (IMS) meeting, patients can develop T-cell dysfunction after exposure to these therapies, diminishing their effectiveness over time. This is where costimulatory bispecifics aim to make a critical difference.
How Costimulatory Bispecifics Enhance T-Cell Activity
Costimulatory bispecific antibodies build upon the foundation of existing bispecifics by adding a second signal – targeting the CD28 receptor on T cells. CD28 is a crucial costimulatory molecule that amplifies T-cell activation, enhancing their ability to eliminate myeloma cells. Unlike their predecessors, these next-generation immunotherapies simultaneously target both a myeloma antigen (like CD38) and CD28. This dual-targeting approach isn’t about simply boosting activation; it’s about restoring and sustaining T-cell function, even in patients who have become resistant to initial therapies.
The Role of CD28 in Sustained Response
The CD28 signal is key. It’s not a standalone therapy; it requires the initial “signal one” from a T-cell engager like linvoseltamab to be effective. This design is intentional, aiming to minimize potential toxicity. Dr. Rodriguez-Lorenc anticipates a safety profile consistent with existing bispecifics, as the costimulatory component doesn’t drive activity on its own. The goal is to enhance efficacy without significantly increasing the risk of adverse events.
Sequencing Strategies and Treatment Flexibility
Perhaps the most exciting aspect of costimulatory bispecifics is their potential to unlock new sequencing strategies for RRMM. With a growing arsenal of therapies – including CAR T-cell therapy, lymphoma treatments, and other bispecifics – determining the optimal treatment order is a complex challenge. Costimulatory agents offer a potential “rescue” option for patients who have exhausted standard treatments.
But the flexibility doesn’t stop there. The ability to combine or decouple the two bispecific signals – the initial T-cell engager and the CD28 costimulator – allows clinicians to tailor treatment based on individual patient response. Imagine a scenario where a patient is progressing despite initial therapy; adding the CD28 signal could reignite the immune response. Conversely, once the disease is controlled, the CD28 signal could be turned off to minimize potential side effects. This dynamic approach represents a significant step towards personalized myeloma treatment.
Looking Ahead: The Future of RRMM Immunotherapy
The development of costimulatory bispecific antibodies marks a significant advancement in the fight against multiple myeloma. While still in early stages of development, the potential to overcome T-cell dysfunction and deliver deeper, more durable responses is compelling. The IMS meeting highlighted the growing excitement surrounding these next-generation immunotherapies, and ongoing clinical trials will be crucial in defining their role in the treatment landscape. Learn more about immunotherapy at the National Cancer Institute. The future of RRMM treatment isn’t just about adding more tools to the toolbox; it’s about intelligently orchestrating those tools to maximize their impact and improve outcomes for patients.
What are your predictions for the integration of costimulatory bispecific antibodies into standard RRMM treatment protocols? Share your thoughts in the comments below!
