Bispecific antibodies (BsAs) are emerging as a promising new frontier in cancer immunotherapy, particularly for patients with B-cell lymphomas. Unlike traditional monoclonal antibodies, these innovative therapeutics simultaneously target a tumor antigen and engage immune cells, creating a powerful bridge that enhances tumor cell destruction without requiring patient-derived cells.
The Evolution of Bispecific Antibodies
For over two decades, monoclonal antibodies like daratumumab (Darzalex) have been consistent options in cancer treatment. However, the evolution to bispecific antibody therapy has opened a wider array of targeted treatment options. Currently, nine FDA-approved bispecific antibodies exist, with eight focusing on cancer treatment, including amivantamab-vmjw (Rybrevant), blinatumomab (Blincyto), epcoritamab-bysp (Epkinly), glofitamab-gxbm (Columvi), mosunetuzumab-axgb (Lunsumio), tebentafusp-tebn (Kimmtrak), teclistamab-cqyv (Tecvayli), and talquetamab-tgvs (Talvey).
What makes bispecific antibodies potentially transformative is their ability to target two antigens in cancer that can be independent of each other. This allows for multiple targeted approaches in a single therapy to bridge cancer cells to cytotoxic immune cells. Currently, over 100 bispecific antibodies are in development.
Advantages Over CAR-T Therapy
Unlike chimeric antigen receptor (CAR) T-cell therapies that require harvesting and engineering a patient's own cells, bispecific antibodies are "off-the-shelf" options that don't require anything from the patient. This makes them potentially more accessible and quicker to administer than CAR-T therapy.
For example, in patients with B-cell lymphoma, the CD20 antigen is present in all patients with malignant B cells. Bispecifics targeting this mature antigen can lead to less severe adverse events when targeting just these mature B cells.
Implementation Challenges in Community Settings
Despite their promise, implementing bispecific antibody therapy in community settings presents significant challenges:
"One thing we are realizing now in the community setting is that bispecifics have come to stay," said Ayodele Ayoola, MD. "We know that you can refer all these patients to an academic center, but depending on where they live...some patients don't want to go too far. So, we've concluded that we need to learn about these therapies, we need to know them and do a lot of teaching."
A 2020 survey from the Association of Community Cancer Centers on blinatumomab use found that fewer than half of medical oncologists and hematologists were familiar with it. Additionally, 41% cited transitioning patients from inpatient to outpatient settings as their most common challenge.
Other significant barriers included:
- Managing patients in remote areas (33%)
- Securing insurance coverage (28%)
- Managing adverse events (27%)
- Assisting patients with costs (24%)
- Lacking in-house expertise (22%)
In recent polls at virtual Case-Based Roundtable events, 46% of attendees said they do not administer bispecifics at all, while 38% would send patients to an academic center for initial treatment before continuing therapy at a community center.
Financial Considerations
Financial barriers represent a significant challenge. As Maribel Pereiras, PharmD, BCPS, BCOP, explained: "I think a lot of institutions are also struggling with that financial piece as to how you incorporate bispecific therapy and who's going to assume the cost of it... Some of the companies behind the drugs do provide a new technology payment given on the back end where they will be reimbursed better than with traditional medications. Another one is providing free product for the inpatient administration, and then once the patient gets to the outpatient setting...you would have to purchase the supply."
Not all practices are part of large systems that can weather these costs indefinitely, which is why some physicians make case-by-case judgments about patient admission despite package label recommendations.
Developing Protocols for Bispecific Therapy
Creating standard operating procedures (SOPs) is essential for any center planning to administer bispecific antibodies. Justin LaPorte, PharmD, BCOP, from Northside Hospital, emphasized the importance of developing treatment protocols for managing cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome (ICANS).
"To get to the point to treat patients with CAR T-cell therapy, when that was new, we had to go through the same type of protocol development that those in the community setting might with the bispecifics. This includes talking with the emergency department and intensive care unit staff, developing treatment protocols to treat cytokine release syndrome and immune cell–associated neurotoxicity syndrome with these therapies...and educating the staff," explained LaPorte.
Key considerations for protocol development include:
- Coordinating between nursing and pharmacy staff
- Educating patients on what to expect from treatment
- Developing wallet cards for patients to identify adverse event signs
- Ensuring patients and caregivers can recognize and report symptoms like CRS
Managing Adverse Events
Guidelines for managing adverse events like CRS and ICANS include the Mayo Stratification for Myeloma and Risk-Adapted Therapy (mSMART) guidelines and the American Society for Transplantation and Cellular Therapy (ASTCT) guidelines.
For example, if a patient has a fever but no hypotension or hypoxia, the mSMART guidelines recommend starting with either 10 mg of dexamethasone intravenously or one dose of tocilizumab (Actemra). If there's no improvement, or if the patient has a grade 2 to 4 CRS event, tocilizumab is recommended for up to 3 doses before methylprednisolone.
Promising Clinical Results in Indolent B-cell Lymphomas
Among the bispecific antibodies in development, CD20 and CD19 targeting molecules are frontrunners, potentially due to their higher tumor cell cytotoxicity. Several have shown impressive results in clinical trials:
Mosunetuzumab (Lunsumio)
This CD20xCD3 bispecific antibody was the first in its class to receive accelerated approval from the FDA for patients with relapsed follicular lymphoma after two or more lines of therapy. In a phase 1/2 trial with heavily pretreated patients, complete response rates reached 54% in follicular lymphoma patients, with a median duration of response of 22.8 months. The treatment follows a 21-day cycle with step-up dosing in the first cycle.
Glofitamab
This CD20xCD3 bispecific antibody differs from Mosunetuzumab by having two CD20 binding sites in a 2:1 format, potentially translating to a 40-fold increase in tumor cell lysis. In a phase 1/2 study of relapsed/refractory B-cell lymphomas, patients with follicular lymphoma showed an overall response rate of 81% and complete response rate of 70% with monotherapy.
Epcoritamab
This subcutaneously administered CD20xCD3 bispecific antibody showed a 90% overall response rate and 50% complete response rate in relapsed/refractory follicular lymphoma patients in a phase 1/2 dose-escalation study. When combined with rituximab and lenalidomide, it demonstrated an impressive 97% overall response rate and 86% complete response rate.
Future Directions
As bispecific antibodies continue to develop, several key considerations emerge:
-
The duration of therapy and mode of administration are important for widespread adoption. While some bispecifics like Glofitamab and Mosunetuzumab have been tested in fixed-duration schedules, others like Epcoritamab and Odronextamab are given until progression or toxicity in ongoing trials. Subcutaneous administration (as with Epcoritamab) may be preferable for logistics of care delivery.
-
Long-term data and real-world evidence are still needed to establish bispecific antibodies as standard of care. Studies on predictors of immune response and toxicity will help better understand this therapy.
-
Combinatorial regimens that harness multi-targeted approaches, such as Epcoritamab with Rituximab and Lenalidomide, show promise even in difficult-to-treat patient groups.
-
Resistance mechanisms to bispecific antibody therapy are being studied, potentially driven by loss of target antigen by tumor cells, T-cell exhaustion, and factors in the tumor microenvironment.
As bispecific antibodies advance from relapsed/refractory settings to first-line therapy, questions about optimal use (alone or in combination) and sequencing of therapies will need to be addressed through ongoing clinical trials.
Despite implementation challenges, bispecific antibodies represent a significant advancement in cancer immunotherapy, offering new hope for patients with limited treatment options.
