Editor’s Note: Monoclonal antibody-based targeted therapy has significantly improved treatment options for cancer patients. In recent years, advancements in protein engineering have led to the development of bispecific antibodies (BsAbs), marking a paradigm shift in antibody construction usage. BsAbs, recognized for their higher therapeutic response, resistance barrier, and fewer adverse reactions, have caught significant attention in the academic world. The next wave of "bispecific or multispecific antibodies" is also on the horizon. At the 50th European Society for Blood and Marrow Transplantation (EBMT) Annual Meeting, Professor Maria Gomes Da Silva from the Portuguese Oncology Institute delivered an insightful report on the latest advances in BsAb treatments for lymphoma. "Oncology Frontier - Hematology Frontier" invited Professor Da Silva to share the latest developments and challenges in this field with our readers.
Oncology Frontier – Hematology Frontier: In recent years, BsAbs have shown tremendous potential in the treatment of B-cell Non-Hodgkin’s Lymphoma (B-NHL). Could you explain the unique mechanism of action of these drugs and their advantages?
Professor Maria Gomes Da Silva: Recently, BsAbs have become a focal point in B-NHL treatment research. Their “bispecificity” refers to their ability to simultaneously recognize and bind to two different molecules—one commonly found on the surface of tumor cells (such as CD20) and the other on T cells of the human immune system (such as CD3). This unique mechanism allows BsAbs to bring T cells and tumor cells together, while concurrently activating T cells to attack the tumor cells. This is the mechanism of action for BsAbs.
Their advantage lies in their ability to effectively recruit and activate the body’s own immune cells to directly target and kill cancer cells, offering a precision approach that potentially leads to better outcomes with fewer side effects. Additionally, their dual targeting strategy helps in overcoming the resistance often developed against conventional therapies, providing a new line of attack against tumors that might not respond to traditional treatments. This innovative method not only holds promise for improving survival rates but also enhances the quality of life for patients by minimizing the adverse effects commonly associated with cancer therapies.
We are dealing with antibodies engineered to express a dual specificity. In the case of B-cell lymphomas one of them is a B cell surface antigen, most commonly CD20. The other one is an antigen of an immune cell, mostly CD3 in T-cells. When the antibody binds the T cell it will activate it through CD3 in a way that is not restricted by MHC Class I, which is important because many of the aggressive malignancies do not express it. At the same time, they bring the lymphoma cell and the T-cell into close proximity, promoting the formation of an immune synapse and cytotoxicity from the T-cell against the B-cell. Many cytokines can be produced that can help with the amplification of the immune response, and recruitment of more T-cells. So this is the main mechanism. What is happening is that we are harnessing the patient’s immune system to destroy the lymphoma cells. In a general way, this is the mechanism.
Oncology Frontier – Hematology Frontier: Can you share the latest clinical research findings on BsAbs in the treatment of lymphomas in recent years?
Professor Maria Gomes Da Silva: Indeed, there have been many recent advancements in the treatment of B-NHL with BsAbs. At this conference, I mainly presented significant results in Diffuse Large B-cell Lymphoma (DLBCL) and Follicular Lymphoma. The former is a common aggressive subtype, while the latter is indolent. Results have been observed in other types of lymphoma, including Mantle Cell Lymphoma, but time constraints did not allow for coverage of all areas. Concerning B-cell lymphomas, we now have one product approved in Europe and the USA for Follicular Lymphoma—Mosunetuzumab; and two products approved for treating DLBCL, which are Glofitamab, administered intravenously, and Epcoritamab, given subcutaneously. The clinical trials leading to the approval of these drugs involved similar numbers of patients, and results presented at the most recent ASH meeting showed overall response rates of 50%-60% and complete remission rates around 40% over an 18-20 month follow-up period. Importantly, patients who achieved complete response maintained durable responses. In particular, clinical studies of Glofitamab showed that about two-thirds of patients who achieved complete remission maintained this response over an 18-month follow-up. These clinical trials are still ongoing, and we anticipate more progress over time.
On the other hand, we’ve also seen many advancements in the combination therapies of monoclonal antibodies with chemotherapy or other immunotherapies, and antibody-drug conjugates, achieving preliminary research outcomes.
Mosunetuzumab appears less effective as a monotherapy in aggressive subtypes but has achieved high response and complete remission rates (around 60%) in Follicular Lymphoma, with quite durable complete remissions. We must consider the high heterogeneity of Follicular Lymphoma, where patients face resistance post-chemotherapy, especially in second or third-line treatments, where there is still no standardized choice. Thus, the bispecific nature of BsAbs may be a very attractive option.
Whether it’s DLBCL or Follicular Lymphoma, we are still not able to achieve a cure currently. However, with further follow-up studies, we will better understand the therapeutic potential of BsAbs. Additionally, BsAbs have several advantages; we tend to compare their outcomes with those of CAR-T cell therapies. In comparison, bispecific antibody treatments are more convenient as they are off-the-shelf drugs not requiring preconditioning or waiting for cell product preparation. This might be a more attractive option for patients who cannot afford to wait. Perhaps in the future, BsAbs might serve as a bridge to CAR-T cell therapies. However, currently, we are more inclined to first use CAR-T cell therapy in eligible patients and then employ BsAbs for salvage treatment if the tumor relapses. We have initiated clinical trials using BsAbs as maintenance therapy for aggressive lymphoma patients after CAR-T treatment.
I think we have new updates pretty much every meeting. During my presentation, I tried to focus on diffuse large B-cell lymphoma, an aggressive and common subtype, and follicular lymphoma, an indolent subtype. There are results in other types of lymphomas, including mantle cell lymphoma, but due to time constraints it is not possible to cover everything. Regarding B-cell lymphoma, we have in Europe and the US now one product approved for follicular lymphoma (mosunetuzumab) and two products approved for diffuse large B cell lymphoma- glofitamab, which is administered IV for a limited duration of 12 cycles (a little over 8 months); and epcoritamab, which is administered subcutaneously until progression. The trials that led to the approvals of these two antibodies were not comparative, included a similar number of patients, and at this time, share quite similar follow-ups of 18-20 months. What we are seeing is an overall response rate of 50-60%, and a complete response of about 40% for both agents in diffuse large B cell lymphoma. Both translate into very durable responses in complete responders. If you look at the glofitamab results, about two-thirds of the patients that are in complete response maintain this complete response at 18 months follow-up. If you look at epcoritamab at 20 months median follow-up, you have a median 21 months duration of complete response. These trials are still ongoing, so we will probably see more developments. We are also seeing a lot of developments in terms of combinations of these monoclonals with many different agents including chemotherapy, other immunotherapies and antibody drug conjugates. Some of those have results but they are still preliminary. For the time being, there has been approval of these two antibodies for the aggressive subtypes. Mosunetuzumab, in contrast, was approved for follicular lymphoma. Mosunetuzumab seems less effective as monotherapy in the aggressive subtypes, but it achieves high response rate and complete responses (around 60%) in follicular lymphoma. These complete responses are quite durable. We have to take into account that follicular lymphoma is very heterogeneous, and we have today a range of options besides chemotherapy. But during clinical course, at third or forth treatment line, there are no standard choices and many patients develop resistance to chemotherapy. At this stage they need an alternative mechanism of action, and bispecifics can be an attractive option. We are not sure, neither in diffuse large B-cell lymphoma nor in follicular lymphoma, that they will be curative. We have not yet seen a plateau in survival curves, but with further follow-up we might better understand the curative potential of these drugs.Also, they have some advantages. We tend to compare their results to the results with CAR T-cells. The mechanism of action is not that different but common toxicities are less frequent. The complexity of the treatment with bispecifics is also lower, they are an off-the-shelf medication that do not require lymphodepletion nor waiting for manufacturing. For patients who cannot really wait, this might be a more attractive option. Maybe in the future, when we learn more about the effectiveness of CAR T-cells after bispecifics, they may be used as a bridge for CAR Ts. However the data about this sequence of treatment is still very limited. For the time being, it seems preferably to do the opposite – to first use CAR T-cells in patients who are candidates and have access (access to CAR-T is not uniform everywhere), and then salvage the patient with bispecifics if needed. We also have interesting trials using bispecifics as maintenance after CAR-Ts in aggressive lymphomas.
As for all treatments, the health staff needs to learn about toxicities and get trained and experienced with these treatments. I would say it is quite easy for a center that is used to administering CAR T-cells, because toxicities are similar but at a much lower range. We see cytokine releasing syndrome (usually low grade), and we need to know how to treat manage it, because it can become serious if we don’t treat it in the beginning. We have some mitigation strategies, but they might not be entirely effective. So we need to know how to deal with it. Sometimes, we need to admit patients, although we do our best to do most of the treatment as outpatients. This is a prolonged treatment, so we really prefer to develop strategies of training the patients, the physicians and the caregivers to be able to administer as much of the treatment as possible as outpatients. Since not all these treatments are available everywhere, people are thinking about strategies where less experienced centers might be able to get into an arrangement with bigger centers, where patients can receive their first one to two cycles and then go back to their original hospital to continue the antibody administration. I think that would be a very good idea. In the end, everyone will learn how to deal with the most common acute toxicities. What I don’t know yet in detail are the delayed toxicities. I would say that the immune suppression that we are inducing, not only with bispecifics, but with all the treatments we are giving our patients, brings additional important problems, mainly infections. We need to be aware of the risk of infection in these patients, and in the future, develop better prevention and treatment strategies. For the time being though, we need to be very much aware of these risks and to suspect infection early. These are not the only toxicities we have with bispecifics, but I was focusing on the things I think concern most of us to a large degree. We have other concerns: a small numbers of patients will have neurotoxicities (not very significant in terms of numbers or severity); we see cytopenias, which we can deal with using growth factors; we have hypogammaglobulinemia, that we can support by administering immunoglobulins; we sometimes have tumor lysis and infusion reactions.
Oncology Frontier – Hematology Frontier: As treatment progresses, do patients develop resistance to BsAbs? How might we address this challenge in the future?
Professor Maria Gomes Da Silva: Currently, research groups are dedicated to elucidating the mechanisms of resistance to BsAbs, which is a critical issue that we need to understand thoroughly. In addition, other bispecific antibodies targeting different B-cell markers are in development; there are also explorations into combination regimens involving BsAbs, including combinations with chemotherapy or immunomodulators, aimed at enhancing sustained responses in patients. Furthermore, concerning the timing of interventions, our understanding is that treating patients earlier, when there is less T-cell exhaustion, might reduce the rate of resistance; additionally, it may be possible to treat within a limited timeframe—stopping treatment when the disease is in remission and resuming when there is relapse or progression. This approach is also being tested in clinical trials.
These strategies highlight the ongoing efforts to not only manage but also anticipate and counteract the resistance to BsAbs, ensuring that these therapies remain effective for longer periods and continue to benefit patients with B-NHL and other lymphomas. The ongoing research and trials will help refine these approaches and potentially introduce new methods to prevent or overcome resistance to bispecific antibody therapies.
There are groups of investigators working to clarify the mechanisms of resistance to bispecifics. The first thing we need to know is the mechanism of resistance, because if we are using an anti-CD3/CD20 antibody, and the patient loses CD20 from the tumor cells, this type of antibodies will not be effective. There are other bispecific antibodies in development against different targets in B-cells. There are also combinations with other bispecifics that act as immune stimulators. Many combinations including bispecifics and other agents, either chemotherapy or more interestingly, immunostimulators, are being developed and may be able to increase durable responses. Additionally treating patients earlier, when T cells are less exhausted may reduce the probability of developing resistance. Also, it is possibly important to have treatment over a limited period of time. If effective, it can stopped while the patient is in remission. In some trials, patients are allowed to resume treatment if they relapse or progress. That can also be a strategy. If they don’t develop resistance, we might be able to use the same agent, or a similar one, more than once.
