The ‘eharmony of immunotherapy’: Bispecific T-cell engagers vs. CAR-T for multiple myeloma
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Bispecific T-cell engagers have induced impressive response rates among patients with relapsed or refractory multiple myeloma enrolled in early clinical trials.
The durability of this novel immunotherapy compared with chimeric antigen receptor T-cell therapy is less certain, and longer follow-up and possible phase 2 studies are needed to provide these insights.
No bispecific T-cell engager (BTCE) has been approved for multiple myeloma in the U.S. but, if the FDA does approve one, it would be “a game changer” for clinical management of the disease, according to Nina Shah, MD, professor of clinical medicine at University of California, San Francisco, and chair of Society for Immunotherapy of Cancer’s (SITC’s) Multiple Myeloma Immunotherapy Guideline Expert Panel.
In this installment of In Practice, Shah provides insights to help clinicians better understand these two modalities, including the benefits and challenges of each approach.
Healio: How do CAR-T and BTCEs engage the immune system to treat multiple myeloma?
Shah: CAR T-cell therapies and BTCEs both employ the T-cell machinery of a patient — the inherent T-cell machinery in the case of autologous CAR T cells and BTCEs — whereas an off-the-shelf allogeneic T-cell product would engage healthy T cells from a donor. Both modalities rely on T cells as effector-cell mechanisms, but there are also some key differences.
Autologous CAR-T begins with T cells being harvested from the patient and sent off for genetic engineering that helps them recognize and kill specific tumor cells. Allogeneic T cells are harvested from a healthy donor and engineered to not attack the patient who receives them while targeting a specific type of cancer. CAR T cells can be given to potentially eradicate the cancer cells in the patient’s body, and most available CAR T-cell therapies are intended to be one-time treatments.
BTCEs differ from CAR-T in that they are an actual drug. This type of therapy brings together the patient’s T cells and tumor cells by binding to a specific protein on the tumor cell’s surface while also binding at the other end to the T cell at the CD3 co-receptor. This is why I call BTCEs the ‘eharmony of immunotherapy.’ The advantage of this approach is that it’s an off-the-shelf drug similar to many of the therapies we give to our patients, such as monoclonal antibodies. However, BTCEs are not just an antibody against one cell; they also bring the patient’s T cells close to the tumor cell without any need for engineering. BTCEs are a simpler way to get T cells to attack cancer cells, but they require multiple doses. They are not just a one-time deal.
Healio: How do BTCEs and CAR-T compare in terms of efficacy and treatment durability for patients with multiple myeloma?
Shah: It is difficult to say for certain how these two modalities will compare over the long term. Data are available from multiples studies on CAR-Ts, but we don’t have pivotal phase 2 data available on BTCEs yet because this treatment is still in the phase 1 dose-escalation and dose-expansion stages. Despite this limitation, we know that the best a CAR-T can do is a 98% overall response rate, which was seen with ciltacabtagene autoleucel (Janssen, Legend Biotech) in the CARTITUDE-1 trial. With BTCEs, we have seen between a 60% to 80% overall response rate in phase 1 trials. It is important to wait to see how BTCEs perform in phase 2 trials.
Healio: Are certain patients more well-suited to either of these therapies?
Shah: Similar patient populations are eligible for either CAR T-cell therapy or BTCEs. These include disease state — such as relapsed or refractory disease — and having been exposed to novel agents, including [immunomodulatory imide drugs], proteasome inhibitors and CD38-directed monoclonal antibodies. In general, these patients should be able to tolerate cytokine release syndrome, one of the main adverse effects of both modalities. This includes being healthy enough to tolerate a fever and low blood pressure.
There are notable logistical differences between these two treatment types.
FDA-approved autologous CAR T-cell therapies require two major steps. First is collection of T cells from the patient’s peripheral blood followed by a waiting period while the CAR T-cells are being manufactured. Then comes infusion of CAR T cells with an intense 2-week post-treatment monitoring period. Patients who receive this type of therapy require a lot of logistical support because all these steps occur at a specialized institution, and it requires that the patient can delay therapy long enough to allow for this process. It is important that the patient has a lot of support, not only from the clinician providing the CAR T cells but also from their local oncologist and primary care physician, as well as their family. My institution requires that this support system be in place before providing CAR T-cell therapy.
BTCE therapy does not require the engineering step, so clinicians can give it off the shelf. However, the therapy does require some post-infusion monitoring because there is at least a 60% chance that patients who receive BTCEs will experience CRS — especially during the first two doses, during which they would be admitted as inpatients. Thereafter, patients can receive this as an outpatient therapy.
I always say there is enough myeloma to go around, and not every patient with multiple myeloma is the best suited for every therapy. The logistics will probably determine which therapy patients receive when all of this becomes FDA approved.
Healio: How do CAR-T and BTCEs compare in terms of safety?
Shah: The most common similarity between the two modalities is incidence of CRS. This occurs in 80% or more of patients who receive CAR T-cell therapy and can vary depending on which product is used. CRS occurs approximately 60% of the time BTCEs are administered — generally after the first or second dose. Regardless of which therapy is used, CRS events are typically grade 1 or 2 and very easily managed using tocilizumab (Actemra, Genentech) — an interleukin-6 receptor antibody — or, if necessary, steroids.
Neurotoxicity is more common with CAR T-cell therapy and occurs in approximately 20% of patients. It can manifest as confusion, difficulty concentrating or handwriting instability. It is also very treatable using steroids.
Data from the CARTITUDE-1 trial showed that ciltacabtagene autoleucel had a few unexpected neurotoxicities — including cognitive and peripheral motor neuropathy — that didn’t look like typical CAR-T-related neurotoxicity, which we call immune effector cell-associated neurotoxicity syndrome. The rest of the CARTITUDE program after CARTITUDE-1 hasn’t shown any of those additional neurotoxicities yet. Neurotoxicity, by comparison, is less common with BTCE therapy.
Both CAR-T and BTCEs will result in low blood counts and profound immunosuppression. This occurs by design because the therapies target and kill B cells. Many patients who receive either therapy will have low immunoglobulin levels and will require IV immunoglobulin supplementation. Additionally, many patients who receive either CAR-T or BTCE therapy will not mount a response to the COVID-19 vaccine and will require prophylaxis with antiviral drugs — for example, acyclovir for herpes zoster or herpes simplex virus.
Healio: Are there any additional safety issues with BTCEs clinicians should be aware of?
Shah: It is difficult to say at this point what the long-term side effects will be for BTCEs if patients are on them for years because we don’t know their true immunosuppressive effect. This is something we can hopefully understand after the accumulation of long-term follow-up data. Having serial, non-ending treatments will expose patients to some type of toxicity, but we can’t yet define the scope.
Healio: What type of post-infusion care is required for BTCEs?
Shah: After infusion of a BTCE — initially, and for the first few doses —patients require close observation, but for how long will depend on the product. A typical patient receiving BTCE therapy can go home within an hour of completing an infusion, so it ends up being very manageable from an outpatient perspective.
Healio: Can BTCEs can be given in a community setting at a local infusion clinic or do they require the infrastructure of specialized centers?
Shah: I’m hopeful that as BTCEs develop, we will find a way to connect the academic and community settings so that the first dose or second dose can be given in an academic setting or at a hospital that is community-based but staffed with people who know how to respond to patients with CRS. Third and later doses can be given as an outpatient at an infusion clinic. It is a community-friendly treatment program, and I really hope they can be provided in the community setting so patients can have access to these very effective therapies closer to home.
Healio: Do you consult any clinical practice guidelines in your decision-making process?
Shah: Guidelines from our professional societies are valuable and each of them have different foci. SITC’s multiple myeloma immunotherapy guidelines help clinicians understand the toxicities, expected efficacies and other logistical issues they may encounter with various types of immunotherapies, so you may be able to cross-compare therapies to understand what is best for your patient.
Healio: What is the clinical trial landscape for BTCEs in multiple myeloma?
Shah: Multiple BTCEs are being evaluated in clinical trials, including those that focus on [non-B-cell maturation antigen (BCMA)] targets. For example, talquetamab (Janssen) is an investigational BTCE that targets CD3 and GPRC5D, a protein that has been established as a multiple myeloma target. There is also cevostamab (Genentech), which targets Fc receptor-like protein 5 (FCRH5) and CD3. I’m looking forward to publication of data from these trials because they may shed light on how we treat people who have disease progression after the use of BCMA-targeted therapies.
Healio: Do issues related to administration and availability impact decision-making when choosing between these therapies?
Shah: Logistics are a huge factor in decision making. Patients enrolled in clinical trials are not the same patients who you see in your clinic, so providers must consider how a treatment is going to affect not only the patient but everything around the patient. Logistics, availability of treatment, availability of apheresis — all of these variables will factor into making a decision about what is best for the patient.
Healio: What impact has the FDA’s approval of the first CAR-T for multiple myeloma had on clinical care?
Shah: The approval of idecabtagene vicleucel (Abecma; Bristol Myers Squibb, bluebird bio) has made it possible for patients to get access to a CAR T-cell therapy outside of a clinical trial, but there have been some logistical challenges because of demand for the therapy and the limited number of production spots available. Even a large academic facility like my own can’t provide CAR-T to all patients who need it on a given day.
Healio: What impact would FDA approval of a BTCE for multiple myeloma have on practice?
Shah: There would be many logistical advantages to having an FDA-approved BTCE therapy. We could bring patients into our center for the first couple doses and then work with a community-based clinician to provide this type of therapy at a local level. FDA approval of this type of therapy will be a real game changer for our patients with multiple myeloma.
Healio: Is there anything else you think clinicians should know about choosing between these treatments?
Shah: There are so many clinical trials still in progress, which means we are unable to answer many important questions at this point. Can we move BTCE therapies closer to frontline treatment? Can we combine them with other treatments? Can we focus them on high-risk patients? The answers to these questions will require patients to enroll in clinical trials and I continue to be grateful to all the patients who have enrolled and the clinicians who have sent us patients. Our mission is to continue to move the field forward for the benefit of all our patients, now and in the future.
Reference:
Usmani SZ, et al. Abstract 8005. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
For more information:
Nina Shah, MD, can be reached at UCSF, HBC Program, 400 Parnassus Ave., Fourth floor, San Francisco, CA 94143; email: nina.shah@ucsf.edu.
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