Next Generation Novel Agents for Aggressive B-Cell Lymphoma

Jason Westin, MD

During his presentation, “The Next Generation of Novel Agents in Development for Aggressive B-cell Lymphoma,” at 6:45 am on September 28, 2022 at the 10th Annual Meeting of the Society of Hematologic Oncology (SOHO 2022), Jason Westin, MD, from The University of Texas MD Anderson Cancer Center, will discuss the next generation of novel agents in development for aggressive B-cell lymphoma.

During an interview before the meeting, Westin, director, lymphoma clinical research, Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, said his talk will focus on 2 main categories of novel agents that manipulate the immune system to better target aggressive lymphomas. These include novel cellular therapies that improve upon the existing chimeric antigen receptor (CAR) T-cell therapies, with a look toward the next steps for new cellular therapies that are promising in clinical trials.

The other way of trying to manipulate the immune system is using bispecific antibodies, which have a target on the tumor as well as on an immune cell, and act to bring the immune cells and cancer cells in close proximity to have a potent immune effect. He also planned to mention more conventional drugs, including novel antibodies, antibody-drug conjugates, and small molecules that are targeting relevant proteins within aggressive B-cell lymphoma cells.

CAR T-Cell Therapy

New Place in Line

CAR T cells for large B-cell lymphomas (LBCLs) were approved by the FDA in October 2017. Currently approved products include axicabtagene ciloleucel (axi-cel; Yescarta) for relapsed/refractory (R/R) diffuse (D) LBCL, tisagenlecleucel (Kymriah) for adult R/R DLBCL, and lisocabtagene maraleucel (liso-cel; Breyanzi) for R/R LBCL.¹ 

The currently approved CAR T-cell therapies have been game changers,” Westin said, “but what is even more exciting is the move of CAR T cells from a third or greater line into a second-line treatment.” Axi-cel and liso-cel were recently approved for second-line treatment for patients who have had 1 prior treatment.^2,3 “That’s certainly a practice-changing development that’s highly relevant for community physicians to know about,” Westin said.

Advice for Community Oncologists

“Furthermore, what is important for community physicians to know is to make sure that they consider referral to a CAR T center at the time of first relapse,” he continued. If there is a suspicion of relapse of the lymphoma, Westin advises not to wait until the patient has experienced disease progression, is sick, and is having lots of complications. Consider sending them to a CAR T-cell center, he advises, because even as a second-line treatment for large B-cell lymphoma, CAR T cells still take time to arrange, manufacture, and deliver.

“We have treated many patients in third line, and now in second line, but there are still some patients that we actually struggle to deliver CAR T cells to,” Westin said. “Often those are people who had a delay in getting referred. So that’s a take-home message for the community physicians, that if they are considering their patient as a candidate for 1 of these really impressive new therapies, they start that referral process as soon as possible. For other conditions, like multiple myeloma, the rate-limiting step is finding a manufacturing slot because demand is overwhelming supply. That is not the case for those with large B-cell lymphoma. Although the ability to secure a manufacturing slot can take time,” Westin said, “slots are usually available.”

Another problem for patients with large B-cell lymphoma is the speed at which this aggressive cancer moves. As the disease progresses, patients may not be able to wait for the leukapheresis to collect cells, followed by several weeks for the manufacturing of CAR T cells. These patients require “bridging” therapy—often a targeted therapy, radiation, or chemotherapy. That can cause toxicities and make it harder for them to receive the CAR T cells.⁴ “That’s why time is really important for us to get the request for the manufacturing slot put in as soon as possible,” Westin said.

Looking Ahead

CAR T-cell therapy has the potential to move into the first-line setting. This would require a randomized trial to prove efficacy. Currently, discussions are ongoing to evaluate CAR T cells in high-risk patients first line as a randomized trial compared with standard of care.

There are no data from randomized trials of CAR T cells as first-line treatment in large B-cell lymphoma. The results of a single-arm, phase 2 study of axi-cel, ZUMA-12 (NCT03761056), as nearly first-line therapy were recently published.5In the trial, patients (n = 40) whose high-risk disease did not respond well to 2 cycles of initial chemotherapy were switched early to CAR T-cell therapy. The primary end point of complete response rate, met in 37 efficacy-evaluable patients, was 78%, with an 89% overall response rate. At a median follow-up of 15.9 months, 73% of patients remained in objective response, and event- and progression-free survival were not reached. The safety profile was manageable.⁵

“I think the likely next steps for moving CAR T cell beyond third line and even beyond second line would be to look at a randomized trial in the front line in patients that have high-risk disease to see if CAR T cells could eventually improve outcomes vs chemotherapy,”Westin said.

Newer Versions of Cellular Therapies

Westin thinks a lot of newer cell therapy products that are based on natural killer (NK) cells, different types of T cells, or T cells modified in a novel way have significant advantages in that they are off the shelf. “That is very important to patients with an aggressive cancer who might have to wait 3 or 4 weeks for an autologous CAR T cell to be manufactured,” he said. “If the off-the-shelf products prove to have a similar efficacy, the ability to treat a patient [sooner] as opposed to waiting a month is a huge competitive advantage.”

Westin thinks these newer cellular therapies realistically have a potential for use in the clinic. “There are a lot of phase 1 studies and some phase 2 data coming out now for these newer agents. These early trials are usually designed as phase 1/2 trials so the efficacy data come out relatively quickly,” he said. “There are no phase 3 trials yet in a mature stage of enrollment for any of the newer products. There are plans to do that.”

Promising trials include a phase 1/2 trial of an off-the-shelf, allogeneic anti-CD19 CAR T-cell product that targets both CD19 and CD22 (NCT04416984). In this product, human leukocyte antigens and native T-cell receptor gene expression have been disrupted to reduce the risk of rejection and graft-vs-host disease (GVHD).6Another ongoing phase1/2 study (NCT03287817) of this dual-targeting CAR T-cell therapy in R/R DLBCL is exploiting the strategy of adding limited duration anti-PD1 immunotherapy to reduce the likelihood of relapse.⁷

NK cells are innately cytotoxic and can be obtained from allogeneic sources, including umbilical cord blood, human embryonic stem cells, peripheral blood, and NK cell lines.8 Allogeneic CAR-transduced products generated from NK cells appear to have a lower risk of the cytokine release syndrome (CRS) and neurologic toxicities associated with “conventional” CAR T cells, as well as a lower risk of GVHD than T-cell derived cellular therapies. ^6,8

“The cell therapy era is just beginning,” Westin said. “We’ve got high hopes that the existing products are the first available, not the only available, and that we’ll see additional approvals in the next couple of years.”

Trial Challenges and Questions

When asked if the comparator for randomized phase 3 trials of these newer cellular therapies might be standard-of-care or CAR T-cell therapies, Westin said designing the studies and determining the proper end points are complicated. To an extent, that may depend on what comes out of discussions between the FDA and the companies developing these therapies. One issue is that the standard of care is changing, making it difficult to have a proper control arm for a randomized trial as the treatment landscape rapidly shifts, and clinical trials, particularly large ones, take time to reach their primary end point.

You have to be mindful that as the ground is shifting, your study can become irrelevant if you design it in a way that you’re not allowing for that data to line up where the puck is going vs where it is right now. I think that’s certainly a problem for the newer CAR T cells. How do they move into a space that has changed from their initiation to their completion? How do they navigate that? It’s a great problem for our patients that we’ve got so many good options. It is a challenging one from a regulatory perspective to make sure that we are evaluating drugs fairly against modern treatments,” Westin said.

Bispecific Antibodies

Position in the Treatment Paradigm

Westin thinks bispecific antibodies have high potential as a therapy that might be available to patients in the coming year or two. He describes bispecific antibodies as an off-the-shelf, potent immune therapy that brings immune cells “up close and personal” with the lymphoma cells, with an immune-directed therapeutic effect. These agents combine 2 antigen-binding regions targeting CD20 on B cells and engaging T cells via CD3.⁹

Four bispecifics are in phase 1 and/or 2 trials for aggressive lymphomas as single agents or in combination with other agents, including immunomodulatory drugs, other antibodies, antibody-drug conjugates, and/or chemotherapy.⁹ Ongoing phase 3 trials of these agents include glofitamab in combination with gemcitabine plus oxaliplatin vs rituximab (Rituxan) in combination with gemcitabine plus oxaliplatin in R/R DLBCL (NCT04408638); epcoritamab vs investigator choice of chemotherapy in R/R DLBCL (NCT04628494); and mosunetuzumab in combination with polatuzumab vedotin (Polivy) compared with rituximab in combination with gemcitabine plus oxaliplatin in R/R aggressive B-cell non-Hodgkin lymphoma (NCT05171647).

Potential Advantages

Westin said bispecific antibodies have huge potential both as single agents and in combination with other treatments. Another potential advantage of bispecific antibodies is that because their toxicities, including CRS and neurologic toxicities, are less severe than those associated with CAR T cells,⁹ it may be possible to administer them outside a CAR T-cell center.

“It’s certainly possible that bispecifics might have a much bigger reach in terms of geography or logistics where patients may actually receive these treatments, not needing to travel all the way to a CAR T-cell center,” he said. With toxicities usually limited to the first few cycles, bispecific therapy might be administered at a center experienced in transplantation or CAR T-cell therapy for those first few cycles, after which patients could return to their primary oncologist’s office to continue therapy once they are much less likely to experience toxicities.

“I am very impressed by the activity, the efficacy, of bispecifics. I think their potential application may expand to reach more patients than we are currently reaching with CAR T cells,” Westin said.

Open questions

Whereas CAR T-cell treatment is “one and done,” treatment duration for bispecific antibodies remains an issue to resolve. Some agents have an open-ended administration, with treatment until progression or toxicity, whereas others are administered as fixed-duration therapy.⁹ Westin believes patients prefer fixed-duration treatment that allows them to plan for life off therapy. However, it is not clear if remission will be durable once therapy ends. He pointed out that with CAR T cells, a complete response can be durable. “With bispecifics, we’re hopeful that’s the case, but we just don’t have the large data sets to be confident about it,” he said.

Antigen escape or loss of the antigen targeted by a treatment is one mechanism of CAR T-cell therapy failure. It can also occur with bispecific antibody treatment. Westin pointed out that whereas CAR T-cell therapies for large B-cell lymphoma often target CD19, most bispecifics for this disease target CD20, the target of rituximab and other monoclonal antibodies, along with CD3.⁹ Decreased expression or loss of expression is a concern for both targets.

Westin said one of the strengths of bispecific antibodies is their ability to be combined with other treatments. “It’s certainly possible that you could reduce the risk of antigen escape if you are targeting more than one B-cell antigen at the same time,” he said.

In Conclusion

“I’m excited for the SOHO conference, both to learn the most cutting-edge science and how to treat hematologic malignancies, as well as to interact with colleagues and other investigators and community oncologists to try and further our ability to help our patients in all the ways that we can,” Westin said. “It’s wonderful to be able to see people back in person. Zoom has worked very well for what it was intended for, but it’s limited in its ability to foster collaborations and connections the way that being in person can. I’m grateful that we’re able to gather in person, at least for those that are able to attend. We’re happy to see people coming back in the flesh to the SOHO congress,” he concluded.

_References

_{1. Gill S, Brudno JN. CAR T-cell therapy in hematologic malignancies: clinical role, toxicity, and unanswered questions. Am Soc Clin Oncol Educ Book. 2021;41:1-20. doi:10.1200/EDBK_320085}

_{2. FDA approves axicabtagene ciloleucel for second-line treatment of large B-cell lymphoma. FDA. April 1, 2022. Accessed August 24, 2022. https://bit.ly/3AN0Vwj}

_{3. FDA approves lisocabtagene maraleucel for second-line treatment of large B-cell lymphoma. FDA. June 24, 2022. Accessed August 24, 2022. https://bit.ly/3Cx3uUL}

_{4. Westin J, Sehn LH. CAR T cells a second-line therapy for large B-cell lymphoma: a paradigm shift?. Blood. 2022;139(18):2737-2746. doi:10.1182/blood.2022015789}

_{5. Neelapu SS, Dickinson M, Munoz J, et al. Axicabtagene ciloleucel as first-line therapy in high-risk large B-cell lymphoma: the phase 2 ZUMA-12 trial. Nat Med. 2022;28(4):735-742. doi:10.1038/s41591-022-01731-4}

_{6. Haydu JE, Abramson JS. CAR T-cell therapies in lymphoma: current landscape, ongoing investigations, and future directions. J Cancer Metastasis Treat. 2021;7:36. doi:10.20517/2394-4722.2021.39}

_{7. Ramakrishnan A, Ardeshna KM, Batlevi CL, et al. Phase 1 Alexander study of AUTO3, the first CD19/22 dual targeting CAR T cell therapy with pembrolizumab in patients with relapsed/refractory (r/r) DLBCL. Presented at: 62nd American Society of Hematology Annual Meeting; December 5-8, 2020; virtual. Accessed August 24, 2022. https://bit.ly/3TePogt 10.1200/JCO.2021.39.15_suppl.2529}

_{8. Moreno C, Haynie C, Johnson A, Weber KS. Alternative CAR therapies: recent approaches in engineering chimeric antigen receptor immune cells to combat cancer. Biomedicines. 2022;10(7):1493. doi:10.3390/biomedicines10071493}

_{9. González Barca E. Role of bispecific antibodies in relapsed/refractory diffuse large B-cell lymphoma in the CART Era. Front Immunol. 2022;13:909008. doi:10.3389/fimmu.2022.909008}