Immunotherapy Combinations Deliver Outcome-Shifting Responses in Lymphoma

Stephen Ansell, MD, PhD

Immunotherapy has become a valuable tool for the treatment of patients with various types of lymphomas because of its ability to specifically target cancer cells, particularly those in blood cancers, according to Stephen Ansell, MD, PhD.

Compared with chemotherapy of the past, where treatment was focused on killing all quickly growing cells, including cancer cells, evolving research has now shown that immunotherapies can be combined with one another and used to specifically target the cancer cells.

Immunotherapy works well in blood cancers because the tumor may be more accessible in the blood, according to Ansell, who is a professor of medicine in the Mayo Clinic College of Medicine and Science in Rochester, Minnesota, and the chair of the Division of Hematology. “Infused products may get to the tumor cells more easily compared with solid tumors where there are greater barriers due to immune inhibition around the tumor,” he said in an interview ahead of the SOHO 2023 meeting.

Ansell presented “Harnessing the Immune System in Patients With Lymphoma” during the Saturday morning breakfast session in Houston, Texas.¹ “It’s enjoyable to have interactions with other speakers and colleagues related to these topics,” Ansell said. “Many of my collaborations and fun projects have come from conversations that started after a stimulating talk. There is real value to be together in person.”

Engage the Immune System

The presentation focused on 3 key components to help understand what a hematologic oncologist needs to think about when considering immunological therapies: an inflamed versus noninflamed tumor environment, the functional state of immune cells including T cells, and the characteristics of the individual patient.

“Many times, when the tumor is less inflamed with fewer immune cells present, macrophages predominate at the sites of malignancy versus more inflamed tumors where T cells predominate,” Ansell said.

To use the immune system effectively, it’s crucial to know the function of T cells. For instance, while some T cells can be actively targeting lymphoma cells, many are suppressed by other cells or the tumor itself, some are immunologically exhausted, and some are so dysfunctional they are immunologically worthless, he explained.

“As you’re thinking about which therapies you want to use, I think it’s important to understand the state of immune cells around the tumor that you wish to engage,” Ansell said.

Aside from understanding the immune cells in the tumor microenvironment, it is also important to be aware of the immune response in the patient overall, particularly T cells in the peripheral blood—the patient ‘macroenvironment.’ “Therapies such as bispecific specific antibodies may actually engage immune cells in the blood and bring them into the tumor, and so the functional state of T cells in the peripheral blood is important,” he said.

Forefront: CARS and Bispecifics

Many of the FDA-approved immunotherapies are open to a broader group of patients today than years ago because adverse event management has advanced. Historically, monoclonal antibodies and antibody-drug conjugates have been used to treat patients with lymphoma.² More recently, chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies have become front and center.

Pivotal clinical trials have demonstrated that using CAR T-cell therapy has a survival advantage. For instance, lisocabtagene maraleucel (Breyanzi; liso-cel) elicited significant responses in patients with diffuse large B cell lymphoma (DLBCL) and follicular lymphoma who have relapsed or became refractory post stem cell transplant, such as in the phase 2 TRANSCEND FL and phase 1 TRANSCEND NHL 001 studies.³

In the phase 3 TRANSFORM trial, liso-cel improved median event-free survival, 10.1 months compared with 2.3 months in the standard care group.⁴

Another potential second-line treatment option is axicabtagene ciloleucel (Yescarta; axi-cel) for patients with relapsed or refractory large B cell lymphoma. In the ZUMA-7 study, median event-free survival was 8.3 months in the axi-cel arm compared with 2 months in the standard care arm at the median follow-up of 24.9 months.⁵

“These results are really changing our thinking. We initially thought that these treatments should be kept for later lines of treatment but the results in second-line are really making the case that the sooner in the disease course you use CAR-T cells, the better patients will do,” Ansell said.

‘The Beginning of the Beginning’

Cutting-edge research involving lymphomas continues to shine in early-phase clinical trials, such as with armored CARs.

“Armored CARs are CAR-T cells engineered to make products that protect them, or cytokines that keep them activated, or are engineered to actually lack inhibitory receptors that would switch them off,” Ansell said.

Most recently, the first in-human phase 1 clinical trial of cytokine-secreting armored CAR proved to be safe and induced durable responses in patients with lymphoma who were refractory or relapsed following second-generation CD19-targeted CAR T-cell therapies.⁶

Sixteen patients, who were mostly men (77%), were enrolled to receive huCART19-IL8, a 4th generation CAR-T product that expresses humanized anti-CD19 CAR and secretes interleukin 18. The median number of prior therapies was 8. Study findings showed a 3-month overall response rate of 82% and a complete response rate of 55%. At 12 months, the progression-free survival rate was 54% (95% CI, 15%-81%). All patients were alive at a median follow-up of 12 months.

Similarly, in the field of bispecific antibodies, there are new targets on malignant cells being tested and new ways to activate immune cells that are being explored. Bispecific antibodies that bind to different receptors, sometimes on different immune cells, are being tested. These include bispecific antibodies that target multiple immune checkpoints on T cells or antibodies that bind to cells from the innate immune system, such as macrophages and monocytes, Ansell explained.

“We’re only at the beginning of the beginning when it comes to some of these CAR T-cell and bispecific therapies because many of the treatments being tested are going after targets that haven’t been explored before,” Ansell said.

Taking it a step further, trispecific antibodies, also known as TriKEs, are also being examined by investigators for the treatment of lymphoma. These antibodies bring T cells and the tumor cell into close proximity but additionally have a third binding site to provide an additional activating signal to immune cells, according to Ansell. These could become helpful when there are low response rates to previous immune therapies due to anergic T cells. Some phase 1 trials are ongoing exploring trispecific antibodies in DLBCL and non-Hodgkin lymphoma (NHL). In the NHL trial, investigators hope to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of GNC-038 quad-specific antibody injection in relapsed or refractory NHL, relapsed or refractory acute lymphoblastic leukemia, and refractory or metastatic solid tumors.⁷ GNC-038 will also be evaluated for safety and tolerability in those with recurrent or refractory DLBCL.⁸

In addition to T cells, clinical trials are testing the use of chimeric antigen receptor NK cells or monocytes and these may be valuable in the years ahead. Several clinical trials are examining these cells in patients with blood cancers, which could one day potentially lead to an FDA approval.

The Future is Immunotherapy

Ansell is attracted to immunotherapy in the lymphoma space for many reasons. The biggest reason is that immunotherapy has real value in many different types of lymphoma. He also enjoys studying the biology of lymphoma and understanding how lymphoma cells interact with the immune system, and by doing so, helping to develop treatments that may potentially change patient outcomes. While many patients with lymphoma respond well to therapy, we want to make all subtypes of lymphoma highly curable cancers, he explained.

“We have far more tools to treat lymphoma patients now than we did 30 years ago when I started,” Ansell said. “I’m pleased to see that these new tools are impacting the overall survival of patients. We are seeing trials where the overall survival has clearly improved when we compare the standard treatment to immunotherapy. These results are really pushing the field forward.”

References

1. Ansell S. Harnessing the immune system in patients with lymphoma. Presented at: SOHO 2023; Sept. 9; Houston, TX.
2. Understanding Immunotherapy and Lymphoma. Lymphoma Research Foundation. Accessed July 11, 2023. https://lymphoma.org/wp-content/uploads/2021/12/LRF-Immunotherapy_Factsheet.pdf
3. Rosa K. Liso-cel Induces Statistically Significant Responses in R/R Follicular Lymphoma and Mantle Cell Lymphoma. OncLive. May 1, 2023. Accessed July 11, 2023. https://www.onclive.com/view/liso-cel-induces-statistically-significant-responses-in-r-r-follicular-lymphoma-and-mantle-cell-lymphoma
4. Kamdar M, Solomon S, Arnason J, Johnston P, Glass B, Bachanova V, et al. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022;399(10343):2294-2308. doi:10.1016/S0140-6736(22)00662-6
5. Locke F, Miklos D, Jacobson C, Perales M-A, Kersten M-J, Oluwole O, et al. Axicabtagene ciloleucel as second-line therapy for large b-cell lymphoma. N Engl J Med. 2022;386:640-654. doi:10.1056/NEJMoa2116133
6. Svoboda J, Landsburg DL, Chong EA, Barta SK, Nasta SD, Ruella M, et al. Fourth generation huCART19-IL18 produces durable responses in lymphoma patients previously relapsed/refractory to anti-CD19 CAR T-cell therapy. Hematol Oncol. 2023;41(suppl 2):35-37. doi:10.1002/hon.3163_6
7. Phase I clinical study of GNC-038 in patients with hon-hodgkin’s lymphoma or acute lymphoblastic leukemia. ClinicalTrials.gov identifier: NCT04606433. Updated March 15, 2023. Accessed July 16, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04606433
8. A study of GNC-038, a tetra-specific antibody, in participants with R/R diffuse large b-cell lymphoma (DLBCL). ClinicalTrials.gov identifier: NCT05192486. Updated March 21, 2023. Accessed July 16, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT05192486