FCRL5-Directed CAR T-Cell Therapy: A Novel Therapeutic Approach for Multiple Myeloma

In a recent study from Sichuan University, China, investigators identified a potential novel immunotherapeutic strategy for the treatment of multiple myeloma. The study found CAR T-cells specifically targeting Fc receptor-like 5 (FCRL5), a surface protein highly expressed on the plasma cells of patients with multiple myeloma, when integrated with interleukin-15 (IL-15), may improve cytotoxicity, thereby enhancing the therapeutic potency of these cells.¹

"The study's findings align with the known challenges of CAR-T therapy in multiple myeloma, such as antigen escape and T-cell exhaustion,” said Wael Harb, MD, board-certified hematologist and medical oncologist at Memorial Care Cancer Institute at Orange Coast Medical Center in Fountain Valley, California, and vice president of medical affairs at Syneos Health. “However, the successful incorporation of IL-15 to enhance T-cell persistence and anti-tumor efficacy of FCRL5-directed CAR T-cells is promising and may have been somewhat unexpected given the difficulties associated with improving CAR T-cell durability in clinical settings."

Multiple myeloma is a plasma cell dyscrasia characterized by clonal expansion of malignant plasma cells. The disease accounts for 1% of all cancers and 10% of tumors of hematologic origins globally, with a 58% 5-year survival rate in the United States.^2,3 The American Cancer Society estimates that there will be more than 35,000 newly diagnosed cases and more than 12,000 deaths expected in 2024 due to multiple myeloma in the United States.⁴

Although significant advancements have been made in the treatment of multiple myeloma, it remains an incurable disease, as most patients will relapse.⁵ In recent years, CAR T-cell therapy has emerged as a game-changing therapeutic approach in the treatment of refractory/relapsed multiple myeloma. There are various types of CAR T-cell therapies based on the antigen target. Among them, B-cell maturation antigen (BCMA)-targeted CAR T-cells have proven to be the most potent treatment for patients with multiple myeloma.⁶

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Despite the remarkable success of CAR T-cell therapy, a significant portion of patients with multiple myeloma still relapse following treatment. This may be due to several factors, including poor persistence of CAR T-cells, complicated tumor microenvironment, and antigen escape, requiring further exploration of potential alternative therapeutic targets.¹

Commenting on the challenges of CAR T-cell therapies, Harb said, "Current CAR T-cell therapies often face challenges like antigen loss leading to relapse, limited T-cell persistence, and severe side effects such as cytokine release syndrome and neurotoxicity. These challenges necessitate the development of new targets and strategies to enhance the efficacy and safety of CAR T therapies in multiple myeloma."

FCRL5, a protein surface marker highly expressed in plasma cells of patients with multiple myeloma, has recently gained traction among researchers as a potential target. A study published in Cancer Cell found anti-FCRL5/CD3, a T-cell-dependent bispecific antibody, to be a promising treatment strategy for patients with multiple myeloma.⁷ FCRL5 is not only expressed in malignant plasma cells but also promotes B-cell proliferation and isotype expression after antigen exposure, thereby emerging as a promising target for CAR T-cell therapeutic interventions, offering an alternative treatment for multiple myeloma.

"FCRL5 is overexpressed in multiple myeloma cells, particularly in those with chromosome 1q21 gain, making it a promising target for CAR T-cell therapy. It plays a role in B-cell proliferation and isotype switching, which are crucial for the survival and growth of myeloma cells," Harb said. "The current study highlights the potential of using FCRL5 as a new target in CAR T-cell therapy for multiple myeloma, especially given its persistent expression even after other therapies fail due to antigen escape. The incorporation of IL-15 to enhance the survival and persistence of CAR T-cells could represent a significant advancement in treating multiple myeloma."

In the current study published in Nature, the researchers engineered FCRL5-directed CAR T-cells.¹ To counter challenges like limited T-cell persistence and prevent disease relapse, they designed another variant of CAR T-cells that secretes IL-15 and incorporated it into the design of FCRL5-directed CAR T-cells to improve cytotoxicity and T-cell dysfunction, thereby enhancing CAR T-cell survival and activity.¹

While commenting on the clinical implications of the study findings, Harb said, "The study suggests that FCRL5-directed CAR T-cells, especially those engineered to secrete IL-15, could offer a new and effective therapeutic option for multiple myeloma patients, particularly those with a gain of chromosome 1q21, a subgroup known to have poorer outcomes. This approach could potentially overcome limitations related to antigen escape, a common cause of relapse in multiple myeloma treated with existing CAR T therapies."

In the study, the researchers assessed the therapeutic potential of FCRL5-directed CAR T-cells against multiple myeloma in both in vitro and in vivomodels, using a co-culture system and multiple myeloma cell-derived xenograft mouse models, respectively. They found that FCRL5-directed CAR T-cells incorporating IL-15 exhibited potent antitumor efficacy, effectively inhibiting the proliferation of multiple myeloma cells and leading to remarkable tumor suppression, suggesting a potential novel immunotherapeutic strategy for multiple myeloma treatment.¹

IL-15 is a pleiotropic cytokine produced by immune cells. It plays a vital role in the activation and proliferation of NK cells and CD8+ T cells, thereby augmenting the antitumor immune response. As a potent cytokine, IL-15 may also play a role in improving CAR T-cell survival and therapeutic efficacy. Evidence suggests that higher levels of IL-15 could improve CAR T-cell efficacy and in vivo persistence.⁸

"The study specifically leverages IL-15 to boost the survival and efficacy of FCRL5-directed CAR T-cells against multiple myeloma, which could help maintain long-term remission."

The data showed consistently elevated FCRL5 expression in patients with multiple myeloma, particularly among those with chromosome 1q21 gain, a frequent genetic aberration linked with disease progression.¹ Research reveals that the FCRL5 gene is located in the chromosomal breakpoint in 1q21, and a gain of 1q21 can lead to FRCL5 overexpression among patients with high-risk multiple myeloma.⁹

"Multiple myeloma with 1q21 amplification is associated with high-risk disease features and poor prognosis,” Harb said. “The study targeted this genetic aberration due to its prevalence in aggressive cases and known association with increased expression of FCRL5, making it a rational target for developing more effective treatments."

The FCRL5 levels were also elevated in relapsed patients who underwent CAR T-cell therapy targeting BCMA, and the elevated levels were associated with reduced disease-free survival times.¹

"The study's strength lies in its innovative approach to overcoming CAR-T cell therapy's limitations by targeting FCRL5 and incorporating IL-15. However, limitations include the need for clinical validation in diverse patient populations and long-term data on the safety and efficacy of this approach," Harb said. "Future research should focus on clinical trials to validate the efficacy and safety of FCRL5-directed CAR T-cells in patients. Additionally, exploring further genetic modifications to improve the robustness and durability of CAR T-cells would be beneficial."

REFERENCES

1. Yu Z, Li H, Lu Q, Zhang Z, Tong A, Niu T. Fc receptor-like 5 (FCRL5)-directed car-T cells exhibit antitumor activity against multiple myeloma. Signal Transduction and Targeted Therapy. 2024;9(1). doi:10.1038/s41392-023-01702-2
2. Urban VS, Cegledi A, Mikala G. Multiple myeloma, a quintessential malignant disease of aging: a geroscience perspective on pathogenesis and treatment. Geroscience. 2023;45(2):727-746. doi:10.1007/s11357-022-00698-x
3. Multiple myeloma - statistics. Cancer.Net. June 1, 2023. Accessed May 2, 2024. https://www.cancer.net/cancer-types/multiple-myeloma/statistics
4. Key statistics for multiple myeloma. Key Statistics for Multiple Myeloma | American Cancer Society. Accessed May 2, 2024. https://www.cancer.org/cancer/types/multiple-myeloma/about/key-statistics.html
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7. Li J, Stagg NJ, Johnston J, et al. Membrane-Proximal Epitope Facilitates Efficient T Cell Synapse Formation by Anti-FcRH5/CD3 and Is a Requirement for Myeloma Cell Killing. Cancer Cell. 2017;31(3):383-395. doi:10.1016/j.ccell.2017.02.001
8. Gauthier J, Chou C, Hirayama AV, et al. High IL-15 serum concentrations are associated with response to CD19 car T-cell therapy and robust in vivo car T-cell kinetics. Blood. 2020;136(Supplement 1):37-38. doi:10.1182/blood-2020-140120
9. Li J, Stagg NJ, Johnston J, et al. Membrane-Proximal Epitope Facilitates Efficient T Cell Synapse Formation by Anti-FcRH5/CD3 and Is a Requirement for Myeloma Cell Killing. Cancer Cell. 2017;31(3):383-395. doi:10.1016/j.ccell.2017.02.001