Bi-targeting Approach for Overcoming Drug Resistance in Follicular Lymphoma

BACKGROUND

Over a million people across the world have follicular lymphoma.  Lymphoma is a type of blood cancer where a subset of white blood cells (lymphocytes) grows out of control, dividing abnormally or failing to die when they should.  Follicular lymphoma is the second most common subtype that arises from B lymphocytes. Follicular lymphoma is characterized by the formation of abnormal clumps, or “follicles,” of lymphocytes within the lymph nodes and other parts of the body (1).

Follicular lymphoma is generally associated with long survival rates, with improving outcomes in recent years. Important advances include the use of rituximab and other antibodies to the CD20 surface maker (2), and the use of lenalidomide, a second-generation small molecule immunomodulatory drug, that causes degradation of specific proteins crucial for cancer cell survival (3).  This non-chemotherapy treatment has fewer side effects. Although the 5-year survival rate for follicular lymphoma is 90%, approximately 10% of follicular lymphoma patients under treatment with rituximab in combination lenalidomide succumb to the disease and die within five years of diagnosis (2).  The disease would still be fatal to more than 100,000 people worldwide within 5 years of diagnosis if treated with the rituximab/lenalidomide combination.  A publication by Zheng et al in 2025 showed exciting promise for helping those that do not respond to this therapy (4).

SUMMARY

Zheng et al in 2025 investigated a bispecific antibody for use in drug resistant follicular lymphoma, that targets two components of the immune system that are involved with cancer survival, PD-L1 and 4-1BB.

Programmed cell death ligand 1 (PD-L1) is a protein found on the surface of immune cells and cancer cells. It plays a role in regulating the immune response.  When PD-L1 binds to its receptor PD-1, on immune cells, it signals immune cells to stop attacking other cells. This helps prevent the immune system from attacking healthy tissues. In cancer, tumor cells often express high levels of PD-L1. This can help them evade the immune system by blocking the activation of T cells, which are immune cells that fight cancer.  In contrast, 4-1BB is expressed on various immune cells, particularly T cells and natural killer (NK) cells and enhances function, such as the ability to kill tumor cells.

The bi-specific antibody under investigation has two ‘arms’.  One arm of the antibody blocks PD-L1 on tumor cells from binding the receptor on T-cells, thereby preventing immune inhibition.

The other arm binds 4-1BB. The 4-1BB antibody is an agonist that activates T cells.  As a result, the bi-specific antibody has two functions, one to block inhibition, and the other to activate the anti-cancer immune response. Zheng et al. show through human cell in vitro and murine in vivo studies that the use of the PD-L1 / 4-1BB bispecific antibody can be an alternative immunotherapeutic – chemotherapy strategy for follicular lymphoma treatment.

Mechanisms of lenalidomide resistance in follicular lymphoma

Follicular lymphoma patients treated with lenalidomide were analyzed by gene expression.  One gene that stood out was PU.1.  The investigators demonstrated follicular lymphoma PD-L1 and 4-1BB expression were regulated by PU.1.  In vitro (cell culture) models were studied, where follicular lymphoma cell lines were co-cultured with human blood dendritic cells.  Dendritic cells enhance immune responses but are inhibited by follicular lymphoma cells.  The inhibition was found to involve PU.1, which contributed to aberrant tumor immunity and poor response to lenalidomide in progressing patients. The authors concluded that PU.1 mediates lenalidomide resistance through lymphoma cell PD-1 and 4-1BB interaction with adjacent immune cells.

The PD-L1 / 4-1BB bispecific antibody is active in an in vitro model of lenalidomide resistance

In vitro results pointed to the potential for the bi-specific antibody to overcome lenalidomide resistant follicular lymphoma.  Scientists genetically modified the SC-1 human follicular lymphoma cancer cell line to become lenalidomide resistant. The lenalidomide resistant SC-1 cells inhibited activity of peripheral blood dendritic cells in a co-culture system. Dendritic cells function to enhance an anti-tumor immune response. The PD-L1/4-1BB bispecific antibody counteracted the SC-1 mediated inhibition.

PD-L1 and 4-1BB antibody combination inhibits tumor growth in a lenalidomide resistant mouse model

In vivo results demonstrated that the combined PD-L1 / 4-1BB intervention can overcome the lenalidomide resistance.  Mouse B cell lymphoma A20 cells that were genetically modified to become lenalidomide resistant were subcutaneously implanted into mice. Combination treatment of PD-L1 and 4-1BB antibodies enhanced lenalidomide anti-lymphoma activity on modified A20 tumor growth in vivo.

Other bispecific antibodies approved by the US FDA for follicular lymphoma

  •  Mosunetuzumab (Lunsumio): Approved in 2024 for adults with advanced FL who have received at least two prior therapies. It showed an overall response rate of 66% and a complete response rate of 49% in clinical trials.
  • Epcoritamab (Epkinly): Approved in July 2024 for relapsed or refractory FL. In clinical trials, 82% of patients responded positively, with 60% achieving complete remission.
  • Glofitamab (Columvi): Received accelerated FDA approval for certain lymphomas that have relapsed or worsened after at least two other treatments.

CONCLUSION

Rituximab plus lenalidomide are an effective chemotherapy-free immunotherapy treatment for follicular lymphoma in most cases.  Unfortunately, a significant number of patients do not respond to treatment and succumb to disease.  As an alternative to current therapy, Zheng et al. demonstrate an exciting potential treatment using a bispecific antibody to overcome lenalidomide resistance.

REFERENCES

  1. Ennishi D. Recent advances in understanding of pathogenesis and treatment development for diffuse large B-cell lymphoma and follicular lymphoma. Int J Hematol. 2025 Feb 10.
  2. Rajamaki et al. Mortality among patients with low-grade follicular lymphoma: A binational retrospective analysis. Cancer 128:2474, 2022.
  3. Fink and Ebert. The novel mechanism of lenalidomide activity. Blood 126:2366,2015
  4. Zheng et al. Dual targeting PD-L1 and 4-1BB to overcome dendritic cell-mediated lenalidomide resistance in follicular lymphoma. Nature Signal Transduction and Targeted Therapy 10:29,2025

 

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