Immune Microenvironment a Key Target in CLL

Immunotherapies may be able to improve outcomes for patients with chronic lymphocytic leukemia (CLL) by counteracting the immunosuppressive microenvironment of the cancer, according to a new report.¹ The new review article, published in the European Journal of Haematology, outlined some of the latest evidence supporting immunotherapy in CLL and discussed how immunotherapy may help overcome treatment resistance.

The authors explained that while molecularly targeted therapies like Bruton tyrosine kinase (BTK) inhibitors and B-cell leukemia/lymphoma-2 (BCL-2) inhibitors can target aberrant signaling pathways and molecular defects associated with CLL, many patients go on to develop resistance to therapy. Reasons for resistance, they noted, include tumor heterogeneity, disease clone persistence, and the supportive tumor microenvironment.

They said the tumor microenvironment “facilitates a complex, dynamic, and redundant signaling network” that promotes the survival and proliferation of the disease clone. “In turn, the disease clone modifies the tumor microenvironment to create a protective niche from eliciting an immune response,” they wrote.

Thus, they said, targeting the immune microenvironment itself has become an important avenue of investigation in CLL.

Recent trials have explored potential strategies for using immunotherapy in chronic lymphocytic leukemia. | Image credit: Spectral-Design - stock.adobe.com

The researchers used the National Library of Medicine’s PubMed database to identify current research related to the immune microenvironment of CLL. They found 19 trials of emerging or novel therapeutic agents targeting the immune microenvironment in CLL and more than 2 dozen active trials of novel combination strategies for CLL or small lymphocytic leukemia (SLL) with immune microenvironment implications.

Among the therapies being investigated are immune checkpoint inhibitors (ICIs), though the authors explained that such studies have largely failed to spark meaningful responses. One significant exception, though, is in patients with Richter transformation to aggressive lymphoma. Multiple studies have suggested that the combination of the programmed cell death protein-1 (PD-1) inhibitor nivolumab (Opdivo) and the BTK inhibitor ibrutinib (Imbruvica) achieves responses in patients with RT. One study, a phase 1/2a trial published in 2019, found 65% of patients with RT responded to the combination.² The authors noted that the National Comprehensive Cancer Network currently recommends ICIs with or without ibrutinib as a treatment option for RT.

Therapeutic antibodies have also been developed for the treatment of CLL. The authors said novel bispecific antibodies and other immunotherapies are being investigated for patients with relapsed or refractory CLL. Among them are epcoritamab (Epkinly), a CD3xCD20 bispecific T-cell engager. A trial published last year found it led to encouraging results in patients with relapsed or refractory CLL, regardless of high-risk features, such as TP53 aberrations.³

Trispecific antibodies and combination therapies are also being studied to improve tumor specificity or immune-cell activation.

Chimeric antigen receptor (CAR) T-cell therapies are another area of significant study in CLL. The results have generally been mixed, though the authors noted that the CAR T-cell therapy lisocabtagene-maraleucel (Breyanzi) did show promise in a 2023 phase 1/2 trial of patients with relapsed or refractory CLL and SLL and at least 2 prior lines of therapy, including a BTK inhibitor.⁴ Those findings led the FDA to grant accelerated approval for the therapy in certain patients with CLL or SLL.

The researchers concluded a number of key questions surrounding the immune microenvironment in CLL still need to be resolved. Among them is how to address the large cohort of patients who relapse or experience progression despite therapy. However, they said the evolving evidence suggests immunotherapies may play a key role in overcoming the immunosuppressive microenvironment of CLL.

References

1. Chung C, Doan D. Targeting the Immune Microenvironment in Chronic Lymphocytic Leukemia: An Evolving Therapeutic Strategy. Eur J Haematol. Published online March 11, 2025. doi:10.1111/ejh.14408
2. Younes A, Brody J, Carpio C, et al. Safety and activity of ibrutinib in combination with nivolumab in patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukaemia: a phase 1/2a study. Lancet Haematol. 2019;6(2):e67-e78. doi:10.1016/S2352-3026(18)30217-5
3. Danilov A, Fakhri B, Awan FT, et al. Epcoritamab monotherapy in patients (pts) with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL): Results from CLL expansion and optimization cohorts of Epcore CLL-1. Blood. 2024;144(Suppl 1):883. doi:10.1182/blood-2024-199708.
4. Siddiqi T, Maloney DG, Kenderian SS, et al. Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1-2 study. Lancet. 2023;402(10402):641-654. doi:10.1016/S0140-6736(23)01052-8