Recent findings published in Blood identify the potential role of CD20 loss in causing resistance to mosunetuzumab in relapsed or refractory (R/R) non-Hodgkin B-cell lymphomas.1
CD20’s relatively selective expression on B cells makes it a good target for the treatment of non-Hodgkin B-cell lymphomas; CD20-targeted therapeutics, initially with rituximab, helped revolutionize disease treatment. More recently, scientists have investigated the potential of bispecific antibodies such as mosunetuzumab, a first-in-class agent that targets CD20 while also engaging with CD3 on T cells, redirecting them to eliminate malignant B cells.2
One mechanism of resistance to B-cell directed therapies is the loss of the target antigen, which has been shown in several lymphoid malignancies. For example, loss of CD19 to chimeric antigen receptor (CAR) T-cell therapies and loss of CD20 on relapse following rituximab can lead to resistance via mechanisms such as alternative splicing.1,3
Mosunetuzumab has shown an overall response of 78% in a phase II trial of adult patients with R/R follicular lymphoma (FL) who had received at least two lines of therapy with durable response; it received accelerated approval for this indication.1,4,5
Stephen J. Schuster, MD, director of the lymphoma program at the Abramson Cancer Center at the University of Pennsylvania in Philadelphia, explained that he and his colleagues wanted to use biopsy data from this same trial to explore the regulation of CD20 expression, which is encoded by the MS4A1 gene.
“We had observed that a significant number of our patients who had progression of their lymphoma during CD20-directed bispecific antibody therapy had lost the CD20 target on their tumor cells,” Dr. Schuster said.
The team analyzed CD20 expression in cancer biopsies collected before treatment with mosunetuzumab. A smaller group of biopsies was also available as paired samples at pretreatment and during treatment or at pretreatment and progression. They studied the biopsy samples using immunohistochemistry (IHC), RNA sequencing, and whole-exome sequencing.1
Before treatment, 5.5% (n=16) of the 293 biopsies had a low proportion of tumor cells that expressed CD20 (<10%), and thus had already had significant CD20 loss. Analyses of sequential biopsies showed that 97% (29 of 30) maintained CD20 expression during treatment. In contrast, 34% (11 of 32) of samples taken from patients who had progressed showed loss of CD20.1
Using genetic analyses and in vitro modeling, the team concluded that reduced transcription or mutations in the MS4A1 gene explained most of the cases of CD20 loss, but not all. The binding site for mosunetuzumab was absent or ineffective in these cells.1
The relatively low number of paired samples is one potential limitation of the study. Additionally, the study does not identify the mechanisms of treatment resistance in the patients who progressed but without loss of CD20.
Biopsy IHC for CD20 is a readily available test, and biopsy results may impact clinical management in some patients. “It is essential to perform a biopsy to determine CD20 expression by tumor cells in patients who have had prior anti-CD20-directed therapy,” Dr. Schuster emphasized. “Even the presence of heterogeneous CD20 expression by tumor cells may be an indication that a CD20-negative clone may emerge.”
Dr. Schuster pointed out that the antibody used by clinical labs is unaffected by recent exposure to other anti-CD20 antibodies, but evaluating for CD20 via flow cytometry might be misleading in this setting.
Dr. Schuster also believes that the mechanisms of CD20 loss are likely to be similar when using a monospecific monoclonal antibody therapy such as rituximab, although they may not occur as frequently.
Updated data from the original phase II study in R/R FL were recently presented as an oral abstract at the 2023 ASH Annual Meeting and Exposition; the therapy continues to show durable results at three-year follow-up.5
Any conflicts of interest declared by the authors can be found in the original article.
References
- Schuster SJ, Huw LY, Bolen CR, et al. Loss of CD20 expression as a mechanism of resistance to mosunetuzumab in relapsed/refractory B-cell lymphomas [published online ahead of print, 2023 Dec 4]. Blood. doi: 10.1182/blood.2023022348.
- Tavarozzi R, Zacchi G, Pietrasanta D, et al. Changing trends in B-cell non-Hodgkin lymphoma treatment: the role of novel monoclonal antibodies in clinical practice. Cancers (Basel). 2023;15(22):5397.
- Ang Z, Paruzzo L, Hayer KE, et al. Alternative splicing of its 5'-UTR limits CD20 mRNA translation and enables resistance to CD20-directed immunotherapies. Blood. 2023;142(20):1724-1739.
- Budde LE, Sehn LH, Matasar M, et al. Safety and efficacy of mosunetuzumab, a bispecific antibody, in patients with relapsed or refractory follicular lymphoma: a single-arm, multicentre, phase 2 study. Lancet Oncol. 2022;23(8):1055-1065.
- Schuster SJ, Sehn LH, Bartlett NL. Mosunetuzumab monotherapy continues to demonstrate durable responses in patients with relapsed and/or refractory follicular lymphoma after ≥2 prior therapies: 3-year follow-up from a pivotal phase II study. Blood. 2023;142(Suppl 1):603.
