CD83 Could Be Meaningful Target Against MCL, Study Finds

A new study suggests the protein CD83 could be an important pathway to finding better therapies to treat a subgroup of patients with mantle cell lymphoma (MCL).

MCL is a relatively uncommon type of lymphoma, accounting for just 2.5%-6% of all non-Hodgkin lymphoma (NHL) cases in western countries. The cancer is currently incurable, with a median overall survival (OS) of 4-5 years.

A team of Australian investigators, including corresponding author Georgina J. Clark, PhD, of the University of Sydney, wanted to investigate whether the current treatment paradigm could be improved upon. Specifically, the team wanted to find out the extent to which CD83 is expressed in NHL, and whether or not it had therapeutic potential for the treatment of MCL.

Their findings were published in the journal Clinical & Translational Immunology.

The team analyzed CD83 expression using MCL cell lines as well as lymph node and bone marrow biopsies of patients with MCL. Samples from a total of 18 patients were used. Sixteen of the 18 were men, and the average age was 65.7 years. Clark and colleagues found that CD83 was upregulated in half of the primary MCL samples, and in some of the cell lines. Moreover, they found that upregulation of CD83 was tied to nuclear factor 𝛋B (NF-𝛋B) activation.

Of the 18 patients, 55.6% were in the “high-risk” category based on the Average Mantle Cell Lymphoma International Prognostic Index (MIPI). The remaining 44.4% were split evenly between the intermediate and low-risk categories. The authors said they found no correlation between CD83 expression levels and patient risk categories or stages.

The investigators then tested CD83 antibody drug conjugates (ADCs), which pair monoclonal antibodies with small molecules or toxins. The hope was that a CD83 ADC would target MCL effectively, with less toxicity than conventional chemotherapy.

The team tested CD83 ADC in vitro and in vivo, using an MCL mouse model. In both cases, the conjugate was effective.

Furthermore, Clark and colleagues noted that the current treatment for many patients with MCL is doxorubicin (Lipodox) and cyclophosphamide (CP). Those drugs have the effect of boosting NF-𝛋B activity, which in turn increases CD83 expression. Thus, CD83 ADC works “synergistically” with doxorubicin and CP to attack MCL.

“This study provides evidence that a novel immunotherapeutic agent CD83 ADC, incombination with chemotherapy, has the potential to enhance the efficacy of current treatments for MCL,” the authors concluded.

Clark and colleagues said ADCs are promising in part because they have been shown to be more effective than naked antibodies, across a wide range of antigen expression levels. They noted that CD33 ADCs have been shown to lead to meaningful responses against CD33-positive acute myelogenous leukemia tumors, even when the tumors have relatively low levels of CD33 expression. Clark and colleagues believe a CD83 ADC could be similarly successful in a significant portion of patients with MCL.

The authors said their findings could pave the way for better therapies for some patients with MCL. They said if their findings are borne out in further studies, clinicians would need to begin by identifying patients with CD83-positive MCL, and then apply the latest ADC techniques, using the resulting anti-CD83 ADC in combination with chemotherapy.

“In addition, targeting multiple pathways including the NF-𝛋B pathway potentially overcomes resistance as a result of targeting a single pathway to treat MCL,” they wrote.

Reference

Li Z, Abadir E, Lee K, et al. Targeting CD83 in mantle cell lymphoma with anti-human CD83 antibody. Clin Transl Immunology. Published online July 15, 2020. doi:10.1002/cti2.1156