Photo by Linda Bartlett
Monoclonal antibodies
Combination treatment with 2 monoclonal antibodies (mAbs) has demonstrated preclinical efficacy against B-cell lymphomas, according to researchers.
The investigators tested different combinations of mAbs to see how they interact with each other and what effect this has on how the immune system fights cancer.
One combination—an anti-CD27 mAb and anti-CD20 mAb—greatly increased survival in mouse models of B-cell lymphoma.
The researchers reported these results in Cancer Cell.
“By combining 2 specific antibodies—anti-CD27 and anti-CD20—we’ve increased the ability of the immune system to destroy cancer cells,” said study author Sean Lim, MBChB, PhD, of the University of Southampton in the UK.
“It’s very exciting to see that this drug combination has an impact on survival of mice with lymphoma, as improvements in treatment are urgently needed. The next stage will be to see if what we’ve discovered can be replicated in patients.”
For this study, Dr Lim and her colleagues tested combinations of tumor-targeting mAbs and immunomodulatory mAbs. The group found that an anti-CD27 mAb enhanced anti-CD20 therapy in various preclinical models.
The investigators first tested anti-CD20 and anti-CD27 (both alone and in combination) in the murine B-cell lymphoma model BCL1.
All control BCL1 mice had died by 30 days from baseline, all mice that received anti-CD20 alone died by day 40, and 30% of mice that received anti-CD27 alone were still alive past 100 days.
In contrast, 100% of mice that received anti-CD20 and anti-CD27 in combination were still alive and lymphoma-free past the 100-day mark.
The researchers also tested the mAbs in the A31 B-cell lymphoma model and the Eµ-TCL1 B-chronic lymphocytic leukemia model.
Results were similar to those observed with the BCL1 model. The combination of anti-CD20 and anti-CD27 significantly improved survival in A31 and Eµ-TCL1 mice, with all mice that received this combination surviving past 100 days.
As far as mechanisms of action, the investigators noted that anti-CD20 binds to B cells and mediates antibody-dependent cellular phagocytosis of the mAb-opsonized cells.
The researchers said the addition of anti-CD27 stimulates CD8+ T cells and natural killer cells, which induces the release of CCL3, CCL4, and CCL5, and this potentially attracts myeloid cells.
In addition, anti-CD27 (via the stimulation of CD8+ T and natural killer cells) induces the release of interferon gamma, which activates macrophages to express more Fc gamma receptor IV and promotes their inflammatory capacity. This increases the number of macrophages available for antibody-dependent cellular phagocytosis as well as the cells’ phagocytic ability.
Based on these findings, researchers are now conducting a phase 2 trial to test the anti-CD20 mAb rituximab and the anti-CD27 mAb varililumab in patients with relapsed and/or refractory B-cell non-Hodgkin lymphoma.
