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Preclinical research suggests that immune stimulation through Toll-like receptor 7 (TLR7) agonism can enhance the efficacy of obinutuzumab in lymphoma.
Researchers found that combining the anti-CD20 monoclonal antibody obinutuzumab with the TLR7 agonist R848 improved survival in lab mice with lymphoma.
The combination also demonstrated efficacy against chronic lymphocytic leukemia (CLL) cells in vitro.
Tim Illidge, PhD, MBBS, of the University of Manchester in the UK, and his colleagues reported these findings in the journal Leukemia.
The research was funded by the Kay Kendall Leukaemia Fund and Cancer Research UK in collaboration with Roche Pharmaceutical Research and Early Development.
The researchers said they initially found that R848 activates immune cells in vivo and enhances obinutuzumab-mediated antitumor effector mechanisms in vitro.
The team therefore went on to test R848 and obinutuzumab in C57Bl/6 mice bearing human CD20+ lymphoma (EL4). The mice received obinutuzumab modified to express the murine glycoengineered IgG2a Fc region (m2a) starting 1 day after tumor inoculation and systemic R848 once weekly for 4 weeks.
The researchers found that monotherapy with either obinutuzumab or R848 significantly improved survival compared to control (P<0.0001), but only 8% to 15% of mice that received monotherapy were long-term survivors (living more than 90 days).
Mice that received obinutuzumab in combination with R848 had significantly better survival than mice that received either monotherapy (P<0.0001). And about 70% of mice receiving the combination remained tumor-free out to 95 days.
Furthermore, long-term survivors that had received the combination treatment were protected from tumor re-challenge.
The researchers also tested the combination in a second model—human CD20 transgenic mice, which express the human CD20 antigen on normal B cells. The team said this model is more akin to the clinical situation.
The mice received treatment 7 days after the inoculation of EL4hCD20 cells. Mice that received obinutuzumab monotherapy had significantly better survival than control mice (P=0.02), but there were no long-term survivors. For mice that received R848 monotherapy, survival was not significantly different from that of controls.
Mice that received R848 in combination with obinutuzumab had significantly better survival than mice that received obinutuzumab alone (P=0.003).
In fact, 6 of the 12 mice that received the combination were long-term survivors. And 5 of these mice rejected tumor re-challenge.
“We were excited when we discovered that combining obinutuzumab with TLR7 activation significantly enhanced survival of animals with lymphoma by effectively eradicating tumors,” Dr Illidge said. “Clearly, more work needs to be done to assess the impact of this combination on humans, but this study is, nevertheless, very promising.”
The researchers said the primary antitumor activity of the combination is dependent on natural killer cells and CD4 helper T cells but not on CD8 killer T cells.
“While the combination therapy was highly effective, CD8 killer T cells did not play a major role in the therapy,” said Eleanor Cheadle, PhD, also of the University of Manchester.
“Given the important role that killer T cells can play in long-term protection from tumor regrowth, we are looking at ways to enhance activation of these cells after obinutuzumab therapy.”
The researchers also found that, in vitro, R848 significantly enhanced natural killer cell-mediated antibody-dependent cellular cytotoxicity against obinutuzumab-opsonized CLL cells and significantly increased non-specific, antibody-independent killing of CLL cells. 
Preclinical research suggests that immune stimulation through Toll-like receptor 7 (TLR7) agonism can enhance the efficacy of obinutuzumab in lymphoma.
Researchers found that combining the anti-CD20 monoclonal antibody obinutuzumab with the TLR7 agonist R848 improved survival in lab mice with lymphoma.
The combination also demonstrated efficacy against chronic lymphocytic leukemia (CLL) cells in vitro.
Tim Illidge, PhD, MBBS, of the University of Manchester in the UK, and his colleagues reported these findings in the journal Leukemia.
The research was funded by the Kay Kendall Leukaemia Fund and Cancer Research UK in collaboration with Roche Pharmaceutical Research and Early Development.
The researchers said they initially found that R848 activates immune cells in vivo and enhances obinutuzumab-mediated antitumor effector mechanisms in vitro.
The team therefore went on to test R848 and obinutuzumab in C57Bl/6 mice bearing human CD20+ lymphoma (EL4). The mice received obinutuzumab modified to express the murine glycoengineered IgG2a Fc region (m2a) starting 1 day after tumor inoculation and systemic R848 once weekly for 4 weeks.
The researchers found that monotherapy with either obinutuzumab or R848 significantly improved survival compared to control (P<0.0001), but only 8% to 15% of mice that received monotherapy were long-term survivors (living more than 90 days).
Mice that received obinutuzumab in combination with R848 had significantly better survival than mice that received either monotherapy (P<0.0001). And about 70% of mice receiving the combination remained tumor-free out to 95 days.
Furthermore, long-term survivors that had received the combination treatment were protected from tumor re-challenge.
The researchers also tested the combination in a second model—human CD20 transgenic mice, which express the human CD20 antigen on normal B cells. The team said this model is more akin to the clinical situation.
The mice received treatment 7 days after the inoculation of EL4hCD20 cells. Mice that received obinutuzumab monotherapy had significantly better survival than control mice (P=0.02), but there were no long-term survivors. For mice that received R848 monotherapy, survival was not significantly different from that of controls.
Mice that received R848 in combination with obinutuzumab had significantly better survival than mice that received obinutuzumab alone (P=0.003).
In fact, 6 of the 12 mice that received the combination were long-term survivors. And 5 of these mice rejected tumor re-challenge.
“We were excited when we discovered that combining obinutuzumab with TLR7 activation significantly enhanced survival of animals with lymphoma by effectively eradicating tumors,” Dr Illidge said. “Clearly, more work needs to be done to assess the impact of this combination on humans, but this study is, nevertheless, very promising.”
The researchers said the primary antitumor activity of the combination is dependent on natural killer cells and CD4 helper T cells but not on CD8 killer T cells.
“While the combination therapy was highly effective, CD8 killer T cells did not play a major role in the therapy,” said Eleanor Cheadle, PhD, also of the University of Manchester.
“Given the important role that killer T cells can play in long-term protection from tumor regrowth, we are looking at ways to enhance activation of these cells after obinutuzumab therapy.”
The researchers also found that, in vitro, R848 significantly enhanced natural killer cell-mediated antibody-dependent cellular cytotoxicity against obinutuzumab-opsonized CLL cells and significantly increased non-specific, antibody-independent killing of CLL cells.
Preclinical research suggests that immune stimulation through Toll-like receptor 7 (TLR7) agonism can enhance the efficacy of obinutuzumab in lymphoma.
Researchers found that combining the anti-CD20 monoclonal antibody obinutuzumab with the TLR7 agonist R848 improved survival in lab mice with lymphoma.
The combination also demonstrated efficacy against chronic lymphocytic leukemia (CLL) cells in vitro.
Tim Illidge, PhD, MBBS, of the University of Manchester in the UK, and his colleagues reported these findings in the journal Leukemia.
The research was funded by the Kay Kendall Leukaemia Fund and Cancer Research UK in collaboration with Roche Pharmaceutical Research and Early Development.
The researchers said they initially found that R848 activates immune cells in vivo and enhances obinutuzumab-mediated antitumor effector mechanisms in vitro.
The team therefore went on to test R848 and obinutuzumab in C57Bl/6 mice bearing human CD20+ lymphoma (EL4). The mice received obinutuzumab modified to express the murine glycoengineered IgG2a Fc region (m2a) starting 1 day after tumor inoculation and systemic R848 once weekly for 4 weeks.
The researchers found that monotherapy with either obinutuzumab or R848 significantly improved survival compared to control (P<0.0001), but only 8% to 15% of mice that received monotherapy were long-term survivors (living more than 90 days).
Mice that received obinutuzumab in combination with R848 had significantly better survival than mice that received either monotherapy (P<0.0001). And about 70% of mice receiving the combination remained tumor-free out to 95 days.
Furthermore, long-term survivors that had received the combination treatment were protected from tumor re-challenge.
The researchers also tested the combination in a second model—human CD20 transgenic mice, which express the human CD20 antigen on normal B cells. The team said this model is more akin to the clinical situation.
The mice received treatment 7 days after the inoculation of EL4hCD20 cells. Mice that received obinutuzumab monotherapy had significantly better survival than control mice (P=0.02), but there were no long-term survivors. For mice that received R848 monotherapy, survival was not significantly different from that of controls.
Mice that received R848 in combination with obinutuzumab had significantly better survival than mice that received obinutuzumab alone (P=0.003).
In fact, 6 of the 12 mice that received the combination were long-term survivors. And 5 of these mice rejected tumor re-challenge.
“We were excited when we discovered that combining obinutuzumab with TLR7 activation significantly enhanced survival of animals with lymphoma by effectively eradicating tumors,” Dr Illidge said. “Clearly, more work needs to be done to assess the impact of this combination on humans, but this study is, nevertheless, very promising.”
The researchers said the primary antitumor activity of the combination is dependent on natural killer cells and CD4 helper T cells but not on CD8 killer T cells.
“While the combination therapy was highly effective, CD8 killer T cells did not play a major role in the therapy,” said Eleanor Cheadle, PhD, also of the University of Manchester.
“Given the important role that killer T cells can play in long-term protection from tumor regrowth, we are looking at ways to enhance activation of these cells after obinutuzumab therapy.”
The researchers also found that, in vitro, R848 significantly enhanced natural killer cell-mediated antibody-dependent cellular cytotoxicity against obinutuzumab-opsonized CLL cells and significantly increased non-specific, antibody-independent killing of CLL cells.