Benefits of combining targeted therapy, immunotherapy remain unclear
NEW YORK — A rationale exists for the combination of targeted therapy and immunotherapy, but the value of this approach has not yet been determined, according to a presenter at the HemOnc Today Melanoma and Cutaneous Malignancies meeting.
“BRAF inhibitors could theoretically increase the immunogenicity of melanoma by increasing antigen expression, as well as increasing T-cell activation and infiltration into the tumor,” Paul B. Chapman, MD, of the Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center, said during a presentation. “Smaller tumor burden and MEK inhibition could theoretically decrease immunogenicity. Yet, it’s not clear if any of these effects will end up being clinically important.”
A study by Frederick and colleagues, published in 2013 in Clinical Cancer Research, showed treatment with either a BRAF inhibitor alone or BRAF and MEK inhibitors in combination was associated with increased expression of melanoma antigens. Treatment also was associated with an increase in CD8-positive T-cell infiltrate in all patients.
“Why might this work?” Chapman said. “If you treat with a drug like a BRAF inhibitor — or chemotherapy or radiation, for that matter — and you kill a lot of the tumors, that could be good for two reasons. First, smaller tumor volume may make immunotherapy more effective. Also, killing tumor will release proteins that can then be taken up by antigen-presenting cells and presented to T cells, so you could increase the ability of the immune system to see these protein antigens and make the tumor more immunogenic.”
Another possible explanation is that the BRAF inhibitor itself can activate T cells, Chapman said.
Callahan and colleagues conducted an experiment with T cells specific for NY-ESO94-102 peptide. They exposed T cells to the peptide and measured activity by the amount of interferon gamma it makes.
“If you don’t give the peptide, there’s not much activity,” Chapman said. “If you repeat that experiment by using progressively higher concentrations of a BRAF inhibitor, you get increased amounts of T-cell activation. The question is, do we think this increase of gamma interferon is going to end up being clinically significant?”
However, some preclinical data suggests the combination of targeted therapy and immunotherapy may not work.
In a paper published in 1981 in British Journal of Cancer, Gatenby and colleagues explored the “sneaking through” phenomenon — the ability some tumors demonstrate to elude the immune system.
Researchers injected various numbers of methylcholanthrene sarcoma cells in immunocompromised mice, and they assessed associations between tumor development and the number of injected cells.
Nearly all mice injected with 1 million cells developed tumors. Fewer mice injected with 100,000 cells developed tumors, and only a small percentage of those injected with 10,000 cells developed tumors.
However, as the investigators continued to inject fewer and fewer cells into each subsequent cohort of mice, tumor take began to increase.
“This was defined as ‘sneak through,’ the idea being there just aren’t enough cells there for the immune system to see,” Chapman said. “In the setting of [regulatory T cells], there may actually be a disadvantage to the immune system to try to deal with a smaller volume of tumor … The immune system can be fooled and allow these tumors to sneak through.”
Limited data exist about the potential effectiveness of targeted therapy–immunotherapy combinations.
Among the most relevant investigations is a phase 1 study by Ribas and colleagues, who assessed the combination of vemurafenib (Zelboraf, Genentech) and ipilimumab (Yervoy, Bristol-Myers Squibb) in patients with advanced melanoma. Patients received vemurafenib in doses of 720 mg or 960 mg twice daily. At 1 month, patients also received ipilimumab 3 mg/kg every 3 weeks.
Results, published in 2013 in The New England Journal of Medicine, showed six of 12 patients developed grade 3 liver function test elevations.
These elevations “were asymptomatic and of unclear medical significance,” but the sponsor required the trial to be stopped, Chapman said.
“This gives us a couple lessons,” he said. “One is that combining these drugs may not be completely simple, and there may be toxicities we hadn’t anticipated. Another lesson might be that we may need to be a little more sophisticated with dose-limiting toxicities so we don’t stop combinations prematurely when we’re not hurting anybody but possibly helping people.” – by Mark Leiser
Chapman PB. Combining targeted therapy with immunotherapy. Presented at: HemOnc Today Melanoma and Cutaneous Malignancies; April 10-11, 2015; New York.
Disclosure: Chapman reports consultant or scientific advisory board roles with Bristol-Myers Squibb, Daiichi Sankyo, Genentech/Roche and Provectus.