Yes, wonder drugs though they are, checkpoint inhibitors (a.k.a CPI) drive anti-drug antibodies (ADA) too. We’ve been concerned for a while that “releasing the brakes” will drive T cell response to CPI, and have been watching to see what happens. Fortunately, many have been carefully engineered to contain few T Effector (Teff) epitopes, while Treg epitopes remain intact (Tregitopes).

However, CPI modify the immune response – dramatically increasing Teff and suppressing Treg response. This is especially true if the CPI are directed against Tregs. What happens next? Turning off Tregs that normally suppress immune response to monoclonals “reveals” the immunogenic side of CPI.

Because we were concerned, we now score CPI for both Tregitope adjusted (as if Tregs are functioning), and ‘raw scores’ (no Tregs) which would count Tregitopes as if they were T effector epitopes. See example below and for the PDF of this image, click here.

In fact, there is now clinical evidence that there was a very impressive increase in immunogenicity of Nivolumab (anti PDL-1) anti-drug antibodies and even neutralizing antibodies (NABS) when Pembro is used in combination with Ipilimumab. This is from the Nivo package insert (Thanks Amy!):

Of 2085 patients who were treated with OPDIVO as a single agent 3 mg/kg every 2 weeks and evaluable for the presence of anti-nivolumab antibodies, 233 patients (11.2%) tested positive for treatment-emergent anti-nivolumab antibodies by an electrochemiluminescent (ECL) assay . . .

Of 394 patients who were treated with OPDIVO with ipilimumab and evaluable for the presence of anti-nivolumab antibodies, 149 patients (37.8%) tested positive for treatment-emergent anti-nivolumab antibodies by an ECL assay and 18 patients (4.6%) had neutralizing antibodies against nivolumab.

What happened? Turning off Tregs “reveals” the immunogenic side of molecules. Removal of Tregitopes will make even the Tregitopes (in the monoclonals) look like T effector epitopes. Does this happen with other checkpoint inhibitor monoclonal antibodies?

Get your Nivo-Ipi Combo PDF here: Nivolimumab + Ipilimumab ADA Story 2017