The study we presented here was AMG330, a CD33 T-cell recruiting antibody construct in relapsed, refractory AML. This construct is the sister molecule of blinatumomab targeting CD33 which is ubiquitously expressed in AML in this early phase I trial.
What was the methodology?
The expected problem with T-cell recruiting antibody constructs is cytokine release so we started with a very low continuous infusion as these BiTE molecules are very small and have a restricted half-life of less than two hours. We eventually encountered cytokine release syndrome and mitigating this we implemented dose steps to increase. So currently we have two dose steps and extending the time of the infusion of the AMG330 to now 28 days.
As I said, side effects have been manageable and were expected and are mainly cytokine release. In contrast to the T-cell recruiting antibody construct in the ALL setting we did not encounter a significant number of neurotoxicity. For efficacy clearly this is hard to say in a phase I trial but now in the higher doses we have observed several complete remissions or incomplete remissions so we are optimistic that we eventually now achieved a concentration and we are still moving up where we will see efficacy. But clearly a lot of patients have been treated where we did not observe a clinical benefit.
Next is we’re going to escalate until we have achieved our final dose and then there’s going to be an extension phase to see for efficacy. But, very similar to blinatumomab, we have to change the clinical setting; so T-cell recruiting antibodies are most beneficial in the MRD setting. We have been discussing to integrate also patients who are MRD positive and this could serve as a bridge to transplant or we can see if MRD conversion is taking place in a setting where the T-cell compartment is more fit and probably the antibodies are going to work much better than in the very advanced setting. So these patients had four or more treatment lines prior to the integration to the trail so clearly very heavily pre-treated patients where T-cell exhaustion, T-cell dysfunction might be a problem.
These are exciting times and we’ll see how the success stories of BiTEs and CAR T-cells in the lymphoid settings are going to translate into the myeloid setting. There are several trials that are reporting with other target antigens and a few trials on CAR T-cells but clearly it’s early days and identifying a suitable target antigen in AML is much more difficult than in the lymphoid setting.