Background: Strategies to improve anti-GD2 immunotherapy include: avoiding sensitization (as can occur with murine and chimeric MAbs); augmenting affinity of MAb for Fc-receptor, thereby enhancing antibody-dependent cellular cytotoxicity (ADCC); and reducing pain associated with complement activation. Murine-3F8 anti-GD2 MAb is active against HR-NB but hu3F8 may be preferable because it has significantly greater ADCC and less complement activity in vitro. GM-CSF is well tolerated clinically and increases ADCC.
Methods: In a phase I study (NCT01757626) (opened in 12/2012), patients with resistant HR-NB receive cycles of hu3F8+GM-CSF monthly x4 in the absence of human antihuman antibody (HAHA) and then with 1-to-2-month intervals if clinically indicated. MAb dosing follows the standard 3+3 design, beginning at 0.9mg/cycle, to identify the maximum-tolerated dosage (MTD) (assessed in first cycle). MAb is infused intravenously (30”) on Mon-Wed-Fri (i.e., 3 days/cycle). Daily GM-CSF is administered subcutaneously 5 days pre-hu3F8 through the last day of hu3F8. After cycle 2, hu3F8 can be increased to the highest dosage level that completed dose-limiting toxicity assessment.
Results: At study entry, the 51 patients enrolled to date were 2.4-31.3 (median 6.8) years old and 0.6-8.9 (median 3.2) years from HR-NB diagnosis. Pharmacokinetic studies showed dose-dependent increases in peak serum concentration; terminal half-life was >3 days. Treatment has been outpatient without unexpected acute, late, or cumulative toxicities, even in patients who received >10 cycles. MTD has not been reached. Current hu3F8 dosage is 9mg/kg/cycle. HAHA developed post-cycle 1 in only 1/9 patients who had no prior treatment with any anti-GD2 MAb. Major responses and prolonged progression-free survival have been observed at all dosage levels.
Conclusions: Modest toxicity allows high dosing of hu3F8 (>2.5x dosage of murine-3F8 and ch14.18) which, in addition to powerful in vitro cytotoxic features, can account for the notable anti-NB activity of hu3F8+GM-CSF. Pharmacokinetic studies support the alternate-day schedule.