Induction of Ab3 and Ab3 ' antibody was associated with long-term survivalafter anti-G(D2) antibody therapy of stage 4 neuroblastoma

Treatment with anti-G,, monoclonal antibody 3F8 (Abl) at the time of remiss ion may prolong survival for children with stage 4 neuroblastoma, A transie nt human antimouse antibody (HAMA) response was associated with significant ly longer survival (Cheung et at, J, Clin, Oncol,, 16,- 3053-3060, 1998), B ecause this response was primarily anti-idiotypic (Ab2), we postulate that the subsequent induction of an idiotype network that included an elevation of anti-anti-idiotypic (Ab3) and anti-G(D2) (Ab3') antibody titers may be r esponsible for tumor control. Thirty-four patients with stage 4 neuroblasto ma diagnosed at >1 year of age were treated with 3F8 at the end of chemothe rapy, Most had either bone marrow (31 of 34) or distant bony (29 of 34) met astases at diagnosis. Thirteen patients were treated at second or subsequen t remission, and 12 patients in this group had a history of progressive/per sistent disease after bone marrow transplantation; 21 patients were treated in the first remission after N6 chemotherapy, Their serum MAMA, Ab3, and A b3' titers prior to, at 6, and at 14 months after antibody treatment were m easured by ELISA, Among these 34 patients, 14 are alive, and 13 (1.8-7.4 ye ars at diagnosis) are progression free (53-143 months from the initiation o f 3F8 treatment) without further systemic therapy. Long-term progression-fr ee survival (PFS) and survival correlated significantly with Ab3' (anti-G,, ) response at 6 months and with Ab3 response at 6 and 14 months, By definin g Ab3 threshold ranging from the ratio of 1.1 to 2.6 above pretreatment lev el, the difference in PFS and survival between the high-Ab3 and low-Ab3 gro ups became markedly widened. Similarly, increasing the Ab3' threshold at ei ther 6 or 14 months to 300% above pre-3F8 levels also increased the spread between the high versus low Ab3' groups for both PFS and survival curves. N on-idiotype antibody responses (anti-mouse-IgG3 or anti-tumor nuclear HUD a ntigen) had no apparent impact on PFS or survival, In conclusion, despite t he high-risk nature of stage 4 neuroblastoma, long-term remission without m yeloablative therapy can be achieved with 3F8 treatment. Ab3 and Ab3' antib ody response correlated with prolonged PFS and survival. We postulate that successful induction of an idiotype network in patients may be responsible for long-term tumor control.