High-dose cyclophosphamide inhibition of humoral immune response to murine monoclonal antibody 3F8 in neuroblastoma patients: broad implications for immunotherapy.
BACKGROUND
The murine monoclonal antibody 3F8 mediates lysis of neuroblastoma (NB) by complement and leukocytes (including neutrophils) but is neutralized if human anti-mouse antibody (HAMA) forms. We assessed the impact on rapid HAMA formation of prior chemotherapy in NB patients.


METHODS
For the 153 patients treated with 3F8 after conventional therapy (Group 1), the analysis included time from chemotherapy to the start of 3F8. For the 103 patients treated with 3F8 after myeloablative alkylator-based therapy (MAT) (Group 2), the analysis included both chemotherapy administered before stem-cell collection and time from MAT to the start of 3F8.


RESULTS
In Group 1, the incidence of HAMA-positivity was significantly lower if patients received high-dose cyclophosphamide (HD-Cy, > or = 4,000 mg/m2) before 3F8 treatment (P < 0.001). In addition, HAMA-positivity was least likely if 3F8 treatment was initiated <90 days post-HD-Cy (2/76 compared to 3/19 first treated at 90-120 days, and 17/27 first treated at >120 days, P < 0.001). In Group 2 patients who were transplanted with stem cells collected after HD-Cy, HAMA-positivity occurred in 1/60 patients treated <90 days post-MAT versus 13/23 treated >90 days post-MAT (P < 0.001). Among Group 2 patients transplanted with stem cells collected after no prior HD-Cy, the incidence of HAMA-positivity was significantly higher (15/19, P < 0.001), including 5/7 whose 3F8 treatment began <90 days post-MAT.


CONCLUSIONS
HD-Cy reliably blocks humoral responses to a murine antibody. This capacity to prevent host rejection of foreign or not fully humanized proteins raises the possibility of a broad role for HD-Cy in immunotherapeutic strategies.
Kushner
Brian H
BH
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA. kushnerb@mskcc.org
Cheung
Irene Y
IY
Kramer
Kim
K
Modak
Shakeel
S
Cheung
Nai-Kong V
NK
D000293:Adolescent; D000328:Adult; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000096:biosynthesis* / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use; D058846:Antibodies, Monoclonal, Murine-Derived; D000917:Antibody Formation / Q000187:drug effects; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D016190:Carboplatin / Q000008:administration & dosage; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D004317:Doxorubicin / Q000008:administration & dosage; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology* / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007167:Immunotherapy; D007223:Infant; D008297:Male; D008558:Melphalan / Q000008:administration & dosage; D051379:Mice; D009447:Neuroblastoma / Q000188:drug therapy / Q000276:immunology / Q000601:surgery / Q000628:therapy*; D012189:Retrospective Studies; D013852:Thiotepa / Q000008:administration & dosage; D019772:Topotecan / Q000008:administration & dosage / Q000627:therapeutic use; D019172:Transplantation Conditioning; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D014750:Vincristine / Q000008:administration & dosage; D014916:Whole-Body Irradiation
C419226:3F8 antibody; D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018906:Antineoplastic Agents, Alkylating; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D014750:Vincristine; D005047:Etoposide; D019772:Topotecan; D004317:Doxorubicin; D003520:Cyclophosphamide; D013852:Thiotepa; D016190:Carboplatin; D008558:Melphalan