Long-Term Survival after Anti-GD2 Antibody Therapy of Stage 4 Neuroblastoma
Long-Term Survival after Anti-GD2 Antibody Therapy of Stage 4 Neuroblastoma
ABSTRACT & COMMENTARY
Synopsis: Patients with stage 4 neuroblastoma received treatment with anti-GD2 monoclonal antibody 3F8 at the end of chemotherapy and at a time of remission. Long-term remission without additional myeloablative therapy was achieved following 3F8 treatment. Induction of Ab3 (anti-anti-idiotypic) and Ab3' (anti-GD2) antibody responses correlated with prolonged progression-free and overall survival. Cheung and colleagues postulate that successful induction of an idiotype network in these neuroblastoma patients may be responsible for long-term tumor control.
Source: Cheung NK, et al. Clin Cancer Res 2000;6:2653-2660.
Monoclonal antibodies (mabs) have been used for the detection, diagnosis, and treatment of several types of cancer.1 Clinical trials with tumor-reactive mAbs have achieved some degree of measurable antitumor benefit in patients with certain cancers that can be recognized by monoclonal antibodies.1,2 The mechanisms for the antitumor activity are usually considered to include complement-mediated and cell-mediated antibody-dependant cytotoxicity.1,2 Immune responses against the therapeutic antibody, such as human antimouse antibody (HAMA) responses following administration of murine mAbs, can cause toxic reactions and rapid clearance of the administered antibody. Immune responses can also be formed against the antigen-binding component (idiotype) of the therapeutic antibody.3,4 These anti-idiotypic (anti-Id) responses could also result in decreased interactions between the administered antibody and tumor cells as well as rapid clearance of the therapeutic antibody by the host immune response. However, anti-Id antibodies could also recognize the antibody-binding site of the immunizing mAb, and therefore, mimic the original antigen. Immune responses against the anti-Id antibodies (human anti-anti-Id response; Ab3) could then result in an activation of an idiotypic network and has been hypothesized to be important in antitumor immunity.5-8
Cheung and colleagues report on a study that used the anti-GD2 monoclonal antibody 3F8 for treatment of children with stage 4 neuroblastoma following chemotherapy and at a time of remission. The disialoganglioside GD2 molecule recognized by 3F8 is preferentially expressed on human neuroblastoma, melanoma, glioblastoma, small-cell lung cancer, certain sarcomas, and some normal cells of neuroectodermal origin.1 The relatively tumor-selective expression of GD2 makes it a suitable target for anti-GD2 mAb therapy. The study included 34 patients with stage 4 neuroblastoma in either a second or third remission (13 patients) or a first remission (21 patients). Serum measurements of HAMA, Ab3 (anti-anti-Id), Ab3' (anti-GD2), antimouse IgG3, and anti-HUD were measured and evaluated for correlation with progression-free and overall patient survival. Long-term, progression-free survival and overall survival was shown to correlate with the Ab3' response at six months and with the Ab3 response at six and 14 months. The non-Id responses (HAMA or anti-tumor nuclear HUD antigen) had no apparent effect on either progression-free or overall survival. Cheung et al conclude that the successful induction of an idiotype network may be responsible for the long-term tumor control in these neuroblastoma patients.
Comment By Mark R. Albertini, MD
Anti-GD2 antibodies can mediate antibody-dependent cellular cytotoxicity and complement dependent cytotoxicity against GD2 expressing tumor targets in vitro.1 In addition, anti-Id responses have been demonstrated in several trials evaluating therapeutic administration of anti-GD2 antibodies to patients.1,4,7,8 The current report of long-term survival in patients with stage 4 neuroblastoma receiving 3F8 antibody following chemotherapy and at a time of remission is impressive. The results from this study suggest that Ab3 (anti-anti-Id) and Ab3' (anti-GD2) were induced in patients following treatment with 3F8. The relationship between Ab3' and Ab3 titers with progression-free and overall survival also suggests a potential antitumor role for this anti-Id network. When the median was used as a cutpoint, Ab3' values above the median at six months correlated with significantly better progression-free and overall survival. In addition, Ab3 values above the median at six and 14 months also correlated with improved progression-free and overall survival. Patients with higher Ab3' and Ab3 levels appeared to do the best, and the Ab3 level was a strong predictor of survival, especially if measured at 14 months from initial 3F8 treatment. It is relevant to note that the non-Id antibody responses (anti-mouse-IgG3 and antitumor nuclear HUD antigen) had no apparent influence on these disease end points.
While the current results are suggestive of a potential role for the idiotypic network in antitumor responses for these patients, several additional points need to be considered. Patients with disease progression prior to the defined evaluation timepoint of six months were not reported in this study. It would be informative to know if patients had elevated Ab3' and Ab3 titers at the time of disease progression. The influence of prior chemotherapy on antitumor results can also not be determined with the current study design. A prospective, randomized study in which patients are randomized to receive either best chemotherapy alone, or best chemotherapy followed by 3F8 antibody therapy, would be a means to resolve this question.
Cheung et al describe an interesting and potentially important rationale for subsequent clinical investigation of treatment with anti-GD2 antibodies for patients with GD2 expressing tumors. The idiotypic network may have a role to play for antitumor responses in patients with neuroblastoma, and further clinical investigation of this approach appears indicated.
References
1. Hank JA, et al. Cancer Chemother Biol Response Modif 1999;18:210-222.
2. Schlom J. Monoclonal antibodies in cancer therapy: Basic principles. In: DeVita VT, Hellman S, and Rosenberg SA, eds. Biologic Therapy of Cancer. 2nd ed. Philadelphia, Pa.: JB Lippincott; 1995:507-520.
3. Kennedy RC, et al. J Clin Invest 1987;80:1217-1224.
4. Foon K, et al. Clin Cancer Res 1998;4:1117-1124.
5. Herlyn D, et al. Science 1986;232:100-102.
6. Fagerberg J, et al. Cancer Res 1995;55:1824-1827.
7. Albertini MR, et al. Clin Cancer Res 1997;3:1277-1288.
8. Cheung NK, et al. J Clin Oncol 1998;16:3053-3060.
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