Alkuzweny, Baha

Abstract CD80 is an immune costimulatory molecule expressed on the cell surface of follicular and other lymphomas. Galiximab, a macaque-human chimeric anti-CD80 monoclonal antibody, has been shown to have antitumor activity in patients with relapsed or refractory, follicular lymphoma. Preclinical work suggested antibody-dependent cellular cytotoxicity (ADCC) as a mechanism for galiximab-induced cell lysis. Single-nucleotide polymorphisms (SNPs) for high-affinity Fc gamma receptor IIIa and high interferon-gamma production have been associated with increased ADCC activity. For this report, genomic DNA from peripheral blood of clinical study patients was analyzed for Fc gamma receptor IIIa and interferon-gamma gene SNPs after PCR amplification. In addition, the frequency of interferon-gamma secreting cells in peripheral blood samples was evaluated by ELISPOT. SNP and ELISPOT results were then evaluated for correlation with clinical response (CR or PR) to galiximab and reduction in tumor burden (SPD of indicator lesions). Of 35 follicular lymphoma patients evaluable for response to galiximab, 2 CRs and 1 PR were observed; time to best response was delayed (Months 3, 9, and 12). Of 34 patients with Fc gamma receptor IIIa SNP results, 6 were homozygous for the high-affinity receptor. Of 33 pts with interferon-gamma SNP results, 4 were homozygous for the high-producing allele. None of the 3 responders were homozygous for high-affinity Fc gamma receptor IIIa or high interferon-gamma production, and the degree of tumor burden reduction was smaller in these homozygotes than in the others. In addition, pretreatment interferon-gamma ELISPOT data did not predict clinical response to galiximab or tumor burden reduction. In summary, high-affinity Fc gamma receptor IIIa and high interferon-gamma production do not predict clinical responsiveness of follicular NHL to galiximab, suggesting that ADCC may not be a primary mechanism of action for this antibody. Ongoing studies are evaluating other potential mechanisms including the immunomodulatory effects of blocking CD80.

PurposeThis multicenter, dose-escalation study evaluates the safety, pharmacokinetics, and efficacy of galiximab (anti-CD80 monoclonal antibody) in patients with relapsed or refractory follicular lymphoma.Patients and MethodsPatients had follicular lymphoma that had relapsed or failed to respond to primary therapy; the majority (90%) presented with stage III or IV disease. Four weekly intravenous infusions of galiximab were administered at doses of 125, 250, 375, or 500 mg/m2.ResultsThirty-seven patients received galiximab treatment and were evaluated for safety; 35 were assessable for response. Antibody infusions were safe and well tolerated with no dose-limiting toxicities. A total of 22 (60%) of 37 patients experienced adverse events related to galiximab. All but one of the events were grade 1 or 2; the most common were fatigue, nausea, and headache. Cytopenias were rare; only one patient experienced anemia and febrile neutropenia, which were unrelated to galiximab and resolved after treatment. No patient developed antigaliximab antibody formation. The mean serum half-life ranged from 13 to 24 days. The overall response rate was 11% (two complete responses and two partial responses). Time to best response was delayed (months 3, 6, 9, and 12). Twelve patients (34%) maintained stable disease. Nearly half of all patients (49%) had a decrease in indicator lesions. Two responders remain on study without progression (22 and 24.4 months).ConclusionThe favorable safety profile of galiximab and evidence of single-agent biologic activity and dose-dependent pharmacokinetics support further evaluation of galiximab as a treatment for follicular lymphoma, possibly in combination with other lymphoma therapies.