Behnaz Taidi

Anti-idiotype antibody response after vaccination correlates with better overall survival in follicular lymphoma

Previous studies demonstrated that vaccination-induced tumor-specific immune response is associated with superior clinical outcome in patients with follicular lymphoma. Here, we investigated whether this positive correlation extends to overall survival (OS). We analyzed 91 untreated patients who received CVP chemotherapy (cyclophosphamide, vincristine, and prednisone) followed by idiotype vaccination. Idiotype proteins were produced either by the hybridoma method or by expression of recombinant idiotype-encoding sequences in mammalian or plant-based expression systems. We found that achieving a complete response/complete response unconfirmed (CR/CRu) to CVP and making an anti-idiotype antibody are 2 independent factors that each correlated with longer OS at 10 years (89% vs 68% with or without a CR/CRu, P = .024; 90% vs 69% with or without tumor-specific antibody production; P = .027). In the subset of patients who received hybridoma-generated vaccines, we found that anti-idiotype production was even more highly associated with superior OS (P < .002); this was the case even in patients with a partial response (PR) to CVP (P < .001).

Generation of CD8 + T cell–mediated immunity against idiotype-negative lymphoma escapees

We investigated the ability of CpG-oligodeoxynucleotide to generate an anti-tumor CD8+ T-cell immune response and to synergize with passive antibody therapy. For these studies, we generated an antibody against the idiotype on the A20 B-cell lymphoma line. This antibody caused the regression of established tumors, but ultimately the tumors relapsed. The escaping surface IgG-negative tumor cells were resistant to both antibody-dependent cellular cytotoxicity and signaling-induced cell death. Addition of intratumoral CpG to antibody therapy cured large established tumors and prevented the occurrence of tumor escapees. The failure of the combination therapy in mice deficient for CD8+ T cells demonstrates the critical role of CD8+ T cells in tumor eradication. When mice were inoculated with 2 tumors and treated systemically with antibody followed by intratumoral CpG in just one tumor, both tumors regressed, indicating that a systemic immune response was generated. Although antibody therapy can eliminate tumor cells bearing the target antigen, it frequently selects for antigen loss variants. However, when a poly-specific T-cell response was generated against the tumor by intratumoral CpG, even large established tumors were cured. Such an immune response can prevent the emergence of antibody selected tumor escapees and provide long-lasting tumor protection.

Prolonged disease-free survival and overall survival with CVP alternating with fludarabine in advanced follicular lymphoma†

Cyclophosphamide and fludarabine are highly active in treating follicular lymphoma (FL). However, many cyclophosphamide and fludarabine combination regimens, although highly effective, exhibited severe infectious toxicities including toxic death [1-7]. We designed a novel sequential regimen consisting of CVP (cyclophosphamide 400 mg/m 2 PO d1-5, vincristine 2 mg d1, prednisone 100 mg/m 2 d1-5) alternating with fludarabine (25 mg/m 2 IV d1-5) as induction chemotherapy for idiotype vaccination, with a goal of obtaining a higher quality of tumor debulking before vaccination. Herein, we report the safety and efficacy of this regimen. Thirty-four consecutive untreated patients with FL received this regimen. Toxicities were modest with no severe infections or toxic deaths. Complete response/unconfirmed complete response (CR/CRu) was achieved in 18 patients (53%) and PR in 38%. At a median follow-up of 12 years, overall survival (OS), event-free survival (EFS), time to progression (TTP), and disease free survival (DFS) were 85, 37, 38, and 70%, respectively. Among a cohort of historical controls with similar characteristics receiving CVP, the CR rate was 34%, 12-year OS, EFS, TTP, and DFS were 64, 20, 21, and 37%, respectively. Thus, CVP/F exhibited favorable safety profile while maintaining the excellent efficacy of combining cyclophosphamide and fludarabine and warrants further evaluation in combination with rituximab.