Use of Dendritic Cells and GM-CSF Adjuvant Are Associated with Anti-Idiotype Cellular Immune Response Following Idiotype Vaccination in Follicular Lymphoma Patients.

Vaccination with idiotype (Id) induces humoral and/or cellular anti-Id immune responses (IR). Recently, we found that anti-Id humoral IR and IgG Fc receptor FcγRIIIa (CD16) 158 Valine/Valine (V/V) correlated with better outcome in patients receiving Id vaccination (JCO 22:4717). Therefore, identifying factors that influence the development of anti-Id IR will provide important information on how to improve Id vaccination by aiming to increase IR. We examined the following factors for their possible effects on IR: prior induction chometherapy or not, prior fludarabine, clinical response to induction chemotherapy, the production method for Id protein, the immunologic adjuvants used during vaccination and the FcγR polymorphisms. One hundred and eighty follicular lymphoma patients who were treated with Id vaccination at Stanford Medical Center between 1988 and 2002 were included. One hundred and sixty four of them received induction chemotherapy, followed by Id vaccination, while 16 patients were treatment naive at the time of Id vaccination. Humoral and cellular IR were determined following Id vaccination by enzyme-linked immunosorbent assays and by T-cell proliferation assays, respectively, as described.

Of these 180 patients, 65 (36%) developed humoral IR and 44 (24%) developed cellular IR after Id vaccination. The development of humoral IR was not affected by receiving induction chemotherapy or not, use of fludrarbine, responses to induction chemtherapy, Id protein production method, type of immunologic adjuvant, FcγRIIIa, FcγRIIa or FcγRIIb genotypes. On the other hand, the development of cellular IR was greatly enhanced by using either dendritic cells or GM-CSF as adjuvant compared to chemical adjuvant (chemical adjuvant: 12% vs dendritic cells: 34%, p=0.003; vs GM-CSF: 48%, p<0.0001) and in patients who received Id protein from molecular cloning (hybridoma: 17% vs molecular cloning: 44%, p=0.0004). However, there was no impact on cellular IR by: induction chemotherapy (23% vs 44%, p=0.072), use of fludrarbine (20% vs 24%, p=0.821), induction chemtherapy responses (CR/CRu: 25% vs PR: 18%, p=0.415), FcγRIIIa genotype (V/V: 27% vs F carrier: 16%, p=0.806), FcγRIIa genotype (H/H: 34% vs R carrier: 23%, p=0.316) and FcγRIIb genotype (I/I: 21% vs T carrier: 37%, p=0.061).

A logistic regression analysis was performed to identify independent prognostic variables influencing the development of either humoral or cellular IR. Use of dendritic cells or GM-CSF adjuvant emerged as the only predictive factor independently predicting the development of cellular IR (odds ratio: 4.72, 95% CI: 1.88–11.85, p=0.001), while no predictive factor was identified for the development of humoral IR. This observation is consistent with the prevailing notion that dendritic cells and GM-CSF adjuvant can facilitate cellular IR immune response to various vaccines. It is interesting that PR patients after induction chemotherapy and fludarabine-treated patients had the same chance of developing humoral or cellular IR as did other patients. Therefore, these two groups of patients should not be excluded from subsequent vaccine trials on the assumption that they have impaired immune systems. It is also important to point out that none of these 180 patients received rituximab during induction therapy, which may significantly impair the ability to develop humoral IR.