Immune Responses and Outcome in Follicular Lymphoma
Authors: John G. Gribben
Journal: Journal of Clinical Oncology (2014)

Follicular lymphoma (FL) has long been considered as particularly immune responsive on the basis of reports of spontaneous regressions, high response rates to monoclonal antibodies, and long-lasting responses to vaccination using tumor-specific idiotype (Id) or immunogenic neoplastic cells. Indeed, the survival of patients with FL has improved since the introduction of anti-CD20 monoclonal antibody therapy (rituximab). Many of the efforts toward developing vaccines against human malignancies have been frustrated by the lack of identification of a tumor-specific antigen that would allow tumor cells to be distinguished from normal cells. Idiotypic determinants of the surface immunoglobulin associated with a given patient’s B-cell lymphoma are unique to that tumor, and can thus serve as a tumorspecific marker. When conjugated to the immune carrier keyhole limpet hemocyanin (KLH), vaccination with an Id protein vaccine has been suggested as capable of improving length of freedom from disease relapse in patients with FL in a minimal residual disease state after induction therapy. In the article that accompanies this editorial, Levy et al report the results of a multicenter, randomized trial comparing a specific vaccine (MyVax; Genitope, Fremont, CA), that comprises Id that is chemically coupled to KLH plus granulocyte-macrophage colony-stimulating factor, compared with control immunotherapy with KLH plus granulocyte-macrophage colony-stimulating factor. This is the third randomized trial to report on the use of different approaches to examine the impact of Id vaccine and adds to the data suggesting that there is little evidence of a beneficial effect of Id vaccine in patients with FL. A total of 513 patients were enrolled onto this study; eligible patients had previously untreated, advanced-stage FL. The trial was commenced in the prechemo-immunotherapy era, and patients received eight cycles of therapy with cyclophosphamide, vincristine, and prednisone. To be eligible for vaccination, patients had to demonstrate sustained partial or complete remission, but there was a relatively low response rate, and 226 patients failed to respond or progressed before vaccination. Only 90 patients achieved complete remission or a complete remission/unconfirmed among the 287 responders, of whom 270 received vaccinations (randomly assigned 2:1 to receive seven monthly injections of MyVax or control immunotherapy). Anti-Id antibody responses (humoral immune responses) were measured before each immunization. The primary end point was progression-free survival (PFS). Secondary end points included immune responses and time to subsequent antilymphoma therapy. The authors report that at a median follow-up of 58 months, there was no significant difference observed in either PFS or time to next therapy between the two arms. However, in a subset analysis, they observed that anti-Id immune responses were observed in 41% of the 195 patients who received MyVax, and that that these patients had improvement in PFS compared with those who did not demonstrate anti-Id immune responses. The trial results add to those of other studies that have shown a failure in improvement in outcome for patients with FL, despite the promising results that were seen in phase II studies. It is unclear whether the improvement in outcome for patients who develop an anti-Id response is a reflection of a beneficial effect of an ongoing immune response against the Id vaccine, or is simply a surrogate marker for a more favorable subgroup of patients. What can explain the inability to translate the promising results seen in the phase II studies into improved outcomes in clinical trials? It is tempting to speculate that those patients who are able to mount an immune response were in some way a more favorable subgroup, but analyses showed no difference in any of the known prognostic factors, and there was also no difference in immune response against KLH among the patients. However, it must be noted that KLH is a highly immunogenic molecule that may be capable of overcoming relative immuno-incompetence in patients with FL who have previously been treated with chemotherapy. Additional confusing data come from the observation that although the PFS was improved in the 41% of patients who mounted an anti-Id immune response, there was no difference in PFS between the vaccinated compared with the control group. This suggests that patients who are vaccinated with Id and who fail to mount an anti-Id immune response actually have an inferior outcome. This was also suggested in a previous phase III trial with the potential to induce T-regulatory cells, although an alternative explanation relates to the imbalance in Follicular Lymphoma International Prognostic Index scores between the anti-Id and control groups. The patients in this study were treated with cyclophosphamide, vincristine, and prednisone, which would currently be considered inadequate therapy in an era in which improved overall survival is seen in patients treated with chemo-immunotherapy. There have been vaccination studies performed after rituximab therapy that suggest that T-cell priming occurs in the setting of the severe B-cell depletion that can occur after rituximab therapy. The authors suggest that it might be possible to omit antibody therapy until after vaccination. However, it does not seem logical to omit a drug with proven efficacy JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 17 JUNE 1