LUGANO, SWITZERLAND—A Phase III trial of a specific, personalized immunotherapy vaccine in patients with follicular non-Hodgkin's lymphoma found no survival or progression-free survival advantage over a non-specific vaccine.
There was a strong correlation between treatment with the vaccine and a clinical immune response, reported principal investigator Ronald Levy, MD, Professor and Chief of the Division of Oncology at Stanford University School of Medicine, presenting the data here at the 10th International Conference on Malignant Lymphoma.
Dr. Levy, well known for his contributions to the development of monoclonal antibodies in general, particularly rituximab, said there was with a highly significant difference among the patients on the specific vaccine arm who mounted a positive immune response compared with those who did not make an immune response, but there was no proof of cause and effect.
“We had an immune response which correlated with outcome, confirming our preliminary work that led to this trial, but we did not establish efficacy,” he said.
MyVax (made by Genitope Corp., the sponsor of the trial) consists of a tumor-specific idiotype protein conjugated to keyhole limpet hemocyanin (KLH) and administered in a series of subcutaneous immunizations along with granulocyte macrophage colony-stimulating factor (GM-CSF).
Since B-cell lymphomas are the clonal proliferation of lymphocytes, the immunoglobulin they express is unique and it can be regarded as a tumor-specific antigen, the researchers explained.
In the multicenter, randomized, blinded, controlled trial, outcomes in patients treated with MyVax were compared with those of control patients who received non-specific KLH—without the idiotype protein—and GM-CSF. All patients had previously untreated follicular NHL.
“We're not going to continue this vaccine; it's over,” said Dr. Levy, who nonetheless in his presentation and in an interview afterward, appeared undaunted by the trial's outcome.
‘Back to a Biomarker-Discovery Effort’
“We validated the correlation [between immune response and outcome], and now we have to discover it before the fact,” he said. “We're back to a biomarker-discovery effort.”
But he added that “we have the best set of annotated samples in follicular lymphoma that there has ever been so we will be able to mine it for discovery purposes.”
At a session later in the meeting, Dr. Levy described a new vaccine he is moving forward with, CpG for in-situ vaccination in patients with B-cell lymphoma. CpG is a TLR-9 ligand, which activates dendritic cells and induces antigen presentation.
Intratumoral injection of CpG “induces a T-cell immune response to attack tumors elsewhere in the body,” Dr. Levy said.
In the trial, 287 patients were randomly selected, and 278 received at least one immunization. Patients received eight cycles of cyclophosphamide, vincristine, and prednisone (CVP) followed by a six-month rest period. Patients who maintained at least a partial response for six months post-CVP were randomized to receive MyVax or control immunotherapy in a 2-to-1 ratio.
All patients received GM-CSF at each immunization and for the following three days. Patients received a series of seven immunizations over 24 weeks.
Causal or Just Biomarker?
Anti-idiotype responses were observed in 41% of evaluable patients. While there was no statistical difference in progression-free survival and time to subsequent anti-lymphoma therapy in patients who received MyVax compared with those who received the control immunotherapy, a highly statistically significant improvement in progression-free survival was seen in patients mounting a positive anti-idiotype immune response compared with nonresponders, with a two-fold increase (39.7 vs 16.1 months) in progression-free survival.
But there was no statistical difference in progression-free survival or time to subsequent anti-lymphoma therapy seen in the patients who received MyVax compared with controls.
Time to subsequent anti-lymphoma therapy was a median of 43.4 months for MyVax and 48.4 months for controls. Both arms of the study had a plateau of progression-free survival of greater than 30% at five years.
The question of whether the immune response correlating strongly with clinical outcome was causal or only a biomarker remains unanswered.
‘Everybody Had Their Eyes on This Trial’
Session Co-Moderator Kanti R. Rai, MD, Professor of Medicine at Albert Einstein College of Medicine and Chief of the Division of Hematology/Oncology at Long Island Jewish Medical Center, said in an interview after the session that the results were definitely disappointing: “There are other vaccines being tested [in lymphoma], but this was the one everybody had their eyes on because it seemed to be the most promising.”
He said the trial did have a positive contribution in that there appeared to be a group of patients who had evidence of positive response to the antigen and had shown immunological response, and they were the ones who had advantage and benefit from the vaccine.
But unless clinicians are able to determine prospectively the factors that identify patients likely to respond and administer the vaccines selectively, there will be the disappointment of those patients who not have a response: “This is the next step of the challenge.”