ORLANDO—An autologous tumor-derived idiotype vaccine significantly prolonged the disease-free survival time in patients with advanced follicular non-Hodgkin's lymphoma who had a durable response to chemotherapy, according to data reported as Abstract #2 at the ASCO Annual Meeting here.
In patients with a chemotherapy-induced remission of at least six months, the vaccine (BiovaxID) nearly doubled the time before the disease recurred, compared with a control vaccine, said Stephen J. Schuster, MD, Associate Professor of Medicine at the Abramson Cancer Center of the University of Pennsylvania School of Medicine.
The results show that “production of a tumor-specific idiotype vaccine can be successfully manufactured in real time using current technologies.” The vaccine ushers in “an era where we can safely use a patient's immune system to effectively fight follicular lymphoma,” he said.
Follicular lymphoma is the second most common subtype of the disease—accounting for about 25% of the total number of cases. But even with aggressive chemotherapy and other recent advances in therapy, the disease is considered incurable, with 90% of patients dying within seven years of diagnosis, he said.
Making the Vaccine
The vaccine is made by extracting cells from a tumor biopsy taken from each patient's lymph nodes. The tumor cells from the specimens are then fused with a mouse myeloma cell line. The resulting heterohybridomas produced large amounts of tumor idiotype, which is then combined with an immune stimulant called keyhole limpet hemocyanin (KLH).
The vaccine is administered by local injection, along with granulocyte-macrophage colony-stimulating factor (GM-CSF) as an immunologic adjuvant, Dr. Schuster said.
Vaccine production took an average of eight months, with a range of six to 12 months. In previous trials, tumor-specific purified idiotype protein conjugated to KLH and administered with GM-CSF induced follicular lymphoma-specific immune responses and molecular remissions, he said.
Phase III Trial
The current prospective, randomized, double-blind, placebo-controlled multicenter Phase III study involved patients who had achieved a complete response after standard chemotherapy with prednisone, doxorubicin, cyclophosphamide, and etoposide (PACE), and maintained that remission for at least six months.
The introduction of rituximab as the standard of care made it difficult to recruit patients to the study, leading to a decision by the independent Data Monitoring Committee's decision to terminate the study prematurely, Dr. Schuster said.
At the time the study was closed, 177 patients were in the intent-to-treat analysis; however, 60 patients did not meet the remission requirement. The modified intent-to-treat group consisted of 117 patients who had maintained complete remission for at least six months and received at least one dose of either the idiotype or control vaccine.
All the patients had to have an affected lymph node at least 2 cm in size, since that is the minimum adequate for vaccine production.
After a median follow-up period of 56 months, the median disease-free survival time for the 76 patients who received the vaccine was 44.2 months, compared with 30.6 for the 41 patients in the control group. The difference translated to a significant 38% decreased risk of relapse in the vaccine arm, Dr. Schuster said.
The vaccine was well tolerated, with no serious adverse events reported by patients taking with the vaccine.
ASCO 2008–2009 President Richard L. Schilsky, MD, called the results “quite remarkable—It's the first example of an individual vaccine for lymphoma that works,” he said.
Discussant: Establishes Proof of Principle
The Discussant for the study, Ronald Levy, MD, Professor and Chief of the Division of Oncology at Stanford University School of Medicine, said, “This study establishes the proof of principle for active vaccination in the management of follicular lymphoma.”
Dr. Levy was introduced as a “pioneer in the field of immunotherapy for lymphoma,” having spearheaded much of the research on which the new vaccine was based, and an article on the Stanford Web site calls him “The Antibody Hero.”
The idiotype cells “provide a tempting target for treatment because they are unique to cancer cells and not to healthy cells,” he said.
But Dr. Levy went on to ask, “Is this result a positive result? Could there be a role for active vaccination in patients with this disease?”
Still, only 117 Patients Were Recruited—Fewer than a Third of the Goal of 375
Among the problems, he said, was the small size of the study, with only 117 patients recruited, when the goal was 375 patients.
About 25% of the patients were excluded after randomization but before vaccination because they failed to achieve complete remission on chemotherapy, and another 25% were excluded because they failed to maintain the complete remission for up to six months.
“So the results apply to only about 50% of patients…[who represent] “the best of the best,” he said.
Dr. Levy compared the study population with those of two other lymphoma vaccine studies that were discontinued because they failed to meet their primary endpoints (the Genitope recombinant idiotype conjugated to KLH vaccine and the Favrille autologous tumor cell vaccine coupled to keyhole limpet hemocyanin and sargramostim): In those trials, the inclusion criteria were broader, with one study including patients in partial remission and the other including patients with partial remission or stable disease, he noted.
Also, the time between drug treatment and vaccination was shorter, and there were subtle differences in the protein products used to make the vaccines, Dr. Levy noted.
“These factors could be why the results of this trial were positive while the results of the other trials were negative.”
In response to a question, Dr. Schuster acknowledged that complete durable remission could be the prerequisite for achieving benefit from this vaccine.
Rituximab Now Standard
Dr. Levy noted that in the time since patients were recruited, rituximab has added a “powerful advantage” in improving the treatment of follicular lymphoma.
“There still could be a role for vaccination,” but there need to be trials in which the vaccine Is given before and/or after treatment with chemotherapy plus rituximab, he said.
Also needed are methods to produce the vaccine more quickly. Dr. Levy's conclusion: a “qualified yes” that the trial is a positive result. But, he said, much more work needs to be done.
Said Dr. Schuster, “With the addition of rituximab, I would expect even better results, although that has to be studied.”
The approach might also be useful in other forms of B cell cancer, such as chronic lymphocytic leukemia, Dr. Schilsky noted.