Tumor-Specific Idiotype Vaccines Promising in B-Cell Lymphomas

ORLANDO—"Vaccines based on characterized tumor antigens have the advantage of potential tumor specificity from the start," Ronald Levy, MD, chief, Division of Oncology, Stanford University School of Medicine, said at an ASCO satellite symposium on cancer vaccines. Development of such vaccines requires definition and isolation of a specific target, and production of the purified target antigen, he said.

In patients with B-cell lymphomas, the opportunity to create a specific vaccine is possible because of the presence of a tumor-specific antigen, in the form of a clonally expressed immunoglobulin protein present on the surface of the malignant lymphocytes.

As Dr. Levy explained, surface immunoglobulins that are present on B cells display antigenic determinants within the variable regions of their light and heavy chains. These determinants, or idiotypes, are unique because of the combinatorial process by which they are formed. Because B-cell malignancies are monoclonal, all of the tumor cells display the same idiotype. Since the chemical nature of at least the common portions of the immunoglobulin proteins is known in advance, it is possible to isolate and purify tumor-specific idiotypes, he said.

Idiotype vaccines can stimulate both cellular and humoral immune responses, Dr. Levy said. While induction of T-cell responses is an important feature for vaccines, production of an antibody response is also important, given the efficacy of mo-noclonal antibody therapies against this particular target.

"In the case of vaccines, we would like to generate a polyclonal response that would target many different aspects of the antigen, one that would have a long-lasting effect and could produce immunologic memory," he said.

The vaccines used by Dr. Levy and his colleagues to treat B-cell lymphomas are customized to individual patients. The initial approach they devised was to obtain a tumor sample from the patient and fuse the malignant B cells, which bore the target immunoglobulin idiotype antigen, with myeloma cells, to produce hybridomas. From the hybridomas, they could then isolate and purify unlimited quantities of the specific tumor antigen. To create a vaccine, the tumor antigen was combined with the carrier protein KLH (keyhole limpet hemocyanin, a strongly immunogenic protein) and mixed with an immunologic adjuvant.

Improved Survival

In a study from Stanford, 41 patients with non-Hodgkin’s B-cell lymphomas received standard chemotherapy, then therapy with a specific idiotype vaccine derived from their individual tumors (Blood 89:3129-3135, 1997).

The study showed that the median duration of freedom from disease progression and overall survival were significantly prolonged in the 20 patients who mounted an anti-idiotype immune response, compared with the patients who did not mount an immune response.

"We found that if we could induce immune responses in patients, those patients stayed in remission longer," Dr. Levy said. He also noted that none of the patients who developed an anti-idiotype immune response had died within the years of follow-up, whereas the overall survival of patients who did not develop anti-idiotype immune responses appeared to mirror that of historical controls.

A similar study conducted at the National Cancer Institute by Maurizio Bendandi and his colleagues also demonstrated that idiotype vaccination could induce specific immune responses (Nature Med 5:1171-1177 1999). In addition, Dr. Levy said, in some patients, all molecular evidence of disease was eliminated, based on gene rearrangement detectable by PCR in the blood. The investigators also noted durable long-term remissions in patients with immune responses.

At the 2002 ASCO meeting, the Stanford researchers presented preliminary results from an ongoing phase II trial evaluating Genitope’s B cell tumor antigen vaccine, known as GTOP-99, in patients with untreated, asymptomatic low-grade follicular non-Hodgkin’s lymphoma (abstract 13).

In this trial, recombinant idiotype proteins were produced from tumor biopsies using a protein expression technology termed Hi-GET (high-throughput gene expression technology). Hi-GET is designed to accelerate the vaccine development process and improve its efficiency, compared with the hybridoma technique (see also ASCO 2002 abstract 77).

In this study, patients received a series of five doses of vaccine within a 24-week period. GM-CSF was also given as an adjuvant in order to stimulate the immune system. Of 16 patients who received all five injections, 13 had a tumor-specific immune response.

Dendritic Cells

Dr. Levy and his colleagues have also used dendritic cells to produce idiotypic vaccines. In these studies, dendritic cells are first isolated from a patient and then mixed with that patient’s specific idiotypic protein. The dendritic cells take up the protein, process it, and pre-sent it to T cells in the form of the vaccination.

In their study, 23 of 35 patients with B-cell lymphomas who received the dendritic cell vaccine mounted an immune response. Six patients with disease progression after primary dendritic cell vaccination received booster injections of the previously described idiotype/KHL protein vaccine. Tumor regression was seen in three of these patients (Blood 99:1517-1526, 2002).

"From our trials so far, it is only with dendritic cells that we see reproducible evidence of efficacy—actual tumor regression. So we think there is an added value of the dendritic cells," he said. "We don’t know whether the prior sensitization and priming with the dendritic cell vaccine set the patients up for this response with the protein vaccine boost, or whether subsequent or priming with protein vaccine would have done just as well, but this is very intriguing."

He also said that there is very little toxicity associated with these vaccines, "only some local injection site reactions, mostly due to the adjuvant."

These vaccine studies have shown that the induction of an immune response relates directly to longer progression-free survival and also to improved overall survival. But, as Dr. Levy indicated, randomized phase III trials are needed for definitive proof of efficacy.

Phase III Trials Underway

Currently, two phase III trials are underway, one being sponsored by Genitope Corporation and the other by the National Cancer Institute. In addition, Dr. Levy said that several phase I/II studies of idiotype vaccines are also ongoing.

Commenting on the feasibility of customized vaccines, Dr. Levy said "once the vaccines are shown to have an effect, we will be able to make them cost-effective and deliverable to large numbers of patients." ONI