Anti-Idiotype Vaccine for Non-Hodgkin’s Lymphoma Enters Phase-III Trials

STANFORD, California—A recombinant idiotype protein vaccine for treatment of non-Hodgkin’s lymphoma (NHL) induced both cellular and anti-idiotype tumor-specific immunity in phase-I/II trials and has now progressed to phase-III studies, reported John Timmerman, MD, research fellow, Division of Oncology, Stanford University Medical Center, Stanford, California.

The phase-III trial, which opened at the end of November, will be conducted at in 23 centers in the United States and Canada. The aim is to prolong relapse-free survival in NHL patients who achieve at least a partial remission after a cycle of chemotherapy.

Dr. Timmerman explained that tumor-specific variable regions of the clonal immunoglobulin expressed by B-cell NHL (idiotype, or Id) can be exploited as a target for active immunotherapy. The vaccine consisted of idiotype protein coupled to the carrier protein keyhole limpet hemocyanin (KLH) given with locally administered granulocyte-macrophage colony-stimulating factor (GM-CSF).

Idiotype Specific Responses

This phase-I/II study has enrolled 25 patients, 10 of whom have completed at least 4 immunizations and were evaluable for response. All patients had follicular NHL in first remission following chemotherapy.

Treatment consisted of five subcutaneous (SC) injections of idiotype protein coupled to KLH on day 1, along with locally administered GM-CSF (SC days 1-4).

Dr. Timmerman reported that 70% of patients produced idiotype-specific responses. This included cellular proliferative responses in 5 of 10 patients, anti-idiotype antibodies in 6 of 10 patients, and both cellular and anti-idiotype antibodies in 4 of 10 patients.

"Anti-idiotype antibodies can specifically recognize autologous tumor cells," Dr. Timmerman said. "The 70% anti-Id response rate compares favorably to the 50% rate seen in our earlier study. The two patients with persistent bcl-2 PCR signal in peripheral blood post-chemotherapy both converted to bcl-2 negative following immunization."

In previous studies, immunizing follicular NHL patients with custom-made Id protein derived from tumor-myeloma hybridomas induced anti-Id immune responses that correlated with improved disease-free and overall survival, tumor regressions, and molecular complete remissions.

‘Molecular Rescue’

The potential clinical utility of this approach was increased by the "molecular rescue" technique, developed by the Genitope Corporation of Redwood City, California, in collaboration with the Stanford group, which was used to produce idiotype protein used in this phase I/II trial. "Isolation of idiotype proteins by traditional hybridoma methods requires live tumor cells obtained by excisional biopsy. In addition, hybridomas can lose idiotype production ability over time, thus limiting wide application," Dr. Timmerman said.

"We were able to streamline production of idiotype proteins by amplifying idiotype genes by PCR, using small numbers of tumor cells obtainable by fine needle aspiration, core biopsies, or bone marrow samples. The amplified genes were cloned into plasmid vectors, and transfected into mammalian cells yielding stable sources of idiotype protein." He concluded that recombinant idiotype proteins can be routinely produced from tumor specimens, that this vaccine is safe, and that 70% of NHL patients vaccinated had clinical responses.

Limited Side Effects

Side effects have been primarily limited to mild local injection site reactions, which occurred in all patients, and "transient flu-like symptoms" in about half of patients.

"We conclude that recombinant idiotype proteins produced by this new technology can induce humoral and cellular anti-idiotype immune responses. A multicenter, phase-III, randomized trial, also being sponsored by Genitope, using recombinant Id is now being conducted for follicular NHL patients in first remission after chemotherapy, with relapse-free survival as the primary endpoint," Dr. Timmerman stated.