At the 2010 American Society of Hematology (ASH) Annual Meeting, Biovest presented an updated Phase III data analysis for BiovaxID which strongly suggests that the improved disease-free survival observed in BiovaxID-treated patients depends on an integral tumor protein fragment administered as part of each patient’s vaccine.  In lymphoma, this protein fragment, termed the “isotype”, was previously believed to be unimportant to vaccine response.  The new analysis further suggests that patients receiving a vaccine with a specific isotype (IgM) experienced a dramatic disease-free survival benefit.

While the manufacture of BiovaxID utilizes each individual patient’s idiotype protein expressed on lymphoma cells, there are different categories of isotypes that differentiate idiotypes.  In follicular lymphoma, approximately 99% of patients have idiotypes expressing either an IgM isotype or an IgG isotype.  As shown below, there are distinct differences between the IgM and IgG protein.

The idiotype (Id) protein expressed on the surface of follicular lymphoma (FL) cells is an immunoglobulin protein characteristic of the single B-cell from which the tumor arose.  The immunoglobulin protein contains a region known as the “heavy chain” and a region known as the “light chain”.  Almost always in FL, the heavy chain region is characterized as either an IgM-isotype or an IgG-isotype.  The figure illustrates the dramatic differences in the structure of immunoglobulin protein characterized as an IgM-isotype as opposed that characterized as an IgG-isotype.

Although a separate BiovaxID manufacturing process is utilized for the IgM isotype and for the IgG isotype in order to match the patient’s isotype with the patient’s vaccine, the BiovaxID Phase III trial protocol did not include planned analyses to address efficacy analysis by isotype.  However, Biovest conducted this subset isotype analysis and discovered a fundamental relationship between vaccine isotype and the efficacy of BiovaxID.

Biovest’s manufacturing process preserves the isotype of the tumor (either IgM or IgG) in each patient’s vaccine.  In the study, IgM-positive patients treated with an IgM vaccine and IgG-positive patients treated with IgG vaccine were compared to isotype-matched control patients.  As shown by the survival curves below, the results comparing the isotypes were dramatically different.

DFS: IgM-version of BiovaxID versus IgM Control

DFS: IgG-version of BiovaxID versus IgG Control

As shown by the disease-free survival curves, we analyzed differences in median DFS in vaccinated patients in our Phase III clinical trial separately by tumor isotype.

In the IgM isotype group, we observed that patients who were treated with isotype-matched BiovaxID had significantly longer DFS (52.9 months, versus 28.7 months) than patients with IgM isotype tumors who received control vaccine. In contrast, in the IgG isotype group, there was no difference in median DFS between the patients who received isotype-matched BiovaxID and the patients with IgG isotype tumors who received control vaccine.

This startling finding establishes that careful initial selection of heavy-chain isotype in idiotype vaccine manufacture may ultimately be a key predictor of clinical benefit.  Accordingly future studies conducted with idiotypic cancer vaccines (including, but not limited to BiovaxID) must take into consideration the potential impact of the heavy-chain isotype on those vaccine’s efficacy.  This unexpected and profound discovery had not been previously demonstrated in any human trial.