UCRF 2012 Innovation Grant Award: IgH Repertoire Sequencing to Predict Early Response to HER-2/neu Vaccination in Breast Cancer
Vaccine-based immunotherapies for cancer show modest though significant rates of clinical response associated with antitumor immune responses following vaccination1-3.
Current techniques require at least 3-4 vaccine treatments to assess immune response. It would be extremely valuable to identify responders early in order to focus therapeutic resources on those patients most likely to benefit.
Our group and others have recently discovered that the B cell response postvaccination predicts clinical outcome in HER-2/neu-specific vaccination for breast cancer; specifically, anti-neu antibody titers in mice4, 5 and avidity in humans6 correlate with tumor regression. Antibody titers reach measureable levels months after vaccination, which precludes their use as an early metric of response.
We hypothesize that the degree of immunoglobulin heavy-chain (IgH) locus somatic hypermutation (SHM) in expanded plasmablasts can serve as an accurate early indicator of response, as SHM and clonal expansion happen within weeks of antigen exposure and precede differentiation into antibody-producing plasma cells. To test this hypothesis, we developed a novel high-throughput sequencing method using the Pacific Biosciences RS platform to assess the SHM status of IgH repertoires in B cell populations7.
Our lab has previously developed robust pre-clinical murine models for HER-2/neu-vaccination8, 9. We propose here to sequence the IgH repertoires of mice after vaccination in order to define predictors of vaccine-driven immune response and tumor regression. We will then extend our experiments to human samples from our lab’s ongoing phase II trial of a dual-epitope dendritic-cell vaccine (LCCC0418), with expectation to identify a biomarker for early vaccine response in humans.