Long-term Sculpting of the B-cell Repertoire following Cancer Immunotherapy in Patients Treated with Sipuleucel-T

Abstract

Sipuleucel-T is an autologous cellular immunotherapy, administered as three infusions, for metastatic castration-resistant prostate cancer (mCRPC). Sipuleucel-T induces T- and B-cell responses to prostatic acid phosphatase (PAP), correlating to improved survival. The long-term impact of sipuleucel-T on tumor antigen-specific immunologic memory remains unknown, in particular, B-cell responses, as measured by antigen-specific antibody responses and B-cell receptor (BCR) sequences. To evaluate whether sipuleucel-T could induce long-term immunologic memory, we examined circulating B-cell responses before and after sipuleucel-T treatment in two groups of patients with mCRPC: those who had previously received sipuleucel-T (treated; median, 8.9 years since the previous treatment) versus those who had not (naïve). Before re-treatment, previously treated patients exhibited persistent antibody responses as well as more focused and convergent BCR repertoires with distinct V(D)J gene usage compared with naïve patients. After re-treatment, previously treated patients maintained high-frequency clones and developed more convergent BCRs at earlier time points unlike naïve patients. With the first sipuleucel-T infusion specifically, previously treated patients had less shuffling within the 100 most abundant baseline clones. In contrast, naïve patients exhibited great BCR turnover with a continued influx of new B-cell clones. Social network analysis showed that previously treated patients had more highly organized B-cell repertoires, consistent with greater clonal maturation. Higher treatment-induced BCR clonality correlated with longer survival for naïve patients. These results demonstrated the capacity of sipuleucel-T to induce long-term immune memory and lasting changes to the B-cell repertoire.