Supplementary Fig. 2A: Changes in rank of the top 100 BCR clones at week 2 for a representative naïve patient are shown. The top 100 clonotypes at week 2 were identified based on their abundances at week 2. The rank of those clones at other timepoints were also obtained, and plotted across all 6 time points. Supplementary Fig. 2B: Pairwise Morisita's distance for both treated and naïve. Morisita's distance of 0 and 1 means maximally and minimally dissimilar of the repertoires from two different time points of the same patient, respectively (27). Each panel illustrates the Morisita's distance of two time points. Within each panel left and right boxplots represent sipuleucel-T treated patients and sipuleucel-T naive patients, respectively. The asterisk shows significant higher in treated vs naïve (Wilcoxon sum rank test p<0.05).
Funding
NIH
Conquer Cancer Foundation of the American Society of Clinical Oncology
Prostate Cancer Foundation Young Investigator Award
Prostate Cancer Foundation
ARTICLE 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.
