Supplementary Fig. 5: Sensitivity analysis of social network analysis of the representative sipuleucel-T treated patient. (A) Density plot of the clone frequency for all clones of the treated patient (red) and density plot of the clone frequency for subsampled clones of the treated patient (green). Subsampling was done by weighted clone frequency. (B) Social network (V04 family gene) of the all clones of the treated patient. (C) Social network (V04 family gene) of the all clones of the naïve patient. (D) Social network (V04 family gene) of the subsampled clones of the treated patient. Subsampling was done by weighted clone frequency. For each patient, social network analysis was first performed using R packages: Ape (24) and igraph (25). A convergent group was defined as the cluster that included the clones with the distance less than or equal to 1 (allowing maximum of 1 basepair mutation among clone sequences sharing the same V-gene, J-gene and CDR3 length). For all social network figures, each node represents a single clone colored by its first presenting time point, and the node size was attributed based on the corresponding abundance. The nodes connected by lines were within the same convergent group.
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.
