![]() S1) and patients who received their first sipuleucel-T treatment (naïve STRIDE study, NCT01981122 Supplementary Fig. To investigate whether prior treatment with sipuleucel-T induced long-term immunologic memory, we compared treatment-induced B-cell responses in patients who were previously treated with sipuleucel-T (treated P10-1 study, NCT01338012 Supplementary Fig. Immunologic studies conducted on samples from a phase III trial that demonstrates improved survival with sipuleucel-T treatment in mCRPC shows that 68% of treated patients developed antibody responses against PA2024, the immunogen used to make the product ( 2, 3). We used social network analysis to assess the maturity of the B-cell memory response, because affinity maturation can result in highly related clonotypes. Here, we assessed the capacity of sipuleucel-T to induce acute and memory B-cell responses by measuring antigen-specific antibodies and determining the treatment induced effects in the B-cell repertoire. The durability of antigen-specific responses induced with cancer immunotherapy is unknown. Most studies of cancer immunotherapies thus far have focused on their impact on the T-cell repertoire, largely ignoring the B-cell response. This treatment functions like a vaccine, inducing increases in both T-cell repertoire diversity and the number of activated T cells within the tumor microenvironment ( 5, 6). Sipuleucel-T functions as a cancer therapy by priming T- and B-cell immune responses to PA2024, both of which associate improved overall survival ( 2–4). Sipuleucel-T is manufactured by culturing isolated peripheral blood mononuclear cells (PBMC) with PA2024, a recombinant fusion protein composed of prostatic acid phosphatase (PAP) linked to granulocyte-macrophage colony–stimulating factor ( 1). Sipuleucel-T is an autologous cellular immunotherapy FDA-approved for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC ref. These results demonstrated the capacity of sipuleucel-T to induce long-term immune memory and lasting changes to the B-cell repertoire. Higher treatment-induced BCR clonality correlated with longer survival for naïve patients. Social network analysis showed that previously treated patients had more highly organized B-cell repertoires, consistent with greater clonal maturation. In contrast, naïve patients exhibited great BCR turnover with a continued influx of new B-cell clones. With the first sipuleucel-T infusion specifically, previously treated patients had less shuffling within the 100 most abundant baseline clones. After re-treatment, previously treated patients maintained high-frequency clones and developed more convergent BCRs at earlier time points unlike naïve patients. 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. 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). 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. Sipuleucel-T induces T- and B-cell responses to prostatic acid phosphatase (PAP), correlating to improved survival. Sipuleucel-T is an autologous cellular immunotherapy, administered as three infusions, for metastatic castration-resistant prostate cancer (mCRPC). ![]()
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