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 up to 3 infusions, for metastatic castrationresistant 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 antigenspecific immunologic memory remains unknown. In particular, B cell responses, as measured by antigenspecific antibody responses and B cell receptor (BCR) sequences, remain unknown. 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 mCRPC patients: 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 retreatment, previously treated patients maintained high frequency clones and developed more convergent BCRs at earlier time points unlike naive patients. With the first sipuleucel-T infusion specifically, previouslytreated 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.

Early changes in the circulating T cells are associated with clinical outcomes after PD-L1 blockade by durvalumab in advanced NSCLC patients

“…As in [19], for each patient a pairwise distance matrix of each pair of amino acid sequences was calculated based on Levenshtein distance. A convergent group was defined as the cluster that included the clones with the distance ≤ to 1 (allowing maximum of 1 bp difference among amino acid sequences).…”

Real-World Effectiveness of Sipuleucel-T on Overall Survival in Men with Advanced Prostate Cancer Treated with Androgen Receptor-Targeting Agents

“…The current study also looked more carefully at the nature of the first- and second-line treatments, observing that most patients who receive an ARTA as first-line therapy continue the same ARTA after sipuleucel-T has been administered. As immunotherapy stimulates the immune system to target prostate cancer cells, the benefits of sipuleucel-T persist beyond the period of its administration [ 8 , 9 ].…”

“…Sipuleucel-T is an autologous antigen-presenting cell-based immunotherapy approved for use by the US Food and Drug Administration (FDA) in 2010 on the basis of its prolongation of overall survival (OS) in patients with asymptomatic or minimally symptomatic mCRPC [ 6 , 7 ]. A single course of treatment with sipuleucel-T, typically lasting 4–6 weeks, mobilizes the immune system to target and destroy prostate cancer cells [ 8 ] with a potential for long-term effectiveness (evidence of effectiveness as long as a median of 8.9 years [ 9 ]). A median OS of 30.7 months from the date of the first sipuleucel-T infusion was demonstrated in the PROVENGE Registry for the Observation, Collection, and Evaluation of Experience Data (PROCEED), a large registry of men with mCRPC who received sipuleucel-T after FDA approval between 2011 and 2017 [ 10 ].…”

A Bayesian network meta‐analysis of comparison of cancer therapeutic vaccines for melanoma

“…Sipuleucel-T (PROVENGE), a first-generation therapeutic cancer vaccine approved by the U.S. Food and Drug Administration (FDA) in 2010, is an autologous dendritic cell-based vaccine for the treatment of metastatic castration-resistant (hormone-refractory) prostate cancer. 12,13 To our knowledge, antitumor responses can be induced by administering vaccines loaded with tumor-associated antigens (TAAs) or tumor-specific antigens to foster cytotoxic T cell (CTL) activation and proliferation and thus promote cellular immune responses. 14,15 Recently, various vaccine approaches for melanoma have been explored in clinical trials.…”

“…Vaccines of different types have been developed and utilized for cancer treatment and prevention throughout the past few decades. Sipuleucel‐T (PROVENGE), a first‐generation therapeutic cancer vaccine approved by the U.S. Food and Drug Administration (FDA) in 2010, is an autologous dendritic cell‐based vaccine for the treatment of metastatic castration‐resistant (hormone‐refractory) prostate cancer 12,13 …”