Prostate Ca immunotherapy induces T-cell response

Results of a study conducted to further elucidate the mechanism of action of sipuleucel-T (Provenge) as treatment for advanced prostate cancer provide fairly convincing demonstration that the autologous cellular immunotherapy agent induces T-cell responses in humans, said Charles G. Drake, MD, PhD.

The research, presented at the American Society of Clinical Oncology annual meeting in Chicago, evaluated the proliferative and lytic phenotypes of antigen-specific T helper (Th) cells and cytotoxic T lymphocytes (CTLs) in patients treated with sipuleucel-T in clinical trials. In addition, it investigated the correlation between CTL activity and overall survival in the treated patients.

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Assays showed that sipuleucel-T generated robust proliferation of the immune cells, particularly of the CTLs, and that as early as 6 weeks post-treatment and persisting for at least 26 weeks, the CTLs were capable of cytolytic activity. Furthermore, an association was found between the magnitude of the antigen-specific CTL response persisting at week 26 and overall survival.

“The assays used in this study, which are based on quantifying T-cell proliferation and production of effector cytokines, are more sensitive than previously used techniques, and therefore allow us to detect patients who seem to respond immunologically to the treatment,” explained Dr. Drake, of Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York.

“The correlation identified between increased magnitude of the CTL responses and longer survival suggests that patients who develop a T-cell response to sipuleucel-T may be more likely to benefit clinically. However, because this is a retrospective study, we cannot separate correlation from causation. Therefore, we cannot determine whether improved T-cell response actually drove survival or if healthy patients destined for longer survival were more likely to mount a better T-cell response when treated with sipuleucel-T.”

Next: How the study was conducted

The study analyzed Th cells and CTLs from 14 men with hormone-sensitive or metastatic castration-resistant prostate cancer who were treated with sipuleucel-T in clinical trials. Peripheral blood mononuclear cells isolated from the patients and from healthy donors as controls were cultured with PA2024, the fusion antigen conjugating human prostatic acid phosphatase (PAP) with human granulocyte-macrophage colony-stimulating factor, or PAP by itself. Flow cytometry was used to quantify antigen-specific proliferation of the immune cells, and cell-surface CD107a expression was measured to assess CTL lytic activity.

The correlation between overall survival and CTL activity in the sipuleucel-T-treated patients was investigated using Pearson’s correlation that showed a statistically significant relationship between longer survival and normalized CTL activity at 26 weeks post-treatment for both PAP- and PA2024-specific cells.

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In addition, with patients divided into two groups based on whether their antigen-specific CTL activity was above or below the median CTL response, Kaplan-Meier analysis showed overall survival was significantly longer in the group of men with the better antigen-specific CTL response.

Looking ahead, Dr. Drake suggested that the assays used in this study might be applied to research for developing combination regimens for enhancing benefit of sipuleucel-T.

“Perhaps they could be used to evaluate which combinations induce the best immune response. In addition, it is possible that the assays might be used to identify patients whose T-cell response to sipuleucel-T is waning and thereby select men who might benefit from another dose of sipuleucel-T in the same manner as we administer a booster vaccine for infectious diseases.”

Several of Dr. Drake’s co-authors have a financial or other relationship with or are employees of Dendreon. For a full list of disclosures, click here.

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