Race-Related Differences in Sipuleucel-T Response among Men with Metastatic Castrate-Resistant Prostate Cancer

Abstract

Sipuleucel-T is an autologous cellular immunotherapy that targets prostatic acid phosphatase (PAP) and is available for treatment of men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). In this single-arm, two-cohort, multicenter clinical study, potential racial differences in immune responses to sipuleucel-T in men with mCRPC were explored. Patients' blood samples were obtained to assess serum cytokines, humoral responses, and cellular immunity markers before and after treatment. Baseline cumulative product parameters (total nucleated and CD54+ cell counts and CD54 upregulation) were evaluated. IgM titers against the immunogen PA2024, the target antigen PAP, prostate-specific membrane antigen (PSMA) and prostate-specific antigen (PSA) were quantified by ELISA. Cytotoxic T-lymphocyte activity was determined by ELISpots, and cytokine and chemokine concentrations were determined by Luminex.Twenty-nine African American (AA) men and 28 non-African American (non-AA) men with mCRPC received sipuleucel-T. Baseline total nucleated cell count, CD54+ cell count, CD54 expression, and cumulative product parameters were higher in non-AA men. Although PSA baseline levels were higher in AA men, there were no racial differences in IgM antibody and IFNγ ELISpots responses against PA2024, PAP, PSA, and PSMA before and after treatment. Expression of co-stimulatory receptor ICOS on CD4+ and CD8+ T cells, and the levels of Th1 cytokine granulocyte-macrophage colony-stimulating factor and chemokines CCL4 and CCL5, were significantly higher in AA men before and/or after treatment. Despite no difference in the overall survival, PSA changes from baseline were significantly different between the two races. The data suggest that immune correlates in blood differ in AA and non-AA men with mCRPC pre- and post-sipuleucel-T.

Significance: Our novel findings of higher expression of co-stimulatory receptor ICOS on CD4+ and CD8+ T cells in African American patients with metastatic castrate-resistant prostate cancer (mCRPC) prior and post-sipuleucel-T suggest activation of CD4+ and CD8+ T cells. The data indicate that racial differences observed in these and other immune correlates before and after sipuleucel-T warrant additional investigation to further our understanding of the immune system in African American men and other men with mCRPC.

Figure 1

Study schema. Treatment schema showing schedule of sipuleucel-T infusions and immune evaluations. Wk, week.

Figure 2

Peripheral antibody and IFNγ ELISpot immune responses in AA men (n = 29) and non-AA men (n = 28). A, Significantly higher serum IgM antibody levels against PA2024 (P < 0.0001) and PAP (PAP; P < 0.0001) were noted at 10 weeks post-treatment above the baseline in each group. No significant differences were observed in either group for anti-PSMA antibody levels at 10 weeks post-treatment vs. baseline. There were significantly higher anti-PSA antibody levels in non-AA group (P = 0.0018) at 10 weeks post-treatment above the baseline. B, IFNγ ELISpot responses to PA2024 increased significantly (P = 0.0008) in non-AA men at 10 weeks post-treatment vs. baseline. In AA men, IFNγ ELISpot responses to PA2024 also increased (P = 0.04) at 10 weeks post-treatment. No significant differences in IFNγ ELISpot responses were seen at 10 weeks against PAP, PSMA, or PSA in either group. For (A and B), there were no significant racial differences in either antibody or IFNγ ELISpot responses against PA2024, PAP, PSMA, or PSA at baseline or at 10 weeks post-treatment. All responses and racial differences were analyzed by the Mann–Whitney test and P values < 0.0032 were considered as significant in the multiple comparisons sense. The horizontal line in each dot plot marks the median value. Base, baseline; wks, weeks.

Figure 3

Co-stimulatory and co-inhibitory marker expression on CD4⁺ and CD8⁺ T cells in two racial groups. A, No differences in the percentage of CD4⁺ T cells were observed at baseline or at 10 weeks post-treatment in AA men (n = 29) vs. non-AA men (n = 28). Expression of co-stimulatory receptor ICOS on CD4⁺ T cells was significantly higher at baseline and at 10 weeks post-treatment (P = 0.0006; P = 0.0027, respectively) in AA men compared to non-AA men. Expression of co-inhibitory receptor BTLA on CD4⁺ was also significantly higher at baseline (P < 0.0001) in AA men compared to non-AA men. B, The percentage of CD8⁺ T cells was significantly lower (P = 0.0016) at baseline as well as at 10 weeks post- treatment in AA men compared to non-AA men. Expression of co-stimulatory receptor ICOS on CD8⁺ T cells was significantly higher at baseline and at 10 weeks post-treatment (P = 0.0023; P = 0.0026, respectively) in AA men vs. non-AA men. Differences between the two racial groups were analyzed by the Mann–Whitney test and P values < 0.0032 were considered as significant in the multiple comparisons sense. The horizontal line in each dot plot marks the median value. Base, baseline; wks, weeks.

Figure 4

Differential cytokine and chemokine responses in AA men (n = 29) and non-AA men (n = 28). Of all Th₁ cytokines, only the baseline levels of GM-CSF were significantly higher (P = 0.001) in AA men vs. non-AA men. The levels of chemokine CCL4 (MIP-1β) were significantly higher at baseline (P = 0.0003) in AA men vs. non-AA men. The levels of CCL5 (RANTES) were significantly higher at baseline (P < 0.0001), as well as at 10 weeks post treatment (P = 0.0006) in AA men vs. non-AA men. Differences between the two racial groups were analyzed by the Mann–Whitney test and P values < 0.0032 were considered as significant in the multiple comparisons sense. The horizontal line in each dot plot marks the median value. Base, baseline; wks, weeks.

Figure 5

A, Longitudinal PSA levels by race groups. Curves were fitted with LOESS smoothing method. Dot and triangle symbols indicate mean log₁₀(PSA) at the given time point. Vertical error bars indicate standard errors. B, Waterfall plot: PSA change from baseline to nadir.