Safety and Potential Effect of a Single Intracavernous Injection of Autologous Adipose-Derived Regenerative Cells in Patients with Erectile Dysfunction Following Radical Prostatectomy: An Open-Label Phase I Clinical Trial

Abstract

Background: Prostate cancer is the most common cancer in men, and radical prostatectomy (RP) often results in erectile dysfunction (ED) and a substantially reduced quality of life. The efficacy of current interventions, principal treatment with PDE-5 inhibitors, is not satisfactory and this condition presents an unmet medical need. Preclinical studies using adipose-derived stem cells to treat ED have shown promising results. Herein, we report the results of a human phase 1 trial with autologous adipose-derived regenerative cells (ADRCs) freshly isolated after a liposuction.

Methods: Seventeen men suffering from post RP ED, with no recovery using conventional therapy, were enrolled in a prospective phase 1 open-label and single-arm study. All subjects had RP performed 5-18 months before enrolment, and were followed for 6 months after intracavernosal transplantation. ADRCs were analyzed for the presence of stem cell surface markers, viability and ability to differentiate. Primary endpoint was the safety and tolerance of the cell therapy while the secondary outcome was improvement of erectile function. Any adverse events were reported and erectile function was assessed by IIEF-5 scores. The study is registered with ClinicalTrials.gov, NCT02240823.

Findings: Intracavernous injection of ADRCs was well-tolerated and only minor events related to the liposuction and cell injections were reported at the one-month evaluation, but none at later time points. Overall during the study period, 8 of 17 men recovered their erectile function and were able to accomplish sexual intercourse. Post-hoc stratification according to urinary continence status was performed. Accordingly, for continent men (median IIEFinclusion = 7 (95% CI 5-12), 8 out of 11 men recovered erectile function (IIEF6months = 17 (6-23)), corresponding to a mean difference of 0.57 (0.38-0.85; p = 0.0069), versus inclusion. In contrast, incontinent men did not regain erectile function (median IIEF1/3/6 months = 5 (95% CI 5-6); mean difference 1 (95% CI 0.85-1.18), p > 0.9999).

Interpretation: In this phase I trial a single intracavernosal injection of freshly isolated autologous ADRCs was a safe procedure. A potential efficacy is suggested by a significant improvement in IIEF-5 scores and erectile function. We suggest that ADRCs represent a promising interventional therapy of ED following prostatectomy.

Funding: Danish Medical Research Council, Odense University Hospital and the Danish Cancer Society.

Keywords: ADRC, adipose-derived regenerative cells; Adipose-derived regenerative cells; Adipose-derived stem cells; Adipose-derived stromal vascular fraction; BMI, body mass index; CFU-F, fibroblastoid colony forming units; Cell therapy; Clinical trial; ED, erectile dysfunction; EHS, erection hardness score; Erectile dysfunction; ICIQ-UI SF, incontinence questionnaire – urinary incontinence – short form questionnaire; IIEF-5, international index of erectile function-5; LUTS, lower urinary tract symptoms; NSAID, nonsteroidal antiinflammatory drug; PDE-5, phosphodiesterase-5; RP, radical prostatectomy; SVF, stromal vascular fraction.

Supplemental Fig. S1

The time between prostatectomy and ADRC intervention was similar in all groups. The time interval in months between radical prostatectomy and ADRC injection was tested (Mann–Whitney test) in patients grouped according to their (A) urinary continence status, or (B) ability to have sexual intercourse after 6 months. In both cases, no significant difference was observed.

Supplemental Fig. S2

Urinary continence was improved. Improved urinary continence scores with a reduction in ICIQ-UI SF score 6 months post-transplantation was significant for continent men, and a trend was revealed for incontinent men as well (Wilcoxon matched pairs signed rank test).

Fig. 1

Study overview. *Some patients were excluded based on several criteria. (IC:Intracavernous; RP:Radical Prostatectomy).

Fig. 2

Characterics of the isolated ADRCs. (A) The total yield of nucleated ADRCs per isolation was positively correlated to the input volume of liposuction. (B) ADRC yield per gram fat tissue was independent of donor age. (C) Representative histograms showing expression levels of CD34, CD31, CD73 and CD90 (green) in single-stained ADRCs as analyzed by flow cytometry. The appropriate isotype control is depicted as overlay (purple) in each case. Population percentages are given as mean ± SD, n = 17. (D) The population of CD235a-CD45-CD31-CD34 + ADRCs was identified in multi-stained samples by flow cytometry using a stepwise gating strategy as indicated by the arrows. The number of cells is expressed as a percentage of the entire single-cell ADRC population (mean ± SD, n = 3). In each density plot (from one representative patient), the corresponding isotype control is shown as overlay (purple). P-values represent Pearson correlation coefficients in A and B.

Fig. 3

Effect of ADRC therapy. (A) IIEF scores for each patient at inclusion, 1, 3 and 6 months after a single intracavernous bolus of autologous ADRCs. Patients that regained their ability to have sexual intercourse (green closed circles) had significantly better IIEF scores after 3 and 6 months, but not after 1 month (Two-Way ANOVA following log transformation). (B, C) Patients were stratified according to their urinary incontinence status. (B) In the group of continent men (n = 11), significantly improved IIEF scores were observed after 3 and 6 months compared to their inclusion scores (RM one-way ANOVA with Sidak's multiple comparisons test following log transformation). (C) No changes in IIEF scores were observed in the group of incontinent men (n = 6) during the study period (RM one-way ANOVA with Sidak's multiple comparisons test, following log transformation). Similarly, the EHS scores were significantly improved after 6 months in the continent (D) but not in the incontinent group (E) (Friedman's test with Dunn's multiple comparisons test). (F) Spontaneous reversion of ED post RP in our department was established reviewing 165 medical records. In groups of 135 urine continent men and 30 incontinent men, 40 and 4 men, respectively, showed spontaneous reversion of ED.