Investigation of mechanisms of resistance to ipilimumab therapy with a pre-surgical trial in patients with high-risk, localized prostate cancer.

Abstract

5081 Background: Anti-CTLA-4 therapy ipilimumab (BMS) has led to clinical benefit in patients with metastatic melanoma. However, in multiple clinical trials in patients with prostate cancer, ipilimumab has not demonstrated significant clinical benefit. To identify potential immune inhibitory pathways responsible for resistance to ipilimumab therapy, we evaluated tumor samples from a pre-surgical clinical trial and performed correlative laboratory studies. Methods: We carried out a pre-surgical clinical trial with androgen deprivation therapy (ADT), (leuprolide acetate, Tap Pharmaceuticals) plus ipilimumab in patients with localized, high-risk prostate cancer. Each patient received one injection of leuprolide (22.5 mg) on week 0 and ipilimumab (10 mg/kg) on weeks 1 and 4. Patients then underwent surgery at week 8. Tumor tissues were collected at baseline and then at surgery for flow cytometry, IHC, multiplex immunofluorescence, and gene profiling analyses. In vitro studies were carried out for functional analysis. Results: Sixteen patients completed treatment with ipilimumab plus ADT and surgery. We observed a significant increase of immune cells including T cells and macrophages into prostate tumors after ipilimumab therapy, similar to data observed in ipilimumab-treated melanoma samples. However, compared to melanoma tumors, we found higher expression of PD-L1 and VISTA inhibitory molecules on CD68+ macrophages in prostate tumors. Interestingly, PD-L1 and VISTA were expressed on distinct subset of CD68+ macrophages, with high expression of CD163, suggesting an M2 subtype. In vitro studies demonstrated that engagement of PD-L1 and/or VISTA pathways inhibited T cell responses. Co-culture with monocytes resulted in suppression of T cell function, which can be reversed with anti-VISTA blocking antibody. Conclusions: These data suggest that evolving compensatory inhibitory pathways including PD-L1 and VISTA may mediate resistance of prostate cancer to ipilimumab therapy. Concurrent blockade of other immune checkpoints such as PD1/PD-L1 and/or VISTA may be necessary to provide significant clinical benefits for patients with prostate cancer. Clinical trial information: NCT01194271.