Immunomodulation by Entinostat in Renal Cell Carcinoma Patients Receiving High-Dose Interleukin 2: A Multicenter, Single-Arm, Phase I/II Trial (NCI-CTEP#7870)

Abstract

Purpose Based on preclinical data suggesting that the class I selective HDAC inhibitor entinostat exerts a synergistic antitumor effect in combination with high dose interleukin 2 (IL-2) in a renal cell carcinoma model by down-regulating Foxp3 expression and function of regulatory T cells (Treg), we conducted a phase I/II clinical study with entinostat and high dose IL-2 in patients with metastatic clear cell renal cell carcinoma (ccRCC). Experimental Design Clear cell histology, no prior treatments, and being sufficiently fit to receive high dose IL-2 were the main eligibility criteria. The phase I portion consisted of two dose levels of entinostat (3 and 5 mg, PO every14 days) and a fixed standard dose of IL-2 (600,000 units/kg IV). Each cycle was 85 days. The primary end point was objective response rate and toxicity. Secondary end points included progression-free survival and overall survival. Results 47 patients were enrolled. At a median follow-up of 21.9 months, the objective response rate was 37% (95% CI 22%–53%), the median progression-free survival was 13.8 months (95% CI 6.0–18.8), and the median overall survival was 65.3 months (95% CI 52.6.–65.3). The most common grade 3/4 toxicities were hypophosphatemia (16%), lymphopenia (15%), and hypocalcemia (7%), and all were transient. Decreased Treg were observed following treatment with entinostat, and lower numbers were associated with response (p=0.03). Conclusions This trial suggests a promising clinical activity for entinostat in combination with high dose Il-2 in ccRCC patients, and provides the first example of an epigenetic agent being rationally combined with immunotherapy.

Targeting the Immune system and Epigenetic Landscape of Urological Tumors

“…Interestingly, the authors hypothesized about the synergism observed between these two agents based on opposite (but complementary) mechanisms: IL-2 enhances activation of effector T cells (which are reduced by MS-275), while MS-275 causes depletion of Tregs (which are potentiated by IL-2)-resulting in the end of a net antitumor effect mediated by increased effector cells and decreased Tregs. This has been, at least in part, confirmed for other HDAC inhibitors, such as entinostat, which downregulate FoxP3 and hence Tregs [108], leading to a phase 1/2 trial [107]. This study enrolled metastatic 47 ccRCC patients and showed a beneficial response with combining entinostat with IL-2 (objective response of 37%), showing the promises of such therapeutic approaches to metastatic ccRCC.…”

“…A summary of most recent studies addressing combination strategies between epigenetics and immune environment in KCa is presented in Table 2 [103][104][105][106][107][108][109]. Since IL-2 has been used as a form of immunotherapy for KCa for more than one decade, several studies have explored its combination with epigenetic drugs, including methylation-and acetylation-targeting drugs.…”

Epigenetic priming of both tumor and NK cells augments antibody-dependent cellular cytotoxicity elicited by the anti-PD-L1 antibody avelumab against multiple carcinoma cell types

“…Entinostat has recently been shown to decrease the frequency of circulating Tregs in cancer patients. 55 To our knowledge, our findings are the first comprehensive analysis on the effects of these agents spanning 123 immune subsets in PBMCs from heavily pretreated cancer patients (Supplemental Table 3). We observed that vorinostat treatment of PBMCs elevated the frequency of NKT cells (Supplemental Table 5).…”

Combination immunotherapy with interleukin‐2 surface‐modified tumor cell vaccine and programmed death receptor‐1 blockade against renal cell carcinoma

“…As a T‐cell growth factor, IL‐2 has been largely used to treat RCC in the past few years . This study showed that SA‐IL‐2 surface‐modified whole tumor cell vaccine could enhance tumor‐specific cytotoxic T‐lymphocyte activity and antitumor responses in vivo.…”