A Randomized Phase II/III Study of Naptumomab Estafenatox + IFNα versus IFNα in Renal Cell Carcinoma: Final Analysis with Baseline Biomarker Subgroup and Trend Analysis

Abstract

Purpose: To prospectively determine the efficacy of naptumomab estafenatox (Nap) þ IFNa versus IFN in metastatic renal cell carcinoma (RCC).Experimental Design: In a randomized, open-label, multicenter, phase II/III study, 513 patients with RCC received Nap (15 mg/ kg i. v. in three cycles of four once-daily injections) þ IFN (9 MU s. c. three times weekly), or the same regimen of IFN monotherapy. The primary endpoint was overall survival (OS).Results: This phase II/III study did not meet its primary endpoint. Median OS/PFS for Nap þ IFN patients was 17.1/5.8 months versus 17.5/5.8 months for the patients receiving IFN alone (P ¼ 0.56; HR, 1.08/P ¼ 0.41; HR, 0.92). Post hoc exploratory subgroup and trend analysis revealed that the baseline plasma concentrations of anti-SEA/E-120 (anti-Nap antibodies) for drug exposure and IL6 for immune status could be used as predictive biomarkers. A subgroup of patients (SG; n ¼ 130) having concentrations below median of anti-SEA/E-120 and IL6 benefitted greatly from the addition of Nap. In SG, median OS/PFS for the patients treated with Nap þ IFN was 63.3/13.7 months versus 31.1/5.8 months for the patients receiving IFN alone (P ¼ 0.02; HR, 0.59/P ¼ 0.02; HR, 0.62). Addition of Nap to IFN showed predicted and transient immune related AEs and the treatment had an acceptable safety profile.Conclusions: The study did not meet its primary endpoint. Nap þ IFN has an acceptable safety profile, and results from post hoc subgroup analyses showed that the treatment might improve OS/PFS in a baseline biomarker-defined RCC patient subgroup. The results warrant further studies with Nap in this subgroup. Clin Cancer Res; 22(13); 3172-81. Ó2016 AACR.

Preclinical development of T-cell receptor-engineered T-cell therapy targeting the 5T4 tumor antigen on renal cell carcinoma

“…The favorable expression pattern of 5T4 has encouraged the development and clinical testing of 5T4-targeted antibody–drug conjugates (ADCs) engineered with superantigen [11] or chemotherapy payloads [12] and a recombinant modified vaccinia virus Ankara (MVA) expressing the full-length 5T4 gene (MVA-5T4). MVA-5T4 is the most extensively studied 5T4-target therapy and has been applied to > 580 subjects with colorectal, prostate, and renal cancer [4].…”

Endogenous HLA-DQ8αβ programs superantigens (SEG/SEI) to silence toxicity and unleash a tumoricidal network with long-term melanoma survival

“…Although a fundamental feature of SAgs is the ability to induce robust T cell mitogenesis, individual SAgs often exhibit differential proliferative strength. 21 22 26 In initial studies, we therefore compared the mitogenic activity of SEG, SEI, SEG/SEI with canonical SAgs SEB and SEA using naïve splenocytes from MHCII HLA-DQ8 humanized mice and C57BL/6 mice (MHCII I-A α b I-A β b ). In l both strains, SEG, SEI, SEG/SEI, induced proliferation in CD4+ and CD8+T cells comparable to that of canonical SEB and SEA ( figure 1A, B ).…”

“…20 22 Indeed, tumor remissions in response to canonical SAgs occurred predominantly in patients with minimal to absent levels of such neutralizing antibodies. 21 In addition, the T cell-mediated tumor cytotoxic effects generated by wild type SAgs in humans have been invariably accompanied by TNFα-mediated hemodynamic toxicity. 20 These findings spawned a quest to identify SAgs that exhibit minimal levels of neutralizing antibodies while conserving T cell effector and silencing TNFα activity.…”

Molecular Aspects and Future Perspectives of Cytokine-Based Anti-cancer Immunotherapy

“…Type I interferons are actively combined with various therapeutic agents in clinical trials (NCT03112590). In the number of clinical trials, IFN-α or IFN-β were used to stimulate the immune response in patients who received therapy with DC vaccines (Schwaab et al, 2009;Duggan et al, 2016) or tumor-specific antigens (Elkord et al, 2015;Hawkins et al, 2016;Shima et al, 2019). Vaccination itself did not always lead to the increase in OS or showed some encouraging results (Shima et al, 2019).…”