Safety and efficacy of p62 DNA vaccine ELENAGEN in a first-in-human trial in patients with advanced solid tumors

Abstract

Elenagen is a plasmid encoding p62/SQSTM1, the first DNA vaccine possessing two mutually complementing mechanisms of action: it elicits immune response against p62 and mitigates systemic chronic inflammation. Previously, Elenagen demonstrated anti-tumor efficacy and safety in rodent tumor models and spontaneous tumors in dogs. This multicenter I/IIa trial evaluated safety and clinical activity of Elenagen in patients with advanced solid tumors. Fifteen patients were treated with escalating doses of Elenagen (1- 5 mg per doses, 5 times weekly) and additional 12 patients received 1 mg dose. Ten patients with breast and ovary cancers that progressed after Elenagen were then treated with conventional chemotherapy. Adverse events (AE) were of Grade 1; no severe AE were observed. Cumulatively twelve patients (44%) with breast, ovary, lung, renal cancer and melanoma achieved stable disease for at least 8 wks, with 4 of them (15%) had tumor control for more than 24 wks, with a maximum of 32 wks. The patients with breast and ovary cancers achieved additional tumor stabilization for 12-28 wks when treated with chemotherapy following Elenagen treatment. Therefore, Elenagen demonstrated good safety profile and antitumor activity in advanced solid tumors. Especially encouraging is its ability to restore tumor sensitivity to chemotherapy.

p62/SQSTM1 – steering the cell through health and disease

“…osteosarcoma, oral squamous cell carcinoma, cutaneous malignant melanoma, esophageal adenocarcinoma, ovarian, colon, breast and non-small cell lung cancers, and solid tumors Daniels et al, 2013;Ellis et al, 2014;Giatromanolaki et al, 2014;Inoue et al, 2012;Iwadate et al, 2014;Liu et al, 2014a;Luo et al, 2013;Ma et al, 2018;Niklaus et al, 2017;Park et al, 2013;Ruan et al, 2018;Schläfli et al, 2016), and has attracted attention as a potential therapeutic target (Yan et al, 2017;Zhang et al, 2016). An antitumor SQSTM1 DNA vaccine has already been developed and trialed in humans (Gabai et al, 2014;Ponomarenko et al, 2017;Sabbieti et al, 2015;Venanzi et al, 2013); however, SQSTM1 can have both beneficial and deleterious effects depending on the pathological context, as is the case for autophagy itself (Dikic and Elazar, 2018). Then, any hope to develop successful therapeutic strategies in pathologies with SQSTM1 alterations needs to keep in mind the complexity of the SQSTM1 signaling network and how it is affected in each particular disease situation: its tight posttranslational regulation, its role in autophagy, its function in the Keap1-Nrf2 axis and its role as a signaling hub.…”

Recent clinical trials of cancer immunogene therapy in companion animals

“…On the other hand, encouraging results were recently reported about a clinical trial of AdCD40L gene therapy combined with cyclophosphamide chemotherapy for human melanoma[31] and p62 protein (SQSTM1) gene therapy for some human solid tumors[32]. These trials were respectively based on previous veterinary trials involving canine melanoma[33] and canine mammary adenocarcinoma[22] patients.…”

p62/SQSTM1 expression in canine mammary tumours: Evolutionary notes

“…Safety and efficacy of p62 DNA injections has been further evaluated in a first‐in‐human trial in patients with advanced solid tumours . Of note p62 DNA treatment of patients partially restored their sensitivity to conventional chemotherapy which they previously failed . However, it remains to be revealed if the anti‐cancer activity of p62‐encoding plasmid in humans is due to a direct adaptive immune response it elicits against the over‐expressed p62 as it was originally hypothesized or if the anti‐cancer effect results from the fact that the plasmid reduces chronic inflammation as observed in animal models for osteoporosis, age‐related macular degeneration and diet‐induced obesity .…”

“…The observed anti‐tumour activity was associated with (CD3 + ) T cell infiltration and tumour encapsulation via fibrotic reaction. Safety and efficacy of p62 DNA injections has been further evaluated in a first‐in‐human trial in patients with advanced solid tumours . Of note p62 DNA treatment of patients partially restored their sensitivity to conventional chemotherapy which they previously failed .…”