Phase 1b Trial of Biweekly Intravenous Pexa-Vec (JX-594), an Oncolytic and Immunotherapeutic Vaccinia Virus in Colorectal Cancer

Abstract

Fifteen patients with treatment-refractory colorectal cancer were enrolled on a phase 1b study of Pexa-Vec (pexastimogene devacirepvec; JX-594), an oncolytic and immunotherapeutic vaccinia designed to selectively replicate in cancer cells. Pexa-Vec was administered intravenously every 14 days, at dose levels of 1 × 10(6), 1 × 10(7), or 3 × 10(7) plaque-forming units (pfu)/kg. The primary endpoint was to determine the maximum tolerated dose. Secondary endpoints were pharmacokinetics and pharmacodynamics as well as antitumor activity. Patients were heavily pretreated (mean 4.5 lines of therapy). All patients received at least two Pexa-Vec doses (median = 4; range = 2-4). No dose-limiting toxicities were reported, and the maximum tolerated dose was not reached. The most common adverse events were grade 1/2 flu-like symptoms, generally lasting <24 hours. During the first and last cycles, genome pharmacokinetics were unchanged. Infectious pfu could be detected in plasma up to 2 hours after cycle 1 and up to 30 minutes after cycle 4 (when antivaccinia antibody titers are known to have peaked). Ten patients (67%) had radiographically stable disease. Given the acceptable safety profile of multiple intravenous Pexa-Vec infusions in patients with treatment-refractory colorectal cancer, further trials evaluating efficacy of intravenous Pexa-Vec, as monotherapy or in combination with chemotherapeutic agents, is warranted in this patient population.

Heterologous Vaccination and Checkpoint Blockade Synergize To Induce Antileukemia Immunity

“…This chronic antigen stimulation may lead to continual high expression of PDL1 and CTLA4 on leukemic cells, which may explain the synergy between therapeutic vaccination (which is susceptible to inhibition by PDL1/PD1 and CTLA4 pathways) and dual checkpoint blockade (which inhibits those pathways). Finally, it is important to note that oncolytic viruses (which include VSV, used in our scheme) have been used for anti-cancer immunotherapy in the past (50) and are currently being used in clinical trials as a treatment option cancer (51, 52). Thus, the approach taken to treat leukemia in our murine model is feasible to consider for human patients with BCR-ABL+ leukemia.…”

Trial Watch—Oncolytic viruses and cancer therapy

“…in combination with low-dose cyclophosphamide (NCT01598129). 182 Intravenous or intratumoral JX-594 (a GM-CSF-expressing oncolytic poxvirus engineered to replicate in cells with specific oncogenic defects, also known as pexastimogene devacirepvec, Pexavec) 183 has been tested as single therapeutic agent in 15 subjects with colorectal carcinoma (CRC) (NCT01469611) 184 as well as in 14 pediatric patients with chemorefractory solid malignancies (NCT01169584). 185 The safety and efficacy of GL-ONC1 (a genetically modified vaccinia virus also known as GLV1h68) 186 have been evaluated in 14 individuals with malignant pleural effusion, who received intrapleural GL-ONC1 as standalone immunotherapeutic intervention (NCT01766739), 187 as well as in 19 subjects affected by HNC, who were treated with GL-ONC1 i.v.…”

“…161,162,171,[174][175][176]182,185,190,267 Although official sources indicate that the status of NCT01469611 (a Phase I testing the biweekly intravenous administration of JX-594 as standalone immunotherapeutic intervention in CRC patients) is "Unknown," preliminary findings have already been published (see above). 184 Results from NCT01048892 (a Phase I trial evaluating NTX-010 in combination with metronomic cyclophosphamide in children with neuroendocrine tumors), and NCT01227551 (a Phase II study testing Cavatak TM as standalone immunotherapeutic intervention in subjects with advanced melanoma), both of which were "Completed" when we submitted our latest Trial Watch dealing with this topic, 247 are also available (see above), 175,194 and so are findings from NCT01740297 (a Phase I/II trial assessing the therapeutic profile of Imlygic Ò plus ipilimumab in melanoma patients), and NCT01766739 (a Phase I study testing intrapleural GL-ONC1 as single immunotherapeutic agent in individuals with malignant pleural effusion) (see above), 165,187 even though their status ("Recruiting") has not been updated during the last 21 mo. NCT00651157 was a Phase II clinical trial testing Reolysin Ò as a standalone immunotherapeutic agent in subjects with metastatic melanoma.…”

Viruses as nanomedicine for cancer

“…Liver toxicities such as elevated serum enzymes related to liver function and hyperbilirubinemia were observed. 85 To avoid such toxicities, a constant dose must be defined. Moreover, adverse events of VV were reported during the smallpox vaccination program, ranging from mild flu-like symptoms to encephalitis.…”