Serum HMGB1 is a predictive and prognostic biomarker for oncolytic immunotherapy

Abstract

With the emergence of effective immunotherapeutics, which nevertheless harbor the potential for toxicity and are expensive to use, biomarkers are urgently needed for identification of cancer patients who respond to treatment. In this clinical-epidemiological study of 202 cancer patients treated with oncolytic adenoviruses, we address the biomarker value of serum high-mobility group box 1 (HMGB1) protein. Overall survival and imaging responses were studied as primary endpoints and adjusted for confounding factors in two multivariate analyses (Cox and logistic regression). Mechanistic studies included assessment of circulating tumor-specific T-cells by ELISPOT, virus replication by quantitative PCR, and inflammatory cytokines by cytometric bead array. Patients with low HMGB1 baseline levels (below median concentration) showed significantly improved survival (p D 0.008, Log-Rank test) and radiological disease control rate (49.2% vs. 30.0%, p D 0.038, x 2 test) as compared to high-baseline patients. In multivariate analyses, the low HMGB1 baseline status was a strong prognostic (HR 0.638, 95% CI 0.462-0.881) and the best predictive factor for disease control (OR 2.618, 95% CI 1.004-6.827). Indicative of an immune-mediated mechanism, antitumor T-cell activity in blood and response to immunogenic-transgene coding viruses associated with improved outcome only in HMGB1-low patients. Our results suggest that serum HMGB1 baseline is a useful prognostic and predictive biomarker for oncolytic immunotherapy with adenoviruses, setting the stage for prospective clinical studies.

A century of oncolysis evolves into oncolytic immunotherapy

“…Many of the more promising viruses were used to treat cancer patients in an individualized therapy scheme, the Advanced Therapy Access Program: (ATAP), PETCT D Positron emission tomography-computed tomography, between 2007 and 2012. [2][3][4][5] In general, the adverse events were tolerable and less severe than those related to common chemotherapy.…”

“…2,8 Many patients seemed to show signs of antitumor efficacy or surprisingly long survival. 5 The best results seemed to associate with patients treated with GM-CSF or CD40L armed viruses 4 or viruses based on serotype 3 2 . With these viruses ca.…”

“…An explanation for this finding could be that anti-viral antibodies help in induction of danger signaling at the tumor, breaking immunosuppressive tolerance, thus contributing to antitumor immunity. [2][3][4][5] Moreover, viruses may be able to hide from antibodies by using cells as stealth vehicles, or the mere quantity of virions produced by large tumors may simply overwhelm the opsonizing capacity of humoral immunity. Over and above antibodies, there might be also other relevant differences between different adenoviral serotypes.…”

“…Induction of neutralizing antibodies was seen regularly after treatments, but this is of unknown clinical relevance as there were examples of patient benefit in all classes of patients: those who had antibodies at baseline or not, and those whose antibodies were induced or not. [2][3][4][5][6] Based on quantitation of viral genomes in blood, oncolytic replication seems to taper off after several days or weeks in some cases, and repeated doses result in smaller replication peaks. However, there were frequent examples of patients where replication seemed to persist for months, but this did not correlate with efficacy or lack thereof.…”

“…Nevertheless, it can be summarized that all of the 10 used viruses were able to cause oncolysis and immune response while case examples of efficacy were repeatedly seen in patients. [2][3][4][5][6] Viruses were given safely intravenously and intratumorally. Induction of neutralizing antibodies was seen regularly after treatments, but this is of unknown clinical relevance as there were examples of patient benefit in all classes of patients: those who had antibodies at baseline or not, and those whose antibodies were induced or not.…”