Oncolytics ($ONCY) CMO Rita Laeufle, MB, BCh
Oncolytics Biotech ($ONCY) is today announcing acceptance and publication of an abstract for the 2019 American Association of Cancer Research (AACR) that first describes a biomarker for tumor responsivity to the company's lead agent, intravenous pelareorep (an oncolytic reovirus). AACR's annual meeting will be 30 March through 3 April in Atlanta, GA, and will be covered live for BioPub readers by the editors.
Acting via multiple mechanisms, Oncolytics' pelareorep therapy acts to turn immunologically inert, "cold" tumors into lymphocyte-infiltrated "hot" tumors that shrink in response to checkpoint inhibitor administration. Even so, the cold-to-hot transition has been if not entirely subjective, then certainly qualitative, and difficult to quantify. Among the most popular of thrusts these days for clinical studies is pinning outcomes of them to behavior of biomarkers, adjudged to be quantitative and rigorously objective, not susceptible to errors in interpretive judgement or distortion. Drawing on a sustained interval of concentrated data collection from company clinical studies, CEO Matt Coffey, PhD, and associates have arrived at what appears to be an immunologically novel, even shimmering, method of rigorously making a biomarker "call" as to which patients are responding to the company's reovirus treatment.
“With a quick and simple non-invasive blood draw, this biomarker data allows physicians to understand which patients are likely to respond to treatment, ultimately enabling clinical studies that are cheaper, faster and more predictable of a positive outcome,” said Dr. Matt Coffey, Oncolytics President and CEO. “The biomarker data we will present at AACR is immediately applicable to our clinical studies. Within three weeks of treatment, investigators will be able to predict which patients will respond to pelareorep and this will be validated in our ongoing and future clinical studies, including the AWARE-1 breast cancer study that will being enrollment in the coming weeks. It is this data that large pharma is eager to understand and will be a big part of our business development plans.”
The AACR abstract was primarily written by Dr. Grey Wilkinson, a translational scientist at the firm. It is a study of T-cell immunodiversity acquired in pancreas cancer patients following systemic treatment with chemotherapy, pelareorep and checkpoint inhibitor pembrolizumab. We will post the entire abstract at the end of this article for readers to peruse, entitled “Exploratory analysis of T cell repertoire dynamics upon systemic treatment with the oncolytic virus pelareorep in combination with pembrolizumab and chemotherapy in patients with advanced pancreatic adenocarcinoma.” The thrust of the abstract is this: the broader the acquired immune repertoire is found to be in a given patient following treatment, the more likely an oncolytic virus response is portended. The oncolytic virus not only exposes the tumor to double stranded RNA, but also "churns" tumor, beckoning CD8 T-cells to freshly exposed tumor antigens like ants homing in on a picnic. A robust T-cell response means greater T-cell diversity, and indeed Coffey's colleagues have found an inflection point in T-cell receptor heterogeneity that denotes tumor shrinkage can be anticipated.
“Using patient blood samples from a previous clinical study where patients with metastatic adenocarcinoma of the pancreas were treated with pelareorep, chemotherapy and Merck’s Keytruda, T-cell receptor sequencing was performed with our immunoSEQ® Assay to measure the clonality of the T cell population,” said Dr. Paul Fields, Computational Biologist at Adaptive Technologies. “Results from this analysis demonstrate that the higher clonality after a single three-week cycle of treatment can identify patients likely to respond to treatment with pelareorep and a checkpoint inhibitor.” At BioPub, we regard this not only as elegant work, but as particularly au courant. Indeed, among the many mechanisms by which the natural or inherent immune response to tumors is blunted prior to medical intervention, a certain restrictiveness in T-cell diversity appears to be a major part of the problem, as if the T-cells are bored and obdurate. Refer, for example, to this recent study in Clinical Cancer Research (http://clincancerres.aacrjournals.org/content/23/7/1820). T-cell diversity is desirable in tumors, and data now suggests that Oncolytics' pelareorep can provide an ample augmentation to such diversity without provoking patient intolerance, cytokine "storms" or adverse reactions.
Congratulations to Dr. Coffey and his team for advancing this field in a practical method straightforward to execute, and for a method that clarifies mechanism of action of the company's product. Look for coverage here of the company's poster on the day of its presentation in Atlanta (TBA). Coffey and colleagues, including new Chief Medical Officer Dr. Rita Laeufle (pictured above) and Chief Business Development Officer Andrew de Gautamo, will be our guests at the BioPub conference call in April 2019!
The entire abstract:
Title: Exploratory analysis of T cell repertoire dynamics upon systemic treatment with the oncolytic virus pelareorep in combination with pembrolizumab and chemotherapy in patients with advanced pancreatic adenocarcinoma
Background: Pelareorep is an immuno-oncolytic virus that induces an inflamed tumor phenotype in metastatic adenocarcinoma of the pancreas (MAP). Systemically delivered pelareorep in combination with chemotherapy achieves 1 & 2 year-survival rates of 46% & 24% in MAP pts, respectively. Analysis of tumor tissue from patients (pts) treated with pelareorep, chemotherapy and anti-PD-L1 have shown reovirus RNA and protein replication, T-cell infiltration, and upregulation of PD-L1, highlighting that effective T-cell recognition of tumor antigens may be critical to success for this combination therapy. Thus, we hypothesized that pelareorep in combination with chemo and pembrolizumab in pts with MAP would alter the peripheral T-cell repertoire, creating new T-cell clones via the release of novel neoantigens in addition to expanding existing T-cell clones.
Methods: A phase 1b study enrolled 11 MAP pts who progressed after first-line treatment. Pts received pelareorep (4.5e10 TCID 50 IV, D1 & D2), plus pembrolizumab (2mg/kg IV, D8) plus either 1) 5-FU (LV (200 mg/m2 /5-FU 200 mg /m2 IV bolus, 5-FU 1200mg/m2 continuous IV infusion D1) or 2) gemcitabine (1000 mg/m2 IV, D1), or 3) irinotecan (125 mg/m2 IV, D1) q3w, until disease progression/unacceptable toxicity. DNA from peripheral blood mononuclear cells from nine patients at cycle 1 day 1 (C1D1) & C2D1 (approx. 3 weeks later) was analyzed using the immunoSEQ® Assay (Adaptive Biotechnologies, Seattle) sequencing the T-cell receptor beta chain region to interrogate changes in the T-cell repertoire.
Results: The median Morisita index between C2D1 and C1D1 was 0.83 with 3 samples below 0.6, indicative of significant peripheral repertoire turnover. The median number of expanded clones equated to 45.7 per 100,000 cumulative temples; normal variation over 4 weeks is ~ 5-10 expanded clones. Strikingly, most (median: 86%) peripheral clonal expansion occurred in clones below the limit of detection at C1D1. Cox regression analysis revealed that high peripheral clonality correlates with progression free survival at C1D1 (p=0.01, HR=0.053). Moreover, high clonality correlates with overall survival at both C1D1 (p=0.013, HR=0.124) and C2D1 (p=0.010, HR=0.079).
Conclusions: High levels of peripheral T-cell repertoire turnover occur between C1D1 and C2D1. Repertoire turnover is accompanied by significant clonal expansion, mostly by expansion of new clones (i.e. undetected in C1D1). Higher peripheral clonality is associated with better progression free survival at C1D1, and overall survival at C1D1 and C2D1. This research highlights the potential utility of T-cell clonality as a predictive and prognostic biomarker to pelareorep therapy and warrants further clinical investigation.
Disclosures: The author has a long position in $ONCY shares and will not trade in those for 7 days, reckoned in business days, after this column appears. Pembrolizumab is Keytruda (TM), a product of $MRK. The author has a legacy position in $MRK shares. This column is neither advice nor solicitation to trade in either $ONCY or $MRK shares. Copyright 2019 by BioPubKSS.com and the author, all rights reserved. May not be reproduced or disseminated without permission. BioPub has no business relationship with Oncolytics Biotech or its officers.