NEW YORK – Precision oncology startup OncXerna Therapeutics, formerly known as Oncologie, is aiming to clinically validate the use of its RNA sequencing tumor microenvironment, or TME, Xerna platform in several solid cancers in the hopes of developing a pan-cancer assay to guide precision therapy in solid tumors.
Working with computational precision medicine firm Genialis to improve its 100-gene Xerna TME Panel, the Boston-based firm recently shared new data indicating the panel can help guide colorectal cancer, or CRC, treatment with its two in-licensed investigational therapies.
OncXerna CEO and founder Laura Benjamin explained that she initially developed the fundamental concept behind the Xerna platform while serving as VP of oncology at Eli Lilly. After publishing an early preclinical concept study in Cancer Research in 2016 that highlighted the use of RNA to view a tumor's microenvironment, Benjamin left Eli Lilly to flesh out the gene expression platform.
In 2018, Benjamin launched the startup under the name Oncologie, which signed an asset and purchase agreement with Avid Bioservices for bavituximab, its investigational immune-modulatory monoclonal antibody. The drug targets phosphatidylserine, a phospholipid that inhibits the ability of immune cells to recognize and fight tumors.
Later that year, OncXerna partnered with HTG Molecular Diagnostics to develop biomarkers for its immune-oncology drug candidates.
In January 2020, Oncologie signed a global licensing agreement with Mereo Biopharma for its investigational drug navicixizumab, which Benjamin noted is an antibody designed to inhibit delta-like ligand 4 in the Notch cancer stem cell pathway as well as vascular endothelial growth factor.
She added that the drug has been shown to have antitumor activity in ovarian cancer patients who have progressed on bevacizumab (Genentech's Avastin). OncXerna is now targeting the drug toward patients whose dominant tumor biology is driven by angiogenesis.
The company then partnered with the Moffitt Cancer Center in February 2020 to develop oncology treatments targeting the tumor microenvironment in gastric cancers.
Last fall the firm rebranded to OncXerna because of trademarking challenges with the old name and to reflect emerging clinical data on the RNA-based panel.
The workflow for the Xerna platform involves collecting four to six slides of formalin-fixed paraffin-embedded, or FFPE, tissue initially extracted from a patient's tumor biopsy, then performing RNA-seq on the extracted sample using Illumina's NextSeq instrument.
By applying a proprietary algorithm to the approximately 100 genes measured by the panel, OncXerna then classifies the tissue into one of four phenotype classes: angiogenic, immune suppressed, immune active, or immune desert. The biosignature reflects angiogenic and immunogenic properties of the patient's stromal biology and, according to OncXerna, can help identify which patients will receive maximum benefit from treatment with bavituximab, navicixizumab, and other classes of drugs like checkpoint inhibitors, including pembrolizumab (Merck's Keytruda).
Benjamin said her team built out the TME Panel by selecting genes that were "performing well for all tumors." OncXerna initially chose gastric cancer because it served as a lead indication for bavituximab and due to the cancer's high prevalence in Asian populations. Her team also selected ovarian and CRCs as "very different" tumor types that she believed would work for the firm's therapeutic portfolio.
To optimize the proprietary biosignature for ovarian and colon cancer, OncXerna began working with Genialis in 2019. Benjamin said that Genialis provides artificial intelligence expertise that can improve its biomarker algorithm.
"We've shown that the gene signature works well with OncXerna's in-house ovarian cancer program, and CRC was kind of the obvious next indication to look at," explained Rafael Rosengarten, cofounder and CEO of Genialis. "It's a heterogeneous cancer, and for metastatic colorectal cancer, immune checkpoint inhibitors don't work so well, like Avastin, in all populations. So it requires a stratified approach, where you need to pinpoint which patients would benefit."
The two firms shared the initial results of a study on CRC treatment at the American Association for Cancer Research virtual annual meeting earlier this month.
In the study, Benjamin's team explored if it could use the TME Panel in tandem with the Consensus Molecular Subtypes model, which represents gene expression data from both CRC and their microenvironments, to classify CRC patients in groups that are prognostic for overall survival and progression free survival.
The researchers retrospectively explored the assay's prognostic potential for CRC using two datasets: a public dataset of 566 tumor samples from patients with stages I-IV CRC collected for the Cartes d'Identite des Tumeurs from the French Ligue Nationale Contre le Cancer; as well as 92 samples of metastatic CRC patients who were treated with various regimens including targeted therapies following surgery at the Wood Hudson Cancer Research Laboratory. RNA expression data for the Cartes d'Identite des Tumeurs dataset were previously generated using array-based methods and were among the data used for the Consensus Molecular Subgroups model. For the Woods Hudson samples, gene expression was measured by RNA-seq and each sample was evaluated histologically.
The TME Panel captured the interaction between angiogenic and immunogenomic properties using machine learning to classify patients into one of the four TME phenotypes. Most patients were classified as immune suppressed or immune desert, which the study authors noted were consistent with the idea that CRC has a "cold" tumor microenvironment.
The prevalence of the TME Panel classes spotted in CRC mirrored that of cancers the researchers had previously examined (gastric and ovarian), and the panel was also prognostic for recurrence-free and overall survival in CRC.
The team also found that the TME Panel's phenotypes also reflected the expected biology based on known molecular characterization of CRC by disease stage, distal/proximal sideness, and the Consensus Molecular Subtypes.
However, the researchers believe that the assay's focus on the tumor microenvironment may help it serve as a predictor of response to TME-targeted agents such as immunotherapy and anti-angiogenics.
"We thought it was worth understanding what overlap and non-overlap there was with this colon-specific approach," Benjamin explained. "By focusing on the tumor microenvironment, [we wanted to see] if you get a better result using TME subtyping only … because you don't lose some of those patients that would benefit from those therapies."
Following the proof-of-concept work, Benjamin's team plans to prospectively investigate whether the TME Panel can predict the outcome of targeted therapy in CRC, including trials for bavituximab and navicixizumab and wider exploration of additional clinical sets.
"It's an interesting question to see whether or not you could further the ability to identify patients for checkpoint inhibitors by not just understanding if they're mismatch repair deficient colorectal cancer patients, but to see if they're immune active or immune suppressed," Benjamin said.
Benjamin pointed out that most research in precision medicine has focused on applying DNA to support drugs that target mutated genes in a patient's tumor. However, she believes DNA is "to some degree, irrelevant" because the analyte may not entirely reflect the status of the patient's immune system.
"The more mutations there are, the better the odds that your immune system has latched onto and produced an immune response to the tumor, but it doesn't tell you that the immune system has been activated," Benjamin said. "Meanwhile, RNA indicates what's happening right now, and you can see if the immune system is activated, [rather than] it has a higher probability that it's likely activated."
Because OncXerna's technology analyzes the tumor microenvironment, Benjamin noted the platform can measure real-time response to treatments like bavituximab and navicixizumab.
Alan Venook, a professor of medicine at the University of California, San Francisco, who is unaffiliated with the company or study, agreed that RNA-seq is a better, "more realistic test of what's going on" in the patient's immune system than DNA sequencing. However, he pointed out the dilemma with current testing is performing the method properly and having enough tissue to do so.
"Looking at a cancer patient's transcriptome is much more reflective than the specific mutations themselves because it's all a matter of how the body responds," Venook said. "The idea that a signature is predictive in gastric and prognostic in another cancer may be great for [these] diseases, but the question is how you're translating the targets into action" for therapies.
Benjamin explained that OncXerna was eager to in-license navicixizumab because it had been searching for an anti-angiogenic drug for late-stage ovarian cancer. The group had found the drug in the later stage of a Phase IB study in ovarian cancer and could access tissues from most of the patients.
Benjamin's team then sent out ovarian patient tissue for RNA sequencing, used the panel's algorithm on the results, and then identified patients who would respond well with the drug. She highlighted that the firm successfully shifted from a 43 to 62 percent response rate of patients on the therapy with the 100-gene therapy.
"We jumped past discovery work, confirmed the biomarker worked, and now we have a Phase III study," Benjamin said. "In terms of value creation, it's timesaving and an efficient approach to take."
While Venook believes that increasing the number of genes for a biosignature like the one used in the TME Panel may produce improved results, he argued that using the Consensus Molecular Subtypes model and methods like the Xerna platform need to be extensively validated.
He noted that firms like Irving, Texas-based Caris Life Sciences offer multiomic cancer molecular profiling services to help physicians and patients identify more precise and personalized treatments. The firm's MI Transcriptome CDx assay, which it submitted for US Food and Drug Administration 510(k) approval last spring, uses RNA-seq to detect genomic and transcriptomic alterations in FFPE tumor tissue specimens.
"Reading these posters, you'd think we're close to placing them into play, but we're not even close, not to mention that we don't have a commercial outlet for [consensus molecular subtypes]. Do we really believe the genes they represent are the main ones?" Venook asked. "Having said that, it's important to look at these immune profiles, [as] they are relevant, but in terms of translating them into action, we have a long amount of time unfortunately."
The TME Panel is currently available from OncXerna for research use only, but the firm is currently in discussions with an undisclosed partner to eventually offer the assay out of the partner's CLIA-certified, CAP-accredited lab later this year, Benjamin said.
OncXerna has raised about $100 million through Series A and B financing since it was launched in 2018. Investors include Pivotal BioVenture Partners China, Nan Fung Life Sciences, Panacea Venture Healthcare, and Korea Investment Partners.
OncXerna also has a team in Shanghai to facilitate its Asian collaborations, including a partnership with the Samsung Medical Center in Seoul, South Korea. The company is waiting for updated international regulatory guidance on companion diagnostics before deciding its plans for the Asian and European markets.
The startup has filed IP with the US Patent and Trademark office that includes the Xerna platform approach and its associated portfolio.
OncXerna aims to license tumor microenvironment products and expand to other "biologies of interest" in the future. Because the firm hopes to adapt the panel so that it can be used as a pan-cancer assay, Benjamin said her team is testing the method on additional cancers, including melanoma, breast, and non-small cell lung cancer.
"At the end of the day, we're a therapeutics company, and we've built the assay to support a therapeutic pipeline," Benjamin added. "We believe our lead asset will be utilized in a registration setting later this year."