NEW YORK – BostonGene is in the process of validating an updated version of its Tumor Portrait analytics platform that integrates information about four recently described pan-cancer tumor microenvironment subtypes along with targetable molecular profiles. The addition of these four subtypes, the company is hoping, will improve the tool's ability to predict cancer patients' responses to immunotherapy.
In Cancer Cell last month, researchers from BostonGene and MD Anderson Cancer Center described unique stromal, vascular, and cytokine expression patterns that segmented a variety of cancers into four tumor microenvironment subtypes associated with differential prognosis and immunotherapy treatment benefit. To achieve this, they analyzed RNA sequencing results from more than 8,500 tumor samples across more than 20 tumor types.
They dubbed the four subtypes they identified as immune-enriched, fibrotic (IE/F); immune-enriched, non-fibrotic (IE); fibrotic (F); and immune-depleted (D). The latter two, fibrotic and immune-depleted, were generally associated with decreased overall survival and progression-free survival in patients, compared to the two immune-enriched, IE/F and IE, subtypes.
The researchers first identified the subtypes in tumors from melanoma patients, then expanded their analysis to more cancer types. They pulled tumor samples from several databases, including The Cancer Genome Atlas, International Cancer Genome Consortium, or Genotype-Tissue Expression databases. They normalized gene signature values across the samples to remove tissue-type-specific effects.
Each subtype was characterized by certain cell behaviors and gene expression. In the melanoma samples, the immune-enriched, fibrotic (IE/F) tumors had elevated functional gene expression signatures associated with angiogenesis and with cancer-associated fibroblast activation. The immune enriched, non-fibrotic (IE) melanomas had high levels of immune infiltrate and significantly higher cytolytic scores, reflecting a more immune-active microenvironment. The IE subtype also had the highest mutational load and highest ratio of CD8-positive T cells and M1/M2 macrophages.
The immunosuppressive subtypes, F and D, had little or no leukocyte or lymphocyte infiltration. Subtype D had the highest malignant cell percentage and increased frequency of genome duplications or deletions. Subtype F showed increased functional gene expression signatures associated with angiogenesis and cancer-associated fibroblasts.
Across 24 different types of cancers, researchers found the same four tumor microenvironment subtypes and correlations with survival or treatment response to a checkpoint inhibitor.
"This was a landmark finding that we could look at not only the cancer genetics, but the characteristics of the host immunity of these surrounding tumor microenvironment cells," said Nathan Fowler, an author of the study and chief medical officer at BostonGene. "It wasn't the cancer's genetic composition; it was the behavior or the functional status of the non-immune cells [in the tumor microenvironment] that was predicting the patient's likelihood of response to the immunotherapy."
In a melanoma cohort, the researchers also looked at each subtype's response to treatment with the CTLA-4-inhibitor ipilimumab (Bristol Myers Squibb's Yervoy). They found patients with the immune-enriched subtype IE were more likely to respond to treatment, with 82 percent experiencing tumor shrinkage compared to 10 percent with the immunosuppressive subtype F cancers.
In bladder cancer, 38 percent of patients with IE subtype tumors responded to anti-PD-1 treatment compared to less than 10 percent of patients with the immunosuppressive subtype F. Researchers reported similar trends among lung cancer patients with IE subtype tumors, who had longer overall survival on anti-PD-1 treatment, while among gastric cancer patients, only those with IE subtype tumors responded to these types of immunotherapies.
"Overall, these comparative analyses definitively demonstrate the ability of this tumor microenvironment classification platform to correlate with survival and reveal its potential as a universal biomarker across multiple cancers and immunotherapies," the authors wrote.
BostonGene is now validating the integration of this new data on tumor microenvironment subtypes into its Tumor Portrait data analytics platform hoping to improve its ability to predict which patients are likely to respond to immunotherapy. The interactive Tumor Portrait portal currently allows physicians to visualize a molecular model of patients' tumors by including information about a tumor and its microenvironment's mutational load, immune composition, and immunosuppressive escape mechanisms.
The tool also flags biomarkers that may be targetable by a US Food and Drug Administration-approved drug or have associated therapeutic recommendations in National Comprehensive Cancer Network guidelines or in the published literature. The tool ranks each identified biomarker by the level of evidence validating its therapeutic potential.
The platform also provides a list of relevant and geographically close clinical trials that the clinician could consider for their patients based on identified biomarkers.
"This [tumor microenvironment subtype] analysis … will allow each physician to interrogate individual tumor types and understand prognosis, the composition and the biology of the tumor, and the potential response to targeted drugs, like CTLA-4 or PD-1 inhibitors," Fowler said.
BostonGene is planning large prospective studies in partnership with undisclosed cancer centers in the US to validate the tool with incorporated tumor microenvironment subtype information. The company said both single- and double-arm studies in patients with advanced cancer are underway, but declined to provide more details about the studies.
In the meantime, the Tumor Portrait platform is available, without the tumor microenvironment subtypes, and BostonGene is sequencing patients in its CLIA lab. The company can test patients on a range of assays, data from which flow into the Tumor Portrait visualization platform, including multiplex imaging, flow cytometry, immunohistochemistry, proteomics, RNA sequencing, single-cell DNA sequencing, as well as whole-exome and whole-genome sequencing.
Fowler said BostonGene has set itself apart from many competitors by offering a wide range of assays. The company hopes that by bringing together the different sequencing techniques into one tumor-agnostic platform, it can help clinicians make actionable treatment decisions and accelerate the use of precision medicine.
"We started essentially as a software company looking at big data, analytics, and integrating multiple different platforms, and about two years ago, we built a sequencing facility to analyze this big data," Fowler said, adding that most other competitors went about it the other way, starting out as sequencing companies and then building out bioinformatics capabilities.
"We took the completely opposite approach," he continued. "That allows us a lot of flexibility around the type of information that we're bringing into the platform. Every time we think there is an assay that looks like it has a future, we bring it in-house."