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Algorithm for Identifying Genetic Mutations Likely to Respond to Immunotherapy


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A new model works to determine which genetic mutations may respond best to treatment with immunotherapy. Richman et al published the data on the model’s development in Cell Systems, and the algorithm, antigen.garnish, is already available online as an open source technology to serve as a resource.

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“There are mutations in tumors that can lead to powerful immune responses, but for every one mutation that generates a robust response, about 50 mutations don’t work at all, which means the signal-to-noise ratio is not great,” said the study’s lead author Lee P. Richman, an MD/PhD candidate in Cancer Biology at the Perelman School of Medicine at the University of Pennsylvania. “Our model works like a filter that highlights the signal and shows us which targets to focus on.”

Currently, sequencing a tumor and identifying possible immunotherapies is based on the tumor mutational burden—essentially a measure of the rate of mutations present in a given tumor. Tumors with a high rate of mutation are more likely to respond to immunotherapy targeting inhibitors like programmed cell death protein 1 (PD-1). The problem is that as cancer cells divide, they mutate at random, and since they divide exponentially, the potential mutations are almost infinite. This means that while a given immunotherapy can target some percentage of cancer cells, it may not be enough to be an effective treatment for any given patient.

Model Methods

The Penn team’s model looks instead at protein sequences from samples of individual patients and evaluates how much of it looks similar to healthy cells and how much looks different enough that the immune system might react to it. The more it is dissimilar, the better immunotherapy target it makes because it’s more likely to attract and activate therapies with less collateral damage to healthy cells.

“There are mutations in tumors that can lead to powerful immune responses, but for every one mutation that generates a robust response, about 50 mutations don’t work at all, which means the signal-to-noise ratio is not great. Our model works like a filter that highlights the signal and shows us which targets to focus on.”
— Lee P. Richman, MD/PhD candidate

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The model’s prediction is also personalized to each patient’s sample. The team analyzed samples of 318 patients from five different clinical trial data sets and not only confirmed the association between dissimilarity and promise as an immunotherapy target, but also found that dissimilarity correlated to increased overall survival after PD-1 therapy in patients with non–small cell lung cancer.

“With so many different possibilities of mutations, we essentially boiled the question of which targets to use down to a math problem, then developed an algorithm to solve it,” said co–senior study author Andrew J. Rech, MD, PhD, also of Perelman. “We also knew it was important to make this model available for other researchers to help inform vaccine development and clinical trials.”

The researchers said that in addition to its use in trials, future work will also include applying the tool to more data sets to refine the algorithm.

Disclosure: This study was supported by the National Institutes of Health and the Parker Institute for Cancer Immunotherapy. For full disclosures of the study authors, visit cell.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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