In the final installment of this series, we’ll discuss how IsoPlexis’ Single-Cell Secretome solution is empowering cell therapy researchers with predictive clinical biomarkers to stratify patient response to cell therapies.
Using Single-Cell Functional Proteomics to Identify Predictive Biomarkers
Cell therapy products are heterogeneous, making it challenging to identify attributes that correlate with clinical response and outcomes. By investigating the function of individual cell products, researchers can better understand how cell therapies work in vivo to predict who may receive the most value from these treatments and who may be more at risk of adverse events, such as immunotoxicity. This critical level of insight for homing in on cell function requires highly multiplexed cytokine analysis at single-cell resolution.
With IsoPlexis’ Single-Cell Secretome solution, researchers are empowered to unlock key data insights into cell therapy function with the ability to analyze up to 32 cytokines. Through assessment of cell function in translational settings and in the clinic, researchers can develop biomarkers for predicting response. Specifically, analyzing cell polyfunctionality, the ability of a cell to secrete 2 or more cytokines simultaneously, is a powerful approach that can be used to predict the likelihood of response to treatment, relapse or immunotoxicities following administration of cell therapies. The presence of polyfunctional cells has correlated with clinical outcomes in numerous studies.
In conjunction with polyfunctionality, IsoPlexis’ proprietary Polyfunctional Strength Index (PSI) has also been employed in cell therapy development to predict responders vs. non-responders. PSI captures the percentage of polyfunctional cells in a sample and the intensity of all profiled secreted cytokines. The following case studies highlight how polyfunctionality and PSI are associated with clinical outcomes.
Predicting Both Favorable Outcomes and Adverse Events in a CAR-T Clinical Trial
In a study published in Blood, researchers investigated the correlation between functional characteristics of anti-CD19 CAR-T products and clinical outcomes in non-Hodgkin’s lymphoma (NHL). With IsoPlexis’ functional proteomic platform, researchers were able to investigate CAR-T function at the single-cell level to identify product attributes correlating with response.
The researchers revealed that cell products were heterogenous in function, and that around 20-25% of all cell products were polyfunctional upon stimulation with CD19-expressing target cells. Polyfunctional strength index (PSI) was significantly associated with objective response (OR) (P = 0.0119), and the median PSI was twice as high for responders compared to non-responders. Of note, although CAR-T products were analyzed using a variety of techniques, PSI was the only significant predictor of response. PSI also correlated to ≥ Grade 3 cytokine release syndrome (CRS), highlighting the metric’s ability to predict adverse events in response to cell therapy infusion. Together, these findings demonstrate how PSI can be used as a pre-infusion biomarker for predicting clinical outcomes of cell therapies.
Identifying Biomarkers of Response and Uncover Mechanisms of Relapse to CAR-T Therapy
In a recent publication in Science Advances, researchers sought to identify predictive biomarkers of CAR-T response in therapy for resistant and/or refractory acute lymphoblastic leukemia (r/r ALL). Though clinical outcomes for r/r ALL have been greatly improved with CAR-T therapy, relapse is common. To investigate whether there are characteristics of CAR-T products that are associated with increased risk of relapse, the investigators used a variety of analytical techniques to characterize cell products, including IsoPlexis’ single-cell polyfunctional analysis.
Using IsoPlexis’ Single-cell Secretome, researchers calculated functional strength index (FSI), which combines the frequency of cells secreting a certain cytokine with the average intensity of that cytokine. Researchers revealed that TH2 FSI is a statistically significant biomarker that can be used to discriminate between complete response and CD19-positive relapse in r/r ALL cell therapy. Additionally, the study revealed that IL-5 FSI is a highly predictive biomarker for long-term response.
These findings, made possible using IsoPlexis’ single-cell functional phenotyping, identified early biomarkers of long-term response and mechanistic insights into relapse.
Using Single-Cell Functional Analysis to Gain Insights into Clinical Activity
IsoPlexis’ single-cell analysis has been shown to help reveal key cell therapy product attributes that are associated with clinical outcomes. By gaining a better understanding of how cell therapy products function at the single-cell level, researchers can identify biomarkers that can help to predict response to cell therapy products and provide actionable insight into characteristics that can lead to adverse events or relapse, allowing researchers to develop better products and improve clinical outcomes.
As we conclude this series on how single-cell secretomics can provide critical biomarkers across the cell therapy research pipeline, be sure to check out the Functional Cell Library to see how researchers are gaining critical insights to develop next-generation therapies, or visit previous posts in the series about how single-cell functional analysis can help drive preclinical research and refine cell therapy product manufacturing.