IsoPlexis’ Next Generation Biomarkers Predict Neurotoxicity in CAR-T Therapy

  • Studies have shown that CAR-T therapy can increase the risk of patients developing immune-related adverse events and neurotoxicities such as cytokine release syndrome.
  • IsoPlexis’ single-cell proteomics was the first technology to demonstrate the relationship between single-cell function in CAR-T products, pre-infusion, and clinical outcomes including neurotoxicity.
  • In a study published in Blood, researchers showed that pre-infusion polyfunctional strength index of IL-17A-producing T cell subsets correlated with anti-tumor function against non-Hodgkin lymphoma, while also predicting acute cytokine release syndrome and neurotoxicity.

Impact of CAR-T Therapy on Immune-Related Adverse Events: Neuroinflammation and Neurotoxicity Resulting from CAR-T Therapy

Neuroinflammation is a biological response to nervous tissue injury which plays a key pathological role in a number of neurological disorders and neurodegenerative diseases and can be a complication of some immune therapies. Patients receiving checkpoint and combination therapies for malignancies including metastatic cancer are at high risk for developing immune-related adverse events (IRAEs). Evidence suggests that up to 40% of patients undergoing CAR-T therapy develop severe neurotoxicities in the form of cytokine-release-associated encephalopathy. The neuroinflammatory response is complex, involving many inflammatory mediators such as cytokines, chemokines, and many different cell types.

IsoPlexis’ platform uniquely connects neurotoxicity and inflammation to the function of single cells and their secretomic profiles, revealing an association between polyfunctional cell subsets and prognosis. The unique single-cell polyfunctionality metric is a powerful tool for developing CAR-T products with lower risk of causing adverse effects and predicting outcomes in CAR-T patients.

Because neurotoxicity involves complex interactions of many cells within the CNS, it is crucial to understand how these cells interact with each other to drive disease progression or therapeutic response. Cells use cytokines and chemokines (functional proteins) to communicate with each other and orchestrate the immune response. Thus, characterizing inflammatory response and the functional proteins involved is particularly important to developing better methods of preventing neurotoxicity.

IsoPlexis’ Platform Identifies Rare Polyfunctional Cell Subsets Key to Understanding Biomarkers of Neuroinflammation

Neurotoxicity

In 2018, IsoPlexis characterized neurotoxicity in a CAR-T product in a study published in Blood. Researchers Rossi, et al. investigated how the presence of subsets of polyfunctional T cells that produced cytokines including IL-17A was associated with clinical outcome in non-Hodgkin lymphoma (NHL) patients. IsoPlexis’ single-cell functional immune landscaping technology was used to identify polyfunctional cells, and analysis was performed using IsoPlexis’ Polyfunctional Strength Index (PSI), a unique polyfunctionality metric.

PSI of the pre-infusion CAR product was significantly associated with clinical response. A subset of highly polyfunctional CD4+ T cells was more highly associated with clinical outcome than polyfunctionality of CD8+ T cells. The researchers found that those polyfunctional T cells were also associated with grade ≥3 cytokine release syndrome, and that grade ≥3 neurologic toxicity and anti-tumor efficacy were positively associated with presence of IL-17A-producing polyfunctional T cells. Additionally, pre-CAR-T cell infusion levels of IL-15, combined with PSI, positively correlated with neurologic toxicity. IL-17A PSI combined with IL-15 levels at day 0 had a statistically significant association with grade ≥3 neurologic toxicity. These results suggest that IL-17A and IL-15 producing polyfunctional T cells are associated with anti-tumor efficacy of a CAR-T product against NHL, but also increase risk of neurologic toxicities. This study also highlights CAR-T cell polyfunctionality as a useful metric to predict clinical outcome. Monitoring CAR-T polyfunctionality may be critical to improving CAR-T efficacy and preventing adverse immune responses.

Polyfunctionality Uniquely Correlates to Neurotoxicity in CAR-T Therapy

Genetically and phenotypically identical cell subsets can differ in secretion profiles. Thus, single-cell functional proteomics is key to understanding the heterogeneity of inflammatory responses. T cells are highly heterogenous in terms of their effector functions and the type and number of cytokines that they secrete. Polyfunctional T cells, which secrete multiple cytokines/chemokines, are key contributors to the development of potent and durable cellular immunity.

IsoPlexis’ functional single-cell proteomics bridges this gap to predict in vivo biology by allowing researchers to quantify multiple secreted cytokines across up to 1500 single cells simultaneously, per chip. This unique platform has been used in multiple studies to characterize the relationship between CAR-T product polyfunctionality and neurotoxicity, revealing a significant association with critical implications on the future of CAR-T therapy.

IsoPlexis’ Highly Multiplexed Single-Cell Proteomics Detects Previously Unknown Functional Drivers of Inflammation

The above study shows that polyfunctionality of pre-infusion CAR-T cell products is a significant predictor of Immune Related Adverse Effects, including neurotoxicity and CRS. IsoPlexis’ unique single-cell biology reveals insights that improve the understanding of cytokine mediated adverse effects in a translational fashion. With a highly multiplexed, multifaceted single-cell analysis platform, IsoPlexis uniquely addresses current challenges in neuroinflammatory responses, accelerating the development of personalized and targeted therapies.

To learn more about how IsoPlexis’ polyfunctionality metric allows scientists to predict neurotoxicity in CAR-T, download our neurotoxicity eBook.

1. Rossi J, et al. Preinfusion polyfunctional anti-CD19 chimeric antigen receptor T cells are associated with clinical outcomes in NHL. Blood 2018; 132 (8): 804–814.

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