Connecting Genetic Drivers to Functional Proteomics: IsoPlexis Presents Data at SITC 2021

Recently, we presented data at the 35th Annual Meeting of the Society for Immunotherapy of Cancer (SITC). Below is a brief recap of our presentation.

Single-cell analysis has made great strides in characterizing cellular phenotypes. However, the majority of status quo applications, such as bulk ELISA and flow cytometry, continue to miss critical cell attributes and functions. Single-cell proteomics is the key to solving these complex challenges.

IsoPlexis’s technology platform, the emerging standard in single cell functional phenotyping, provides unique functional proteomic data that traditional technologies often miss. Through our predictive single-cell analytics, rare subsets of highly polyfunctional “super cells” are revealed, correlating to response, immune potency, and persistence in a variety of studies. These robust single-cell subsets of highly functional “superhero” cells are critical to driving long term response in cell and immune therapies via functional proteins.

Our presentation at SITC outlined how to leverage these powerful, proteomically active single cells and their genetic drivers, identified simultaneously via single-cell transcriptomics and proteomics analyses on our new Duomic™ platform.

Also discussed in our presentation was how to fully leverage these superhero cells for clinical CAR-T studies and preclinical development, clinical combination checkpoint inhibitor studies, and immune therapy discovery.

Bridging Cell Type Identification Studies to Single Cell Functional Phenotyping

IsoPlexis has become the standard in identifying the single cells that produce proteomic reactions that form many of the earliest signals of long-term response against diseases like cancer, infectious disease, and inflammatory diseases, termed “superhero cells”. These rare subsets of cells have correlated with biological response in vivo in multiple datasets. We’re now leveraging the ability to perform both sequencing and functional proteomics, diving into the genetic and functional drivers of these individual supercells, for the first time.

IsoPlexis’ new Duomic platform is an application for the next frontier of functional single-cell analysis and involves integrating direct in vivo proteomic activity from cells with the gene regulatory networks driving those reactions.

The IsoPlexis Duomic platform was used to simultaneously measure the proteomic and gene expression (mRNA) levels of individual CD8+ CAR-T cells in response to specific antigen stimulation. Two distinct populations of cells were identified, one with low polyfunctionality and one with high polyfunctionality (simultaneous expression of multiple proteins). These two subpopulations each had a unique gene expression profile, indicating the possible genes that are regulating the polyfunctional protein expression of the cells.

Integrative data analysis was performed using the Duomic dataset to find the genetic drivers of these biologically powerful cells for the first time. This type of combined Duomic data allows for unprecedented insight into the link between polyfunctionality and genetic make-up of individual cells.

Using this technology, both transcriptomic and functional proteomics data can be linked directly from the same single cell, across many cells in parallel, enabling a direct connection for the first time to the gene regulatory networks that drive critical functional proteomic reactions in cell types. This type of data will ultimately help researchers continue to accelerate the creation of advanced medicines.

Early Indicators Making a Difference in CAR T and TILs

In a cutting-edge CD19 and CD22 Bi-specific CAR T study published in Nature Medicine, IsoPlexis’ single-cell functional proteomics demonstrated predictive early signs of response vs. relapse in various patients with B-cell malignancy. “Results suggest that engineering iterations should be guided by careful studies of single-cell CAR polyfunctionality incorporating cytokine production as a critical quality attribute,” the study’s authors wrote.1

Additionally, a tumor-infiltrating lymphocyte (TIL) therapy study also published in Nature Medicine demonstrated that IsoPlexis’ unique functional metric (PSI) provided correlative insights into treatment response and product potency of TILs expanded ex vivo. In this lung cancer Nivo combination TILs study, polyfunctionality of CD8 cells showed comprehensive impact of injection of TILs on immune response of patients.  The authors wrote, “As PSI reflects the ability of a T cell to carry out multiple functions, it is recognized as a metric for the potency of cell therapy and for the efficacy of vaccines.”2

Cancer Immunology Case: Predictive Durability Biomarkers

In a recent Phase 2 clinical trial also published in The Journal of Clinical Oncology, 38 metastatic melanoma patients underwent checkpoint inhibitor and IL-2 agonist therapy. The IsoPlexis platform identified a blood-based biomarker that correlated with patient response and progression-free survival for these metastatic melanoma patients. Our technology showed unique correlations with the single-cell cytokine biomarker and survival in multiple solid tumor studies with trials and therapies from BMS, MD Anderson, Genentech and others.3

References

  1. Jay Y. Spiegel et al. CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial. Nature Medicine, 2021
  2. Creelan, B. et al. Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer: a phase 1 trial. Nature Medicine. 2021.
  3. Diab et al. Bempegaldesleukin Plus Nivolumab in First-Line Metastatic Melanoma. Journal of Clinical Oncology. 2021
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