Second Recent Breakthrough Publication Where IsoPlexis’ Single-Cell Functional Phenotyping Predicts Persistence in Cutting Edge Cell Therapies in Solid Tumor

Gastroenterology Journal, Feb ‘20: “Persistent Polyfunctional Chimeric Antigen Receptor T Cells That Target Glypican 3 Eliminate Orthotopic Hepatocellular Carcinomas in Mice”

Another high impact study showing T cell persistence in solid tumor was recently published using IsoPlexis’ single-cell functional phenotyping technology. Published in Gastroenterology, the article “Persistent Polyfunctional Chimeric Antigen Receptor T Cells That Target Glypican 3 Eliminate Orthotopic Hepatocellular Carcinomas in Mice” comes on the heels of a recent publication in Nature Communications where IsoPlexis’ single-cell functional phenotyping correlated with T cell persistence in solid tumor.

While CAR-T treatments have done relatively well so far in treating B cell malignancies, the conversion to treating solid tumors with CAR-T cells remains a challenge. Glypican-3 (GPC3) is a protein that’s expressed in over 70% of hepatocellular carcinoma (HCC) and other solid tumors, and because it can promote tumor growth, CAR-T cells and bispecific antibodies targeting GPC3 have been developed. This study sought to improve the anti-tumor activity and further modified the CAR construct, in which IsoPlexis’ functional single-cell metrics correlated with persistence of the CAR-T cells in solid tumor.

Insights into Developing Cutting Edge CAR-T Products Targeting Difficult to Treat Liver Cancer Using IsoPlexis’ Single-Cell Functional Phenotyping:

  • Demonstration of a uniquely positive correlation of enhanced polyfunctionality by single-cell IsoCode proteomics with persistence of T cell response and in vivo killing capacity of GPC3-specific humanized YP7 (hYP7) CAR-T cell products to HCC.
  • Earlier information on T cell polyfunctional capacity provides clear value for choice in development of cell therapies against solid tumor.
  • Correlation of enhanced polyfunctionality by single-cell IsoCode proteomics with an in vitro killing capacity of these CAR-T cell products to HCC.
  • As far as uncovering the biological drivers, single-cell functional phenotyping revealed the superior antitumor mechanisms of GPC3-targeted hYP7 CAR-T cell products in inhibiting Wnt signaling and promoting the perforin/granzyme-mediated apoptosis in tumor cells through enhanced polyfunctional CD8+ T cells subsets identified by single-cell functional proteomics.
  • Importantly, researchers demonstrate the antigen-driven persistence and expansion of polyfunctional hYP7 CAR-T cells in the tumor microenvironment which cause tumor regression in HCC mouse models, providing a novel therapeutic candidate of hYP7 CAR-T products for the treatment of patients with liver cancer.

 

heatmaps
(data from Li et al. Gastroenterology, 2020)

Discovery of Polyfunctionality and Immune Persistence in Solid Tumor Enabled by IsoPlexis’ Single-Cell Proteomics

The researchers in this study used the proteomically barcoded IsoCode technology to functionally characterize the CAR-T constructs. The hPY7 CAR-T cells demonstrated remarkably higher PSI than the HN3 CAR-T cells when stimulated with either Hep3B or G1 cells. Furthermore, CD8+ hYP7 CAR-T cells had a PSI 8 to 11 times higher than the CD4+ hYP7 CAR-T cells co-cultured with Hep3B and G1 cells. This indicated that the CD8+ CAR-T cells were more polyfunctional than the CD4+ CAR-T cells. The researchers also discovered that HCC patient-derived polyfunctional CD8+ hYP7 CAR-T cells contained effector cytokines (granzyme B, IFN-γ, perforin) as well as cytokines not secreted by CD8+ hYP7 CAR-T cells from healthy donors (TNF-α, MIP-1β, and IL-8). 66% of mice treated with the hYP7 CAR-T cells had their tumors eliminated by week 3, while mice treated with the HN3 CAR-T cells did not have a reduction in tumor burden. The hYP7 CAR-T treated mice also continued to be free of tumors after additional Hep3B cells were introduced. IsoPlexis’ single-cell functional phenotyping was able to reveal critical functional drivers that correlated to CAR-T cell persistence in solid tumor.

CAR-T Mice

(data from Li et al. Gastroenterology, 2020)

Read the “Persistent Polyfunctional Chimeric Antigen Receptor T Cells That Target Glypican 3 Eliminate Orthotopic Hepatocellular Carcinomas in Mice” article in Gastroenterology here. IsoPlexis’ proteomic hub has become a standard in many leading global labs and the IsoLight and chip product suite have already helped to accelerate numerous therapy programs. Speak to a single-cell functional proteomics expert today to see what IsoPlexis’ proteomic solutions can do for you.

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