Adhesion strength or “avidity” is a critical step in CAR T killing of target solid tumor cells
Join our upcoming webinar to learn how cell avidity measurement helps to uncover the mechanism behind CAR T cell therapy resistance and drives intelligent drug design in battling solid tumors.
Identifying “avidity escape” as a resistance mechanism through cell avidity measurement should now be an essential part of CAR T development for solid tumors
CAR T cell therapy has shown limited efficacy against solid tumors. Solid tumors may employ previously unknown resistance mechanisms to evade CAR T cell cytotoxicity. A recent study published in Nature showed that increasing cell adhesion between CAR T cells and tumor cells through tuning the IFNγR pathway overcomes tumor escape and yields an improved in vivo response. Incorporating cell avidity measurements at an early stage of research enables rational CAR T cell therapy design for solid tumor clearance, with the goal of improving clinical trial outcomes.
Cell avidity defines the total intercellular force between multiple parallel interactions, including co-receptor binding, TCR clustering, cell adhesion proteins, and even orientations and valencies. The total strength of binding activities between the CAR T cell and the cancer cell gives tremendous insight into the future function of that cell. Larson et al. Nature (2022) demonstrated how enhancing cell—cell adhesion between CAR T cells and tumor cells through tuning the IFNγR pathway is essential for the development of effective CAR T cell therapies that lead to clearance of resistant solid tumors.
Even though measuring cell—cell adhesion is shown to be a critical factor in CAR T killing of solid tumors, this is currently not taken into consideration during CAR T cell therapy design. Capturing information of the total binding interactions could be crucial in predicting clinical outcome and preventing failure of the CAR T program. Therefore, incorporating cell avidity measurement allows CAR T drug developers to stay ahead of the competition by making informed decisions at an early stage.
Currently available tools do not adequately address the link between the CAR T development process in solid tumors and successful clinical outcomes. Here we present the z-Movi® Cell Avidity Analyzer: a fast and simple solution for validating and optimizing immunotherapeutic strategies in a highly predictive and reproducible manner. By measuring cell avidity, the z-Movi provides you with quick and accurate results to characterize optimal immune cells for immunotherapy.
See how a leading CAR T lab at Harvard has been using the z-Movi to identify solid tumor evasion mechanism and drive intelligent drug design in battling solid tumors.
Latest publication by Massachusetts General Hospital, Harvard Medical School and Broad Institute
A recent Nature paper “CAR T cell killing requires the IFNγR pathway in solid but not liquid tumors” published by the research team of Dr. Marcela Maus identifies “avidity escape” as a solid tumor evasion mechanism from CAR T cell cancer therapies.
Key findings of the paper:
- The IFNγR1 pathway was identified as an important evasion mechanism of solid tumors, but not liquid tumors, from CAR T cell therapy.
- IFNγR1 signaling leads to upregulation of ICAM-1 and subsequent interactions between ICAM-1 and LFA-1, which stabilize the immune synapse and enhance cell avidity, ultimately leading to increased CAR T cell mediated cytotoxicity.
- Cell avidity measurements with the z-Movi demonstrated that loss of IFNγR1 in solid tumor cells reduced overall cell avidity, causing reduced CAR T cell killing and resulting in tumor escape.
- Their work demonstrated that liquid and solid tumors differ in their interactions with CAR T cells and suggests that enhancing binding interactions between T cells may yield improved responses in solid tumors.
Schematic figure of the z-Movi workflow depicting measurements of two different immune-cell populations with different avidities to the monolayer of target cells and the resulting avidity curves.
Watch our Nature webinar!
In this webinar, Dr. Rebecca Larson will present her work on “Loss of IFNγR signaling and downstream adhesion confers resistance to CAR T cell cytotoxicity in solid but not liquid tumors” in Nature. She will also demonstrate how cell avidity measurements can improve CAR T cell response in solid tumors by identifying important evasion mechanism.