Avidity enhancement” as a promising strategy for clinical success of CAR-T therapies

Learn how cell avidity measurement is essential for identifying the CAR T killing resistance mechanism of solid tumors.

In vitro cell avidity outshines “gold standard” assays in accurately predicting in vivo CAR-T potency

Acute myeloid leukemia (AML) has been challenging to treat, despite the development of otherwise successful CAR-T therapies. The lack of an efficient antigen target in AML cells results in heavy off-tumor effects leading to high toxicities and death in patients. A recent publication in Cancer Cell present “avidity enhancement” on both sides of the cell binding interaction as an efficient strategy to improve CAR-T potency in AML mice models. The authors also prove that cell avidity measurements are superior to other in vitro assays in their correlation with in vivo CAR-T success.

The high unmet clinical need for effective CAR-T therapy against AML sparked numerous publications that present different CAR-T designs with the focus to improve its function in vivo. But the most important challenge remains: How to predict – reliably and early in the design process – whether the engineered CAR-T cells will be effective in killing the tumor in the body or not?

Currently established standard methods like in vitro cytotoxicity and cytokine secretion do not always correlate with the in vivo outcome, as was clearly shown by the recent publication from Marcela Maus lab in Cancer Cell. The researchers tested different CAR modifications using these standardized tests. Although ineffective CAR variants were quickly identified, the assays could not differentiate between the varying potencies the CARs showed in vivo.

The lack of a reliable tool to predict in vivo success is often detrimental to clinical trials, costing tremendous time and money, and obstructing the development of effective treatments.

Now, cell avidity is emerging as the novel predictive biomarker that was missing so far. In their publication, Maus and team show that in vitro cell avidity measurements are capable to display the varying potencies of CAR variants. They prove that the avidity values are highly correlated with in vivo CAR-T potency where higher avidity values lead to greater tumor eradication in vivo.

These insights also show that “avidity enhancement”- increasing cell binding avidity – in CAR-Ts will be crucial for therapy success in vivo. In their article, the researchers present a strategy that efficiently improved tumor eradication in AML mouse models. For this, they pharmacologically increased CD70 antigen density with Azacitidine on the tumor side and engineered a cleavage-resistant hinge in CD27 ligand. Both strategies enhanced avidity and consequently tumor killing, while their combination lead to the most effective eradication of tumors.

The presented avidity-enhanced CD70-targeted CAR-Ts are highly promising for clinical development against AML, supporting avidity measurements as a valuable and unique tool for pre-clinical CAR variant selection. LUMICKS’ z-Movi provides the platform to measure cell avidity within minutes, giving you quick insights into the binding efficiency of CAR-T variants that will accelerate drug research in your lab.

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.

Leick et al. (2022) recently published in Cancer Cell, revealing cell avidity as the best predictive biomarker for in vivo tumor eradication success. The authors present “avidity enhancement” as a promising strategy for efficient CAR-T design against leukemia.

Key findings of the paper:

  • Assessing different CAR-T designs with in vitro cytotoxicity and cytokine secretion assays was not predictive of in vivo tumor killing efficiency (R=0.598 and R=0.548, respectively).
  • In vitro cell avidity values of CAR-T variants highly correlated with in vivo tumor eradication efficiency (R=0.906).
  • Improving binding avidity on both sides of the synapse by engineering more stable CARs and pharmacologically increasing antigen density on AML cells, highly enhanced CAR-T performance in mouse models of AML.

Why cell avidity?

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The classical approach to improving CAR-T cell binding to cancer cells is to measure affinity. But affinity only determines the specific strength between a scFV fragment and the target receptor – ignoring the rest of the attachment complex that is necessary for efficient tumor killing.

Avidity reflects the total binding interactions and their force, thus revealing the highest binding variant among tested CAR-Ts.

The avidity readout with the z-Movi is simple and direct. The graphic illustrates two measurements, depicting immune cells with different avidities (green and orange) pulled away by force from the target cells monolayer (grey). The results curves show clearly that orange cells have high and green cells have low avidity (3), thus providing clear data for further decision-making on CAR-T design.

Join our Nature webinar!

Meet Prof. Marcela Maus, Associate Professor at Harvard Medical School and Director of Cellular Immunotherapy at the Massachusetts General Hospital in our live webinar on July 11. Prof. Maus and her team recently published their work on novel CAR-T approaches in Cancer Cell and Nature/ next to Cancer Cell also in Nature.

In this webinar, Prof. Maus will discuss the generation of productive CARs and how cell avidity measurements render this possible for solid and liquid tumors.

Don’t miss out on this unique opportunity to get an insight into Prof. Maus pioneering research!

Watch online now
By measuring the whole binding event between the effector and the target cell, the z-Movi® Cell Avidity Analyzer provides the ability to quickly and predictively select and validate the best candidates for cancer immunotherapy, potentially leading to significantly accelerated drug development and increased success rates.
Watch our cell therapy (CAR T, TCR, NK, T cell engagers) webinar here

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