A new 3D imaging technique brings the working mode of T-cell immunotherapies into live view. T-cell immunotherapy is already leading to promising results in some children with leukemia. Researchers plan to also use the new imaging technique to improve T-cell therapies for solid tumors. However, extending this approach to solid tumors requires improved in vitro models that reveal therapeutic modes of action at the molecular level.

T-cell therapies, such as chimeric antigen receptor T-cells or CAR T-cells therapies, are a promising type of immunotherapy demonstrating results in treating children with leukemia. These kind of therapies, which use a patient’s own immune system, include T-cells (a type of white blood cell), which have been modified in the lab are administered and subsequently attack the tumor in a targeted manner.

Other T-cell therapy concepts are being developed to target cancer include conventional T cell receptor (TCR) T -cell therapies, as well as αβ T-cells engineered to express a gamma-delta (𝛄𝛅) TCR, known as TEGs, endowing cancer-recognizing properties through metabolic sensing.[1]

Effective T-cell therapies are also being sought for solid tumors, such as neuroblastoma, sarcoma and kidney tumors. However, to improve their clinical efficacy, a better understanding of solid tumor-targeting behavior of T-cells is required.

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To accomplish this goal, 3D imaging specialist Anne Rios Ph.D. a Principal Investigator and Head of the imaging center at the Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands. teamed up with Zsolt Sebestyén Ph.D., and Prof. dr. Jürgen Kuball, MD, Ph.D., T-cell therapy experts and group leaders at University Medical Center (UMC) Utrecht, and organoid specialist Prof. dr. Hans Clevers, Ph.D., Head of pharma Research and Early Development (pRED) at Roche in Basel, Switzerland, and former group leader at the Hubrecht Institute .

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The results of their collaborative research were published Nature Biotechnology.

A wealth of fundamental knowledge
Lead authors of the publication Florijn Dekkers, a Postdoc of the Rios group and Maria Alieva, a senior postdoc from the Rios group developed an imaging and analysis technology called BEHAV3D, a multispectral, 3D image-based platform. The novel technology allows researchers to live-track the efficacy and mode of action of cellular immunotherapy for ~60 human cancer organoid cultures simultaneously and analyze the interaction between T-cell therapies and tumor organoids.

A new 3D imaging technique brings the working mode of T-cell immunotherapies into live view. Dr. @florijn Dekkers and dr. @maria Alieva, both working in the Rios group, developed imaging and analysis technology BEHAV3D. Researchers plan to use this platform to improve T-cell therapies for solid tumors by analyzing the interaction between T-cell therapies and solid tumor organoids. Featured image and Video Courtesy: ©2022 Research group Anne Rios, Ph.D., – Princess Máxima Center for Pedriatic Oncology, Utrecht, the Netherlands. Used with permission.

 

“Unique about this approach is that we are looking at cell therapy efficacy by studying the behavior of the T-cells. In total, we studied the behavior of over 150,000 engineered T-cells,” Florijn Dekkers said.

“This revealed a huge variety in behavior, like very potent behaviors, such as killing of multiple tumor cells in sequence, but also ineffective behaviors, with cells just sitting around and doing nothing. This suggested to us that there is room to improve clinical efficacy by promoting the most potent tumor-targeting behaviors,” she added.

“To be able to stir T-cell therapies towards their most effective behaviors, we need to know the underlying mechanisms that dictate this behavior. Therefore, I developed a method that for the first time links the behavior of the cell to the genes that cause this behavior,” Maria Alieva explained.

[This approach makes it possible] to identify specific gene signatures of highly potent T-cells that are able to kill many tumor cells. Using BEHAV3D in combination with tumor organoids grown from tumor tissue of children and adults, we can now gather a wealth of fundamental knowledge about the behavior and ability of T-cells to target solid tumors.’

Improving targeting
“We initially looked at the behavior of TEG cells, a highly promising therapy based on T-cells that are activated once they notice metabolism changes in tumor cells, developed in the lab of our collaborators; Zsolt Sebestyén and Jürgen Kuball,” Rios noted.

“However, we were able to apply BEHAV3D to different kinds of T-cell therapies, as well as cancer subtypes. Therefore, we believe that this platform can be very useful for further improving the targeted attack on solid tumors by the various T-cell therapies currently under development,” she concluded.

Reference
[1] Dekkers JF, Alieva M, Cleven A, Keramati F, Wezenaar AKL, van Vliet EJ, Puschhof J, Brazda P, Johanna I, Meringa AD, Rebel HG, Buchholz MB, Barrera Román M, Zeeman AL, de Blank S, Fasci D, Geurts MH, Cornel AM, Driehuis E, Millen R, Straetemans T, Nicolasen MJT, Aarts-Riemens T, Ariese HCR, Johnson HR, van Ineveld RL, Karaiskaki F, Kopper O, Bar-Ephraim YE, Kretzschmar K, Eggermont AMM, Nierkens S, Wehrens EJ, Stunnenberg HG, Clevers H, Kuball J, Sebestyen Z, Rios AC. Uncovering the mode of action of engineered T cells in patient cancer organoids. Nat Biotechnol. 2022 Jul 25. doi: 10.1038/s41587-022-01397-w. Epub ahead of print. PMID: 35879361.

 

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