Tag: Canada

As a postdoctoral researcher at the University of Pennsylvania, Haijiao Liu, PhD, helped advance tumor-on-a-chip technology, a feat of bioengineering that mimics the microenvironment of malignant human tumors. Led by Dan Dongeun Huh, PhD, a Penn Engineering professor and trailblazer of organ-on-a-chip technology, Liu and his team explanted lung adenocarcinoma tumors onto the transparent chips to test their perfusion with chimeric antigen receptor (CAR) T cells. Their findings were published in October in Nature Biotechnology, with Liu as first author.

Now on paternity leave in Toronto, Liu spoke with Lindsey Leake about the implications of this work, the challenges inherent to tumor-on-a-chip studies, and his plans to launch a lab of his own this fall.

Q: Walk me through the creation of the tumor-on-a-chip. What went into its design?

Haijiao Liu: It’s essentially inspired by the need for alternative tumor models. This is speaking to the traditionally used animal tumor models and some existing in vitro tumor models, especially for the study of immunotherapies.

For example, when I started at Penn around 2018, Penn Medicine was pioneering this immunotherapy called CAR T-cell therapy, which is basically aiming to harness the patient’s own immune system, specifically the patient’s own T cells, to help fight the cancer. Penn Medicine was demonstrating huge clinical success using this CAR T therapy to treat blood cancers, such as leukemias and lymphomas. In a huge contrast to this, the solid cancer arena has seen a limited response from this new immunotherapy. So there’s this great need to study why this has not been successful, and that comes down to the consensus that the solid tumor has this really complex microenvironment.

In the category called tumor-on-a-chip, people try to control the cultural environment, the biochemical and biophysical environment of tumor cell cultures. We can use this for simple drug testing—see how the tumor growth will be affected or how effectively they can be killed. However, these existing tumor-on-chip or in vitro tumor models are still very simple. They don’t usually recreate or reproduce the complex structure of the human solid tumors that I described, like where they often include complex vessel networks.

I took the lead to address the need and the challenges of reproducing and then investigating, or probing, the dynamic interactions between those CAR T cells and human solid tumors entirely in vitro.

Q: How does the vascularization work on the chip?

Liu: It took several years to start, from the idea of building this more advanced tumor-on-a-chip technology toward proving it’s actually useful. I started by focusing on this one aspect, which is the CAR T-cell trafficking and their functions after they traffic to fight the tumors, and that will involve the recreation of the structural interface between the tumor and this complex vascular network that’s present in human tumors.

I was inspired by in vivo tumor transplantation, where traditionally, people take human tumors and then transplant them in a bulk, intact format into animal models. So my idea was, if we want to focus more on the human biology, if we want to engineer this entirely in vitro, how about we design a vascular bedding, like a miniature living model?

We basically took advantage of the self-assembly capability of human-sourced endothelial cells, combined with certain stromal fibroblasts, or stromal cells. With a bit of optimization, engineering, tweaking, then we can allow them to form capillary-like vascular networks in our engineered models.

Q: What are the advantages of recreating the tumor microenvironment in this way? That is, is the Petri dish becoming obsolete in cancer research?

Liu: The unique advantage of this way of engineering is to have a higher level of control over the structures of the tissue-tissue interface that we can build. For example, we can engineer different culture chambers. We can engineer different access windows with this model. That allows us to construct, step by step, the vascular bedding and then the tumor transplantation. Also, by forming these perfusable vessels—by the way, we can provide the infusion and flow of the CAR T cells, just like they are infused and flow in the patient—that gives us the leverage to reconstruct, probe, and then control these tissue functions in a highly precise manner.

Q: How did you and your colleagues at Penn explore CAR T-cell activity on the chip?

Liu: We first used different functional assays, like immunostaining and ELISA (enzyme-linked immunosorbent assay) assays, to characterize how the CAR T cells are doing and how they are interacting with the tumors in our engineered model. Then we disassembled this engineered tissue to extract all the cells for flow cytometry, to further characterize their functional phenotypes.

With the help of our collaborators and other people in the lab, I took advantage of this engineered model of vascular tumors interacting with CAR T cells for multi-omics analysis. For example, I was able to extract all the cells and send them for single-cell RNA seq[uencing]. We were able to look at the gene expressions of each individual cell from all the cell types that we included in this model. In this way, we have almost like a superpower to probe and read into how each cell—including the CAR Ts and tumors and the vessels—how they are responding and interacting with each other at the molecular gene levels. This is so powerful that it helped me to discover novel interactions between these parties and also new druggable targets.

The message is that through the development of this more advanced tumor-on-a-chip technology—combined with advanced multi-omics analytics and advanced computational analysis—we were able to provide this powerful in vitro technology to apply to accelerate the development of cell therapies, such as the CAR T immunotherapies for cancer, but also other complex diseases.

Q: What are the overall implications of this latest research?

Liu: With a growing understanding of human biology at the cellular and tissue levels, I think we’re seeing that our ability to engineer and design biological systems is also growing. More than ever, we have these advances in the ability to precisely construct, investigate, and then eventually control very complex tissue functions, and even organ functions. For example, our demonstrated tumor-on-a-chip technology is like presenting a miniature sandbox; we can literally see and predict the battlefield of CAR T therapy in cancer.

If we combine these advanced engineering technologies with emerging technologies in spatial multi-omics and the unprecedented productivity of the AI revolution, we will be able to accelerate the understanding of more complex human biology and extract more biological insights, and then apply that to accelerate the development of safer and more efficacious drugs and therapies, such as immunotherapies in cancer.

Q: What are the limitations of organ-on-chip technology that need to be overcome?

Liu: I think there are challenges on two fronts. The first limitation is the lack of complexity. We’re claiming that what we just published is a sufficiently complex system for us to deeply probe and understand the dynamics of CAR T tumor interactions. Still, if we’re speaking next level of translational power or potential, then we need to pursue a higher complexity that incorporates the missing but critical components from in vivo.

The other side of the coin is that if you make this engineered model more complex, you make it more challenging to reproduce or to scale up or to translate to other labs. But also, that points to an opportunity and growing room for translation, to standardize every single step, from the construction to the analysis of these engineered models, and to automate these processes as much as possible.

Q: What do you envision for your new lab?

Liu: I have a lot of things I want to do. I’m eager to establish my own team. The overarching and the unifying theme of the new lab will be to develop the next generation of in vitro complex tissue models, or I call it assembloid tissue models. Assembloid basically means there’s a stem cell-based, three-dimensional complex tissue model that intentionally incorporates different cell types, to emulate the critical tissue-tissue interactions that determine the tissue- and organ-level functions. I still need to make a big decision where the lab could be; it could be in Canada and it could also be in China.

Q: What impact might tumors-on-a-chip have on the future of precision medicine?

Liu: It’s attracting a lot of attention from biologists and clinicians who are heavily focused on using the traditional tissue models—animal models, for example, or the simple dish cultures—for their studies of interest. So the biggest impact I can foresee with our technology is that now it’s more mature. I can see it being gradually, and maybe quickly, adapted into more traditional biological labs, to help them dissect the complex biological questions they’re asking, or to accelerate the evaluation of the exciting new drugs or therapies they’re developing. Overall, I can see that accelerate this development pipeline of new drugs and therapies in precision medicine.

Lindsey Leake is an award-winning, independent health reporter based outside Washington, D.C. She spent 15 years as a staff journalist at outlets including Fortune, the USA TODAY Network and Sinclair Broadcast Group. She holds an MA in Science Writing from Johns Hopkins University, an MA in Journalism and Digital Storytelling from American University and a BA from Princeton University.

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