Pioneering ‘Leukemia-on-a-Chip’ for CAR T Cell Therapy at SLAS 2024

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In this interview, NewsMedical spoke with Chao Ma, Ph.D., research assistant professor at New York University’s Tandon School of Engineering. We first Dr. Mother at SLAS 2022; This conversation aims to explore how this important research has evolved and where it is going.

Before his presentation at SLAS 2024, Dr. Ma shares insights into his innovative “leukemia-on-a-chip” technology, its impact on CAR T-cell therapy, and the future of personalized medicine in the treatment of leukemia.

First, please introduce yourself and outline your career. More specifically, please provide us with a brief description of the current research you are presenting at SLAS 2024.

Thanks for inviting me back to discuss our recent progress in “leukemia-on-a-chip” for CAR T cell therapy modeling and screening. Ask my name mom. Currently, I am a Research Assistant Professor in the Department of Mechanical and Aerospace Engineering at the New York University Tandon School of Engineering.

Adoptive CD19 CAR (chimeric antigen receptor) T-cell transfer has emerged as a successful FDA-approved therapy for B-cell acute lymphoblastic leukemia (B-ALL). However, a high relapse rate of 30~60% in CAR T-cell therapy remains a major problem. The ability to preclinically assess CAR T-cell efficacy and dissect CAR T-cell immunotherapy relapse mechanisms is highly significant but will be challenging with current animal models.

To bridge the gap between animal studies and clinical translation, here we established a 3D microfluidics-based, organotypic immunocompetent ‘leukemia-on-a-chip’ to provide relevant human results of CAR T-cell immunotherapy prior to clinical administration, which I call SLAS. To be presented in 2024.

This unique preclinical platform enables a new paradigm of clinical-on-a-trial, providing a precise, reliable and multidimensional evaluation of CAR T cell therapy, which can be easily extended to evaluate many other immunotherapies for various blood cancers. As solid tumors and beyond.

Image credit: orodenkoff/Shutterstock.com

Dr. Mom, sincerely Previous interview Two years ago, can you highlight the most significant advances in your leukemia-on-a-chip technology?

I would say the application of leukemia-on-a-chip technology from conventional chemotherapy to novel therapies, particularly CAR T cell immunotherapy.

How have your research developments over the past two years impacted the understanding of CAR T-cell immunotherapy relapse mechanisms?

We have realized to model various clinical outcomes of CAR T cell therapy on a chip. Additionally, we found that mobilizing the immune system during CAR T cell activation can promote CAR T cell responses on-chip.

In light of your recent findings, what are the current challenges in modeling leukemia resistance and relapse in leukemia-on-a-chip?

The first challenge, I would say, is to realize long-term cultures that can allow chronological studies of CAR T cells. Second, our system is currently constructed with commercial primary cells and cell lines. Thus, we would need a sample from a large cohort of patients to represent patient diversity and enable precision in personalized therapy.

Finally, how to model acquired therapy resistance in cART cell therapy on-chip remains quite challenging. This requires innovative technological development and a deep understanding of leukemia pathobiology and T-cell immunology.

Can you discuss any novel insights your team has discovered about molecular and cellular changes during clinical outcomes of different CAR T-cell therapies?

As we discussed in question 3, our studies modeled different clinical outcomes of CAR T cell therapy on-chips. One application we have realized on-chip is that incorporating IL-18 into CAR designs can enhance CAR T cell function, which could improve outcomes in patients whose current CAR T cell products have hypofunction.

Also, activation of the immune system during cART cell activation can promote cART cell responses on-chip.

How has the bioengineered leukemia chip evolved in its ability to model and evaluate other immunotherapies for various blood cancers and solid tumors?

We are applying this technology in the lab to analyze CAR T cell therapy in other CAR T cell therapy studies in solid tumors such as acute myeloid leukemia (AML) and pancreatic ductal adenocarcinoma. We hope to share our progress with the SLAS community soon, so keep your eyes peeled.

Image credit: Gorodenkoff/Shutterstock.comImage credit: Gorodenkoff/Shutterstock.com

Since our last conversation, how has the integration of technologies such as single-cell mRNA sequencing increased the capacity and accuracy of your leukemia-on-a-chip system?

Yes, of course. We were able to apply scRNA-seq to verify the cellular similarity of our bioengineered bone marrow niche to the in vivo counterpart. In addition, we can map molecular changes in CAR T cell activation and niche cells.

Reflecting on the past two years, what has been the most unexpected or surprising result from your research using leukemia-on-a-chip?

We found that the incorporation of the vascular network and immune environment into the leukemia-on-chip system enables the creation of a reliable in vitro system, which can provide a systematic test of cART cell therapy, from T cell extravasation, leukemia recognition, immune activation, cytotoxicity. , and killing in interaction with the bone marrow microenvironment.

How do you envision the role of lab-on-a-chip and organ-on-a-chip systems in the future of personalized medicine, especially in the context of immunotherapy?

Patients can undergo only one type of treatment at a time. Suppose we can incorporate patient samples with our platform to develop patient-specific organ chip models. In that case, it would allow multiple treatments to be screened in parallel to identify the best immunotherapy for a given patient.

We are collaborating with clinicians to test this technique with patient samples from clinical trials. We hope to provide in vitro patient-specific systems that realize the so-called “clinical-trial-on-a-chip” concept.

Finally, how do you believe your work will contribute to the broader scientific and medical community’s efforts to combat leukemia and improve patient outcomes?

We believe our research progress will not only fill the technological gap in human disease modeling and therapy screening through bioengineering tools of in vitro organotypic tissue models but also fill the knowledge gap through a deeper understanding of CAR T cell therapy resistance and relapse mechanisms.

Where can readers find more information?

About Chao Ma, Ph.D.

Chao Ma, PhD is currently a research assistant professor at the New York University Tandon School of Engineering. His current research focuses mostly on engineering leukemia-on-a-chip platforms to understand resistance to chemotherapy and CAR T-cell immunotherapy. Dr. Ma received his BS and PhD in Biotechnology in 2013. in Animal Biotechnology (Cellular Engineering) in 2017 both from Northwest A&F University.

During that time, he developed micro-engineering techniques to construct liver tissue in vitro for analysis of metabolism-related drug toxicity and bottom-up liver tissue engineering. Dr. MA has been awarded nationally and internationally, such as College of Innovation and Experiment, NWAFU (2021), National Scholarship Award for Graduate Students from Ministry of Education (2016), National Scholarship Award for Outstanding Graduate Award from College of Veterinary Medicine, NWAFU (2017 ), an Irvington Postdoctoral Fellowship Award from the Cancer Research Institute (2021), a DMM Conference Travel Grant Award from the Society of Biologists (2021), a Post-Doctoral Researcher Travel Award from BMES-CMBE (2022), as well as a Tony B. from SLAS (2022). As an academic award.

Dr. Ma has emerged as an expert in the microfluidic organ-on-a-chip field with invitations to present his findings at local, national, and international conferences (WPC, BMES, ASME, CMBE, and SLAS). Dr. Ma is the co-inventor of two patents involving engineering methods of tissue and tumor modeling for advanced therapies and the author of numerous peer-reviewed publications.

Dr. Extensive research aims for this. MA will develop and leverage a multidisciplinary approach that integrates engineering with biology and medicine for tissue engineering, disease modeling and therapy screening, with the goal of positively impacting human health care and well-being.



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