The integration of mass cytometry with high-throughput drug screening has revolutionized the process of drug discovery and development, offering unprecedented insights into cellular responses to therapeutic compounds at the single-cell level. This chapter explores the applications of mass cytometry in drug screening, its impact on personalized medicine, and its adoption by pharmaceutical companies, including some intriguing developments from unexpected players in the field.
Single-cell Drug Response Profiling
Mass cytometry’s ability to simultaneously measure multiple cellular parameters has transformed our understanding of drug responses at the single-cell level.
Lun et al. (2019) published a landmark study in Molecular Cell, demonstrating the power of mass cytometry in analyzing the human kinome and phosphatome. Their work revealed how overexpression of specific kinases and phosphatases affects cancer-related signaling pathways, providing crucial insights for targeted therapy development.
Building on this foundation, Larsen et al. (2021) introduced a method for high-throughput, single-cell drug screening using mass cytometry in their Cell Reports paper, “A pan-cancer organoid platform for precision medicine”, seen as the bridge between simultaneous testing of multiple drugs on patient-derived organoïds, personalized medicine and high througput screening.
Identifying Rare Drug-Resistant Cells
One of the most significant advantages of mass cytometry in drug screening is its ability to identify rare drug-resistant cell populations that might be missed by bulk analysis methods.
A study by Aissa et al. (2021) in Nature Communications, “Single-cell transcriptional changes associated with drug tolerance and response to combination therapies in cancer,” demonstrated how single-cell RNA sequencing could investigate the emergence of drug-tolerant cells in non-small cell lung cancer treated with tyrosine kinase inhibitors. By analyzing PC9 cells at various timepoints during erlotinib treatment, the researchers identified multiple distinct subpopulations of drug-tolerant cells, each with unique gene expression profiles. These subpopulations exhibited differences in key biological processes such as epithelial-to-mesenchymal transition, drug metabolism, and epigenetic regulation, revealing that drug tolerance is a continuous, multistep process rather than a simple switch from sensitive to resistant. The high-resolution data provided by scRNA-seq allowed for the detection of rare cell populations and transitional states that might be missed by bulk sequencing methods, providing insights into the heterogeneity of drug response. By analyzing the gene expression profiles of these subpopulations, the researchers could predict and validate potential combination therapies to target specific drug-tolerant states. This study demonstrates the power of scRNA-seq in identifying rare drug-resistant cells early in treatment, which could have significant implications for developing more effective cancer therapies and preventing or delaying the onset of drug resistance.
Pharmaceutical Applications and Industry Adoption
The pharmaceutical industry has been quick to recognize the potential of mass cytometry in drug discovery and development. Several major companies have integrated this technology into their R&D pipelines:
- Genentech: A pioneer in adopting mass cytometry, Genentech has used this technology to profile immune responses to cancer immunotherapies.
- Novartis: The company has employed mass cytometry in their drug discovery efforts, particularly in oncology.
- AstraZeneca: In a collaboration with Stanford University, AstraZeneca researchers used mass cytometry to study the effects of their EGFR inhibitor osimertinib on lung cancer cells, as reported by Hartmann et al. (2020) in Cancer Cell (Hartmann et al., 2020, Cancer Cell, 37(4), 557-572.e6).
Intriguingly, even tech giants are entering this space. Google, through its life sciences division Verily, has invested in mass cytometry technology. In 2015, Verily acquired Cytometry by Time-of-Flight (CyTOF) technology from DVS Sciences, which was later acquired by Fluidigm (now Standard BioTools). This move underscores the growing importance of high-dimensional single-cell analysis in drug discovery and development, and hints at the potential for AI integration in future drug screening efforts.
Drugs Developed with CyTOF Technology
While drug development is a complex process involving many technologies, CyTOF has played a significant role in several drug development programs:
- Teclistamab (Tecvayli): This bispecific antibody for multiple myeloma, developed by Janssen Pharmaceuticals, utilized CyTOF in its development process.
- Magrolimab: This CD47-blocking antibody, initially developed by Forty Seven Inc. (now part of Gilead Sciences), benefited from CyTOF analysis during its development. CyTOF was used to profile the immune cell populations in patients treated with magrolimab, providing insights into its effects on different immune cell subsets.
- CAR-T Cell Therapies: While not a traditional drug, the development and optimization of CAR-T cell therapies have significantly benefited from CyTOF analysis. Finck et al. (2013) used CyTOF to characterize CAR-T cell products, helping to optimize manufacturing processes and predict clinical responses (Finck et al., 2013, Cytometry Part A, 83(5), 483-494).
The integration of mass cytometry into high-throughput drug screening pipelines represents a paradigm shift in drug discovery and development. By providing a high-resolution view of cellular responses to therapeutic compounds, this technology is accelerating the pace of drug discovery and bringing us closer to truly personalized medicine.
As we continue to refine these approaches and develop new computational tools for data analysis, we are uncovering new possibilities in drug development. Each experiment becomes a treasure trove of data, revealing not just how drugs work, but also why they sometimes fail. This deeper understanding is paving the way for more effective, targeted therapies and smarter drug development strategies.
The field of high-throughput drug screening, enhanced by the power of mass cytometry, stands at the forefront of a new era in pharmaceutical research. As we decode the complex cellular responses to therapeutic interventions, we move closer to a future where treatments are not just personalized, but precision-engineered for each patient’s unique cellular landscape. This convergence of technologies, from biotech to tech giants like Google, is not just advancing our scientific understanding; it’s reshaping the very process of how we discover and develop the medicines of tomorrow, promising a future where drug discovery is faster, more precise, and ultimately more effective in improving patient outcomes.
I was gobsmacked when I heard Google was investing in CyTOF technology. It felt like worlds colliding - Silicon Valley meets immunology! But then I remembered my trip to Northern England, where I stumbled upon a Fujifilm plant producing mammalian and bacterial cells for antibody production. Talk about a plot twist - from cameras to cell cultures! And it doesn't stop there. Samsung, the tech giant known for smartphones and TVs, has also dipped its toes into the world of biotechnology. They indeed have a biosimilars unit, Samsung Bioepis, which produces antibody-based drugs. It's like finding out your toaster has a secret life as a rocket scientist! These unexpected players in the biotech field remind me that innovation knows no boundaries. Who knows, maybe one day we'll be running CyTOF analyses on our smartphones!
