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The detection of circulating tumor cells (CTCs) can offer considerable advantages over the detection of other material in the peripheral blood, namely cell-free and circulating tumor DNA. Being a whole tumor cell, CTCs can be analyzed in their entirety, revealing a number of insights about the tumor, such as whether the tumor expresses a targetable receptor and the degree of tumor heterogeneity.
In contrast, the alterations detected in cell-free and circulating tumor DNA may not truly represent the alterations harbored in the tumor. Also, this cellular debris is not always present in the blood, often creating reproducibility and sensitivity issues for assays that aim to detect these materials.
Despite the advantages of CTCs, their potential to serve as a liquid biopsy for cancer has largely gone untapped because of the lack of a sophisticated single-cell technology needed to efficiently capture and characterize these cells. A leading provider of single-cell isolation technology, Celsee is starting to change that with its Genesis System.
A Better Way
Historically, single-cell isolation systems have relied on discriminating CTCs from other cells on the basis of cell surface markers, but the problem with this technique is the cells that are released from the tumor may still be undergoing epithelial-to-mesenchymal transition and therefore lack certain surface markers. “When that happens, you are not capturing the cells that are moving through this transition,” explains Shaheen Alanee, M.D., Urologic Oncologist at Detroit Medical Center.
The Genesis System uses a different method. Cells are sorted on the basis of size. Differentiating cells on the basis of size is a better approach because even if the tumor cell loses the surface markers, the system can still detect it, Dr. Alanee says.
The novel method to capture CTCs the Genesis System offers appears to be making a difference. “[The Genesis System has] the highest CTC recovery rate of any platform in the market,” says Bruce Patterson, M.D., CEO of IncellDx, a single-cell diagnostic company.
The Genesis System contains two slide technologies, one of which is the Celselect™ Slide. The Celselect Slide uses patented microfluidics paired with 56,400 microchambers to capture and isolate individual CTCs or other rare cells. Any larger white blood cells that are captured are stained with a common antibody and excluded them from analysis.
Dr. Patterson says that when the Genesis System is used with reagents from IncellDx, the CTC recovery rate is more than 95%, whereas other platforms may have around a 60 to 70% recovery rate for CTCs. “That is the one thing that clinically is the most impressive compared to other instruments,” he adds.
In fact, a clinical research study showed that the Genesis System with Celselect Technology outperformed the CellSearch® System. The study showed that of 18 blood samples from patients with metastatic prostate cancer, the Genesis System successfully detected CTCs in 17 samples, or 94%. In contrast, the CellSearch System successfully detected CTCs in only 11 samples, or 61%1.
“It is highly superior,” says Dr Patterson about the Genesis System.
The Genesis System also supports a second slide technology, called the Celsingle Slide, that has single-cell genomic and proteomic applications.
CTCs in Clinical Research
The detection of CTCs with the Genesis System has several potential clinical research applications in cancer. This technology could guide upfront treatment decisions, predict which tumors will metastasize, and identify therapeutic response early in the treatment cycle, thereby allowing decisions about whether to stop or continue their course of therapy.
Several studies have used the Genesis System to show the feasibility of these clinical applications. For instance, a study in lung cancer was able to identify a signature in the primary tumor using flow cytometry that predicts whether the tumor has already spread, before imaging scans have been done and then treatment monitoring with the Genesis System2. In a different study, CTC enumeration with the Genesis System was able to predict whether treatment with eribulin would be effective in patients with metastatic breast cancer3.
For bladder cancer, a workflow for the detection of CTCs is being developed and tested in a multi-phase clinical study. The workflow starts by collecting a urine sample from a patient who is suspected of having bladder cancer. This urine sample is then tested with the OncoTect iO Bladder Kit from IncellDx, which detects tumor cells and immune cells expressing programmed death-ligand 1 (PD-L1) protein. If PD-L1 is expressed, the patient may receive immunotherapy.
Then, during therapy, blood samples will be collected and monitored for CTCs using the Celselect Slides and the BioINK PD-L1 CTC Kit from InCellDx in conjunction with the Genesis System. Monitoring the CTCs will allow investigators to determine whether the tumor has metastasized and whether the metastases express PD-L1.
A unique feature of this workflow is that blood samples will be analyzed in-house on the Genesis System and results available in a matter of hours. Other assays typically require sending the sample to a central lab where it is analyzed and can take weeks for results to arrive. Not having to send blood samples out of the clinic for analysis is a “very attractive” aspect of the Genesis System, Dr. Alanee says.
To date, the first phase of the study has been completed and shows that CTC detection in patients with bladder cancer is feasible with the Genesis System. Specifically, the proof-of-concept study found that the detection of CTCs in blood samples from patients with bladder cancer can be used to differentiate between those with high-grade and low-grade disease as well as identify patients with benign bladder pathology.
This data was recently presented by Dr. Alanee at the 2020 ASCO Genitourinary Cancer Symposium (Abstracts 288393 “Adaptive genetic algorithms combined with high sensitivity single cell-based technology derived urine-based score is potentially capable of differentiating between high-grade and low-grade transitional cell carcinoma of the bladder” and 204770 “Feasibility of finding circulating tumors cells and assigning PD-L1 receptor status using single-cell technology combined with the Celsee Genesis system”).
The additional phases of the study to further validate this workflow are underway in three larger cohorts of bladder cancer patients.
The Genesis System is for research use only. Not for use in diagnostic procedures.
- Gogoi P, Sepehri S, Zhou Y, Gorin MA, Paolillo C, Capoluongo E, et al. Development of an Automated and Sensitive Microfluidic Device for Capturing and Characterizing Circulating Tumor Cells (CTCs) from Clinical Blood Samples. PloS One. 112016;11(1):e0147400.
- Xiaoyang Wang, Pin-I Chen, Maria Jaimes, Humin Gu, Keith Shults, Santosh Putta, Fariba Fazeli, Janine Fernandez, Vishal Sharma, Will Chow, Priya Gogoi, Kalyan Handique, Bruce K. Patterson. Cell by Cell Immuno- and Cancer Marker Profiling of Non-Small Lung Cancer Tissue: Checkpoint Marker Expression on CD103+, CD4+ T-cells Correlates with Circulating Tumor Enumeration. 2019 Submitted.
- Horimoto Y, Tokuda E, Murakami F, Uomori T, Himuro T, Nakai K, et al. Analysis of circulating tumour cell and the epithelial mesenchymal transition (EMT) status during eribulin-based treatment in 22 patients with metastatic breast cancer: a pilot study. J Transl Med. 2018 Oct 20;16(1):287.