THERAPEUTIC ONCOPHERESIS

There are a number of compelling animal and human studies which demonstrate the efficacy of the principle that removing CTCs is a viable cancer therapy.

1. Removing CTCs correlates with increased survival and often a reduction of distant metastases in animal studies

“Our study explicitly demonstrates that directly eliminating CTCs can reduce metastasis disease in secondary organs”  

-Wayne, King et al.

  1. Removing CTCs correlates with increased survival and often a reduction of distant metastases in animal studies


The efficacy of the concept of removing CTCs as a cancer therapy to slow the progression of metastatic cancer has been demonstrated in several recent studies. 

Scarberry et al. showed in their 2011 paper that removing CTCs from a mouse with cancer significantly reduces tumor progression and increases survival time. After the mice were injected with human ovarian cancer cells, the researchers removed CTCs using magnetic nanoparticles and showed that the median time to death increased by 32.4% even though the CTCs were only removed in a single filtration session. Similarly, due to the reduction in malignant cell burden from that one filtration session, tumor progression slowed to 10.77 times the rate of the control group, which received no treatment.  (Scarberry, K., Mezencev, R., McDonald, J.F. Targeted removal of migratory tumor cells by functionalized magnetic nanoparticles impedes metastasis and tumor progression. Nanomedicine (2011) 6(1), 69-79). 

Li et al. functionalized synthetic silica particles by conjugating them with a tumor-specific ligand cytokine they named TRAIL. These particles became incorporated into CTC-associated micro-thrombi in a mouse model, and dramatically reduced the number of metastases. This reduction was quantified in whole animal luciferase imaging (Li J., King, M., et al., Targeted Drug Delivery to circulating tumor cells bia platelet membrane-functionalized particles. Biomaterials (2016) 76, (52-65).)

This paper was followed up with another study specifically targeting CTCs from a human prostate cancer xenograft model in mice. Again, the King group specifically targeted CTCs using an ES/TRAIL apoptosis ligand attached to the cell surface of leukocytes. They were able to show clearance of CTCs and prevention of distant metastasis in other organs by treating the animals once every three days. 

 (Wayne, E., King, M., et al. TRAIL-coated leukocytes that prevent the bloodborne metastasis of prostate cancer. J Control Release (2017) 10(223), (215-223). 

Other groups have generated pharmacologically active molecules that specifically target CTCs in circulation. The Pellecchia group were able to inhibit lung metastases in a breast-cancer model in mice, resulting in a reduction of the gross lung-metastases count by 75%. (Salem, A., Pellecchia, M,. et al. Reduction of Circulating Tumor Cancer Cells and Metastases in Breast-Cancer Models by a Potent EphA2-Agonistic Peptide-Drug Conjugate. J Med. Chem. (2018) 61, 2052-2061).)

Finally, the Choi group generated a way to selectively target CTCs in mice by using a blue-light laser to excite GFP-tagged lung cancer cells. They were able to show that only a few CTC elimination treatments resulted in a significant decrease in lung metastases. (Kim, Y., Choi J., et al. Selective killing of circulating tumor cells prevents metastasis and extends survival. (2018) J. Hematology & Oncology. (2018).)

2. Collecting CTCs results in fewer metastatic tumors

The Shea group generated some compelling data on the efficacy of collecting CTCs as a cancer therapy by collecting CTCs for 28 days from mice with breast cancer using an implanted “sponge”. Upon autopsy, this technique showed:

  • An 88% reduction of tumor cells in the lungs

  • 30% fewer metastatic lesions in the lungs

  • A 75% reduction in the incidence of liver metastases

(See Azarin, S., Shea, L.et al., In vivo capture and label-free detection of early metastatic cells, Nature Communications (2015) 6:8094) https://www.nature.com/articles/ncomms9094 

3.  Clinical Studies Show That Number of CTCs is a Predictor of Overall Survival (2005-2014)

Clinical studies have shown that low numbers of CTCs correlate with positive survival outcomes. Currently, the only FDA approved diagnostic test to count CTCs is called Cell Search and it was approved in 2004. Many papers show that a higher CTC count is correlated with worse survival outcomes. 

Cristofanilli et al. showed that in patients with metastatic breast cancer, patients with a CTC count of 5 or higher per 7.5 ml of whole blood fared worse than those with fewer than 5 CTCs. They showed that the median progression-free survival for the higher group was 2.7 months, versus 7 months for the lower count. The overall survival for patients in the higher count group was 10.1 months, versus 18 months for the lower group. (Cristofanilli, M., Hayes, D., et al. Circulating Tumor Cells, Disease Progression, and Survival in Metastatic Breast Cancer. N Engl J Med (2004) 351:781-91.)

Bono et al. showed a similar result in patients with castration-resistant prostate cancer. Using the same cutoff count of 5 CTCs per 7.5 ml of whole blood, patients in the higher count group showed a median overall survival of 11.5 months, versus 21.7 months for the lower CTC count group. (Bono, J., Raghavan, D.,. et al. Circulating Tumor Cells Predict Survival Benefit from Treatment in Metastatic Castration-Resistant Prostate Cancer. Clin Cancer Res (2008).

Cohen et al. also showed similar data for metastatic colorectal cancer, but with a slightly lower CTC count of 3 cells per 7.5 ml of whole blood. They showed that patients with more than 3 CTCs had a shorter median progression-free survival of 4.5 months, versus 7.9 months for the group with a lower CTC count. This difference was also apparent with the overall survival as patients with over 3 CTCs showed a median survival of 9.4 months versus 18.5 months for the group with a lower CTC count. (Relationship of Circulating Tumor Cells to Tumor Response, Progression-Free Survival, and Overall Survival in Patients With Metastatic Colorectal Cancer. J Clin Oncol (2008). 26 (3213-3221).)

In addition to overall lower CTC counts having favorable outcomes, clinical studies of CTC counts have shown that a therapy which transitions from unfavorable (≥5 CTCs/7.5mL of blood) to favorable (<5 CTCs/7.5 mL of blood) counts improves survival and, as such, can be used as a predictive factor for treatment response. For example, an evaluation of 296 metastatic breast and prostate cancer patients showed that: (i) the number of CTCs is a powerful tool to predict overall survival if the absolute number of CTCs is reduced below 5 CTCs/7.5 mL of blood, and preferably approaches zero; and (ii) a period of 10 to 12 weeks may be needed before definitive conclusions can be drawn as to whether the CTC count is heading downward (and to zero), using multiple measurements over a period of three months.  (Interpretation of Changes in Circulation Tumor Cell Counts, Coumans, F., Ligthart, S., Tersteppen, L. Translational Oncology (2012) 5, 486-491).