EFFICACY OF THERAPEUTIC ONCOPHERESIS
There are several compelling animal and human studies which demonstrate the efficacy of the principle that removing CTCs is a viable cancer therapy.
1. MIT STUDY (2014)
CTCs + Platelets + Granulocyes = Metastasis
An MIT animal study in 2014 concluded that CTCs emit signals (e.g., tissue factor) which attract platelets, which then attract granulocytes (a subset of white blood cells) to form metastatic niches within two hours. (Labelle, et al, Platelets guide the formation of early metastatic niches, www.pnas.org/cgi/doi,10.1073/pnas.1411082111, July 2014)
Breaking Any of Those Links = No Metastasis
Significantly, that MIT study also showed that interfering with the signal pathways for either CTCs, platelets or granulocytes stops the metastatic process. It suggests potential therapeutic targets to address this key insight; but these are many years away from commercialization.
2. Removing CTCs = Increased Survival (2011)
The efficacy of the concept of mechanically removing CTCs as a cancer therapy to slow the progression of metastatic cancer was demonstrated in a study published by others in 2011. Using magnetic filtration of the ascites of mice that were infected with human ovarian carcinoma, the researchers removed CTCs and showed that the median time to death increased by 32.4% with only one filtration session. Similarly, due to the reduction in malignant cell burden due to 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).
3. University of Michigan Study (2015)
Collecting CTCs = Fewer Metastatic Tumors
Compelling data on the efficacy of collecting CTCs as a cancer therapy was demonstrated by a recent study which collected CTCs for 28 days from mice with breast cancer using an implanted “sponge”. Upon autopsy, this technique (which is precisely analogous to Viatar’s therapeutic oncopheresis) showed:
(See Azarin SM, et al, In vivo capture and label-free detection of early metastatic cells, Nature Communications (2015) 6:8094, DOI: 10.1038/ncomms9094)
4. Therapeutics Target CTCs = Increased Survival (2010-2014)
The efficacy of a cancer therapy based on the concept of obstructing the metastatic process has been demonstrated by four cancer immunotherapy drugs approved since 2010 by the FDA (Provenge, Yervoy, Keytruda, Opdivo) which prolong the lives of patients with metastatic disease. The mode of action for each of them is to sensitize white blood cells to target and attack cell signal pathways in the tumor microenvironment which flourishes once CTCs leave the primary tumor and begin extravasation at distant sites. These immunotherapies are the most significant advance in oncology treatment in decades, and offer the first glimmer of hope in reducing the 90% fatality rate once a patient’s cancer has metastasized. However, they are very expensive ($100K to $300K).
|Therapy||Mode of Action||Clinical Results|
|Sipulence-T (Provenge)||Autologous immune T-cells from prostate cancer patients reprogrammed to reconize and kill CTSs||Overall survival increased from 21.7 months to 25.8 months|
|Lpilimumab (Yervoy)||Activation of the immunoglobulin protien receptor CTLA-4 on T-cells kill CTCs||Overall survival increased from 6.4 months to 10 months|
|Nivolumab (Opvido)||Activation of the immune checkpoint molecule PD-1 on T-cells to kill CTCs||32 percent of particpants showed tumor shrinkage; this lasted for more than six months in one-third of the particpants who experienced this effect.|
|Pembrolizumab (Keytrudata)||Activation of the immune checkpoint molecule PD-1 on T-cells to kill CTCs||One year surivival in advanced melanoma patients was 69%|
5. Clinical Studies Showing That Number of CTCs is a Predictor of Overall Survival (2005-2014)
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) 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).