Interview conducted by April Cashin-Garbutt, BA Hons (Cantab)
Please can you outline how you convert human placental cells into PLacental eXpanded (PLX) cells?
We start with birth and we collect the cells after C-section. The reason for that is we have to have the mother sign a consent letter that she is donating the placenta and, on top of that, we have to have a blood sample from the mother to test for any viral contamination.
Following this we start the processing. At our manufacturing facility we take the region from the placenta that we are interested in and then we extract the cells that we are using to develop our PLX cells.
Once we have selected the cells we then grow them in our 3D bioreactors to make our cell therapy products. About eight weeks after birth we have the product, the PLX cells, prepped that are ready to use, and they can be shipped from our facility across the world without any further manipulation being necessary.
Why does the processing take eight weeks?
We expand the cells we harvested from the placenta with up to twenty-five doublings, so that we can treat approximately ten thousand patients from one placenta. This process of cell expansion is a major determinant of the processing time. They multiply within twenty-four hours. There is a doubling over this period, so there are around twenty-five doublings in twenty-five days.
Then we need more time for processing to deliver them from one state to another, and that’s the reason that we end up with about eight weeks, or about forty days from birth to the product ready to go.
Why do you use a 3D bioreactor and what advantages does this have?
The rationale behind the 3D bioreactor is to try to imitate the natural body structure. Cells in the body are grown in 3D space, not in 2D space such as in a petri dish.
We grow them in a way that we imitate the environment in the patient’s body. The cells are grown at 37 degrees Celsius and at a pH level similar to the pH level in the human body.
Growing cells in a 3D bioreactor allows us to precisely control other aspects of the environment so that we can precondition our cells to secrete certain therapeutic proteins. The 3D bioreactor, in part because it creates a more “natural” environment, also makes it possible to grow cells much more efficiently and reliably.
What signals do damaged tissues produce and how do the PLX cells recognise these signals?
The PLX cells react in response to many signals originating from throughout a patient’s body. The body releases chemical signals called chemokines into the bloodstream. When the chemokines reach PLX cells, the chemicals interact with specific receptors on the cells.
That interaction generates internal responses that instruct the cell nucleus to produce specific proteins. At the end of the process the cells produce proteins that are required based on the signal they received.
In what ways do the PLX cells respond to the signals produced by damaged tissues?
We develop our product by designing the cells for different indications. Today we have one cell product in Phase I and Phase II clinical trials. We are testing our cells for treatment of critical limb ischemia, intermittent claudication, muscle injuries, pulmonary hypertension and shortly we expect to enter into trials for pre-eclampsia.
We have three additional products. One is in preclinical trials to treat bone marrow failure after acute radiation. Another is targeting autoimmune diseases and one is targeting metabolic conditions. The latter two will enter into trials next year.
Do various tissue types respond differently to damage? Do they send out different signals?
Exactly. We are educating the cells. Our therapeutic cells all originate from the placenta, but by changing the culture conditions we can educate the cells to produce the types of growth factors that are needed for specific indications.
For example, when we draw the cell from the bioreactor we can apply a hypoxic condition, less oxygen. When there is less oxygen in the clinical condition, the cells become challenged, in return they start to produce high levels of EDF, ATF and other intergenic factors.
The outcome is that, due to the fact that the cells are challenged by the situation, they produce higher levels of entertaining factors, which converts them into suitable cells for that indication.
If you want to go to the autoimmunity, we do different processing. Similar to axial stem cells, but we need them to produce anti-inflammatory cytokines, like IL-10 and others. They do it in return with the challenging when they are grown with the inflammatory cytokines.
What types of tissue damage do you hope PLX cells will treat?
The first one is the lack of blood flow in the lower extremities. What the cells do when they feel the lack of blood flow is secrete a hypergenic factor that induces the body to generate new blood vessels.
The second example is in muscle injuries associated with trauma or an operation. By generating growth factors that are associated with the generation of blood vessels, what the cells actually do is promote endogenesis.
By promoting endogenesis in the traumatic tissue, due to the fact that there is better blood flow, the recovery process is better, the muscles are recovered, the fibrosis, the scar, is diminished because of good blood flow in the scar area.
So they improve the generation and the outcome is improvement in the force and the volume of the muscle following the PLX treatment.
How are the PLX cells administered?
It depends on the indication. When we are dealing with muscle trauma, critical ischemia, intermittent claudication, we inject them into the muscle. Not necessarily into the damaged muscle, but we inject them into the muscle because we want them to stay longer.
They actually use the muscles as some kind of human incubator so the cells can last from the injection for about four to six weeks. During that time they interact with body and secrete the growth factors needed for the therapeutic effect.
Other indications, like pulmonary hypertension, we inject them intravenous because we want them to be stuck in the lungs for a while. When they are stuck in the lung they receive a signal from the hypertension situation and they secrete higher levels of intergenic and other factors to improve the hypertension.
What stage of development are you at?
We have a product in phase 2 and we are shortly initiating a phase 2/3 study in Korea associated with critical limb ischemia. So we are a phase 2/3 company.
What are Pluristem Therapeutics’ plans for the future?
I strongly believe that cell therapy is the next generation of biological product. If you look back into history and you look into the development of the antibody market, which today is representing about 1.7 billion dollars in sales, I believe that cell therapy will be in the same development curve.
We are only at the beginning. You can compare our situation to the antibody business fifty years ago. From the beginning some clinical trials will fail, some will be successful, but step-by-step the companies will be developed.
I believe that we can become one of the leaders of this phase, mainly because of the fact that we take control from A to Z. The manufacturing, the developing and all of the stuff that’s going around and we have a variety of product, a variety of clinical indications going around.
We believe the probability of success is high. We have two clinical studies that have demonstrated significant efficacy in clinical ischemia and muscle trauma. We have ongoing clinical studies. We are building a lot of evidence to support our claims that we can become the next generation of biological product.
How has our understanding of cell therapy changed?
The world has shifted in its understanding of cell therapy since it started about twenty years ago. In the beginning, the cell therapy drivers, the people that were involved in cell therapy claimed that the mechanism of action would be the replacement of damaged tissue.
A lot of hope has been built-in there because a lot of people were thinking that we can replace hearts and heart muscles that had been damaged due to a heart attack, and so on.
I think that today we can understand that in the coming years the cell therapy product will be more a secreted therapeutic proteins, and not replace the heart.
I think that the fact that this is an understanding, and luckily we are one of the drivers of this understanding.
I’m not saying that in the future no one can take embryonic stem cells and replace a heart, but not now. It takes time. As of today I believe that the center of the way the cells secrete a variety of proteins that are of a therapeutic effect, that is the existing generation of cell therapy.
The next generation some time will be replaced. By understanding the change in the understanding of the whole collection, it will help people to understand the mechanism of the dynamics in that field and we are moving forward in that dynamic.
Where can readers find more information?
About Zami Aberman
Zami Aberman Chairman & CEO joined Pluristem in September 2005 and changed the Company's strategy towards cellular therapeutics. Mr. Aberman's vision to use the maternal section of the Placenta (Decidua) as a source for cell therapy, combined with Pluristem's 3D culturing technology, led to the development of the Company's unique products.
Mr. Aberman has 20 years of experience in marketing and management in the high technology industry. He has held positions of Chief Executive Officer and Chairman in Israel, the USA, Europe, Japan and Korea. He has operated within high-tech global companies in the fields of automatic optical inspection, network security, video over IP, software, chip design and robotics.
Mr. Aberman serves as the Chairman of Rose Hitech Ltd., a private investment company. In the past he has served as the Chairman of VLScom Ltd., a private company specializing in video compression for HDTV and video over IP and as a Director of Ori Software Ltd., a company involved in data management. Prior to that, he served as the President and CEO of Elbit Vision Systems (EVSNF.OB), which supplies inspection systems for the microelectronics industry.
Mr. Aberman has served as President and CEO of Netect Ltd., specializing in the field of internet security software and was the Co-Founder, President and CEO of Associative Computing Ltd., which developed an associative parallel processor for real-time video processing. He has also served as Chairman of Display Inspection Systems Inc., specializing in laser based inspection machines and as President and CEO of Robomatix Technologies Ltd. (RBMXF.OB).
In 1992, Mr. Aberman was awarded the Rothschild Prize for excellence in his field from the President of the State of Israel. Mr. Aberman holds a B.Sc. in Mechanical Engineering from Ben Gurion University in Israel.