We interviewed Dr. Anthony Gringeri, President and CEO of Immunocellular Therapeutics, a company developing immune-based therapies for the treatment of cancer. ImmunoCellular is focused on advancing its Stem-to-T-Cell research program, which engineers hematopoietic stem cells to generate cytotoxic T cells. Joining Dr. Gringeri is Dr. Steven Swanson, Senior Vice President of ImmunoCellular.
Dr. Gringeri was appointed Chief Executive Officer in December 2016, but joined ImmunoCellular Therapeutics in August 2013 as Senior Vice President of Strategic Resources. Dr. Gringeri has more than 25 years of executive experience in the pharmaceutical and biotechnology industry, having successfully led multiple functions and cross-functional teams throughout his career, including in the areas of clinical, regulatory and commercial planning and operations, finance, licensing and alliance management.
Read below for a transcript of Dr. Gringeri’s discussion on the latest updates at Immunocellular Therapeutics, and their use of dendritic cells to target tumors.
Brett Johnson: In layman’s terms, how would you describe to how your technology works?
Anthony J. Gringeri: Basically, using starting materials from the patient’s own body, we develop dendritic cells, which are the key mediators in directing the immune response. We take these dendritic cells and we expose them to peptides, that is, fragments of protein, that are derived from critical markers contained in cancer cells. We focus on peptides that are over expressed in cancer cells, and specifically in cancer stem cells. Then we put these activated dendritic cells back into the patient, and the dendritic cells then interact with killer T-cells and activate them against the peptide markers. The killer T’s then go after the tumor. Think of the dendritic cells as the piece of clothing that you hold under a bloodhound’s nose, and then the bloodhound goes after the target.
BJ: When you say specifically the cancer stem cells why is that significant?
Steven Swanson: The cancer stem cell aspect of it is very important. So, with cancer, one of the biggest problems is that it recurs. With Glioblastoma, it virtually always recurs. The reason that scientists think this happens is that there is a population of cells in tumors that are called cancer stem cells. What these cancer stem cells can do is differentiate into all the other cell types in the tumor. Just like our own stem cells in our body that are programmed to become other types of cells, for example hematopoietic stem cells are in the bone marrow, and they start producing red blood cell precursors and white blood cell precursors as needed. These cancer stem cells reproduce very slowly. They are resistant to chemotherapy and radiation because they reproduce so slowly. Remember that the key for most chemotherapeutic and other treatments for cancer is to kill rapidly dividing cells. Cancer stem cells don’t grow rapidly; they don’t follow the pattern of other types of tumor cells. You need to have a special way to go after them. With our immunotherapy, by adding these dendritic cells, we can train killer T-cells to seek these cancer stem cells and destroy them. That’s the best chance we have of preventing recurrence in diseases like Glioblastoma. If you can weed out every one of those cancer stem cells, you will destroy the tumor completely and may be able to eliminate recurrence.
BJ: Can you give us your perspective on the field of immunotherapy in general?
SS: I think the field of immunotherapy is a very dynamic area right now. There are a lot of areas where we can make a tremendous impact in changing how physicians are able to treat cancer. One of the things that’s very frustrating for me is the devastating effects of all the therapeutic options available for cancer patients right now — the cure is as bad as the disease in many cases. With immunotherapy, harnessing the patient’s own immune system has a chance to really impact the field of oncology. Immunocellular’s cutting edge technology could make a positive impact on patients’ lives.
AG: The concept of immunotherapy of cancer, the idea of it, has been around now for more than a century. We’ve finally reached a place in the last several years where the technology is catching up to the theory. We’re actually able to make, in a predictable way, changes in the patient’s condition using these new immunotherapies. I agree with Steve. I think it’s an extremely exciting time to be in the field.
BJ: Why do you like this approach better than the other approaches?
SS: The big thing for me about dendritic cells is that they are a very safe method for treating cancer. With dendritic cells, the safety record has been amazing. There are very few side effects. The patients react to the treatment extremely well. In the case of our products, there is little chance for the patient to reject any of the biological material that is being injected into them because the starting material is autologous.
BJ: What is the patient situation today with Glioblastoma?
AG: The current standard of care is chemotherapy plus radiotherapy. Chemotherapy is with Temozolomide, which is the only product approved. If I remember correctly, it was approved about 15 years ago, and there has been no advance in treatment since then. If you look at the papers published by Roger Stupp when they did that trial, the average patient with the best standard of care from diagnosis to death lives 14.6 months, and there is a 5 year survival rate of about 10 percent. The fact is that glioblastoma is the most lethal cancer that arises in the brain, treatment options are very few, and survival is terrible. Thus, the clinical need is enormous. There are over 10,000 patients diagnosed per year in the US about 25,000 in Europe. Those are the only two regions for which I have data. So it is definitely an orphan disease.
BJ: Who is in this business and who is meeting these needs now? What are the alternatives?
AG: There are other companies investigating treatments for glioblastoma, but the only chemotherapy that I know of is Temozolomide. That’s really all there is.
BJ: As for the use of dendritic cells, can you comment about other firms, Dendreon for example?
SS: Dendreon is the one company that has a dendritic cell immunotherapy approved in the US. It’s for prostate cancer. They have been the trailblazers for all of us to follow. One of the challenges with Dendreon’s product was logistics. When you have an oncology product where you’re getting cells from a patient, manufacturing it into something else, and then delivering it back to the patient, there is a short, critical period of time where you have to be able to transport this material. You cannot do the manufacturing at the patient’s bedside. You have to do it at a GMP facility. The challenge that Dendreon had was that they weren’t able to make their product in a way that it could be shipped easily. In other words, it couldn’t be frozen and shipped. We came up with a method that allows us to freeze all of these cells so they can be stored for long periods of time, shipped frozen, and then are available for the patient as needed. We were able to overcome some of these logistical challenges that Dendreon has not been able to overcome yet.
BJ: What are the challenges of the Dendreon approach?
AG: Dendreon had to work with fresh material, both ingoing and outgoing, and that placed severe time constraints on the process. There was one other constraint; because they couldn’t freeze the final product and preserve it, they had to do a manufacturing run essentially for every single dose. You can understand that with an involved process like this, the manufacturing run is where the greatest expense occurs. With our approach, we were able to do a single manufacturing run that produced enough final product to cover the patient’s entire treatment period. We would get fresh material from the patient, and within 48 hours, process it into multiple doses. In phase 2 we were able to produce on average about 28 doses per run. This means that, in a single manufacturing run, we would produce more than enough to treat the patient over a period of years. Dendreon had to do a manufacturing run and shipment for every single dose. That changed the pricing profile.
BJ: Would Dendreon be the principal competitor?
AG: No, their focus is prostate cancer. I don’t know that they’ve had any success with any other tumors. Our approach, we believe, could be extended to any tumor that has unique and identifiable markers. I don’t know enough about where Dendreon is in their development plan, but we expect to tackle multiple targets, that is, multiple tumor types. Our initial trial is with the newly diagnosed Glioblastoma, but we also have a program ready to go in Ovarian cancer. We did not want to be tumor-limited.
BJ: Another approach that is being used that getting a lot of press which is CAR-T therapy. How does that approach compare to CAR-T?
SS: One of the challenges with CAR-T therapy is it seems to work extremely well, in fact it almost works too well in many patients. Patients can get a cytokine release syndrome, and it can be devastating for the patient. We don’t see any of that with dendritic cells. It’s more of a measured approach. You’re not directly supplying T-cells, which are the agents that cause the cytotoxicity; you’re supplying the dendritic cells, which then produce T-cells. Dendritic cells produce T cells at a more measured rate. I think that’s a very important reason why dendritic cells have been safer than CAR-T because you’re impacting the immune system a step prior to when you are going to get the effective cells.
AG: The other thing is, as Steve pointed out, the CAR-T approach has some problems. While they have been shown to be effective, they haven’t been very effective with solid tumors. We think the dendritic cell approach is going to effective with solid tumors.
BJ: What about Checkpoint Inhibitors?
AG: One of the hot topics right now is checkpoint inhibitors. We are beginning to learn a little bit about the safety profile of those too, and, there may be some questions there. Checkpoint inhibitors work by prolonging the immune response. It’s like removing the brakes on a moving car; it keeps things going. But to take full advantage of that, you have to have the car in motion and the ability to steer to begin with. That is what the dendritic cells do: they stimulate and direct the immune response to attack the patient’s tumor. We think there may be real opportunities for this approach in combination with checkpoint inhibitors going forward.
BJ: Can you talk about the safety issues of your approach vs. other approaches?
AG: One of the hallmarks of this approach is safety. We’ve seen no real safety problems. We’ve had over 125 patients treated at this point, and we haven’t seen any sort of a safety problem. The point, I think, is several fold. First, it means that because this approach is safe, it can be combined with other treatment approaches. In the history of effective cancer treatment, it is usually the combination of multiple modalities that is most successful. So, we think this should work well with other modalities and increase efficacy in that way.
BJ: In terms of data and evidence that this works, can you summarize what you have thus far?
AG: The first study done with this approach was a phase one study at Cedars Sinai in Los Angeles around 2008, and now nine years later, six of the sixteen patients that were treated are still living. So, as I told you earlier, the average life span with best standard of care was 14.6 months. These patients are out 9 years.
BJ: What evidence have you seen?
AG: We’ve got several patients from our earlier ICT 107 trials, phase one and phase two, who are still alive after many years. With Glioblastoma, such a devastating disease, the chance for surviving more than a couple years after treatment with dendritic cells is an incredible advance in opportunity for the patients. So we know that this approach works. We have data that show that this works. Yes, we will continue working on the platform to make it better, but again there is tremendous opportunity.
BJ: Are there any disadvantages to dendritic cells?
AG: The one caveat, I would say, about the dendritic cells is that there have been questions about whether or not this is the most efficacious way to do things. I would agree that there are still improvements that need to be made. However, with the data that we have been generating, we’ve shown that dendritic cells do work. We need to get them to work in more patients, clearly. As a field that’s where we’re headed. We’ve certainly been doing research towards that end, trying to make dendritic cells a better option for people. I think that as they stand now, dendritic cells offer tremendous opportunity. Again, the safety profile is incredible, and when the treatment works, it works extremely well.
BJ: You recently stopped clinical programs and terminated your Phase 3 trial. Was it the shareholder lawsuit that was your undoing in terms of continued funding?
AG: Yes, last spring (May 2017) we got hit with shareholder lawsuit problem that was triggered by actions of a previous CEO several years ago, which decreased the market cap of the company by over 70 percent in the first week. So, the ability to raise sufficient funds to keep the program going was lost, and we were forced to stop the trial. We already had about 606 patients on study in the phase 3 trial, and we had to stop it.
Is this patented; are there trade secrets? What is your current IP situation?
AG: I will say that the production of dendritic cells is not a secret; it’s the kind of thing that a skilled graduate student or someone in an academic lab could do. I think what’s unique about our process is the incubation with the peptides, the identification of the peptides, and the process itself. How they are handled, how long are they incubated with the peptides, how they are frozen down. That’s what I would call trade secret. And we do have patents on the product and the process.
BJ: Where are you at now in terms of development, the financing and the upcoming milestones.
AG: As I said we’ve done phase one and phase two with ICT 107 (glioblastoma) Because we were short of money we stopped the phase three program. ICT 121 has completed a phase one study. There are no safety issues there. That’s in recurrent Glioblastoma. ICT-140 is in ovarian cancer. We actually have an FDA approved protocol, but we have not initiated it because of financial constraints. We couldn’t afford to do that trial and the phase three trial simultaneously. So that’s where the three products are.
BJ: Is there anyone out there right now that you would work with?
AG: We are actually doing work now with a group at the university of Maryland, that’s trying to find ways to make dendritic cells more active. In addition to that academic work, we’ve been working with a company, Memgen, that believes that they have a method that will enhance tumor killing in dendritic cell programs. so Memgen might be a partner or perhaps a co-acquisition target. Other than that, we would fit very well with a company that had a checkpoint inhibitor. That would make the most sense
BJ: Could the checkpoint or CAR-T enterprises benefit by your technology?
AG: I think any of the players working with checkpoint inhibitors could work with us. I don’t know whether a combination with CAR-T would be as advantageous. I said earlier, the biggest single factor hindering progress is the cost of manufacturing. If there were a company interested in immunotherapy and it was capable of producing these autologous products, it would bring the cost down considerably. For example, a company like Amgen, that’s used to working with biologics, could make our product quite easily with their existing infrastructure and that would bring the cost of manufacturing and treatment down. The question is, would a company like Amgen be interested in this approach. That would be the third thing I would look at. Who can take this on? A company that has an oncology portfolio of any kind, an immunology portfolio of any kind, could take this on, and through its own internal resources bring down the cost of manufacturing.
PCT worked with us for a long time; they were just acquired by Hitachi. I know Hitachi wants to set up cell therapy manufacturing in Asia. Pharmacell, which is our partner in Europe, also was just acquired by Lonza, the Swiss manufacturing company. So, there is an interest in the cell manufacturing field. We worked with what I thought were the two best companies in the field, and both have been acquired. So maybe a company in China that’s capable of biologic manufacturing would be interested in this.