Chimeric antigen receptor (CAR) T cells have proven to be worthy therapies for blood cancers, but they’re not a quick fix. Patients deemed to need CAR T cell therapy must wait weeks to months for their infusion, mostly owing to the long manufacturing process used to engineer the CAR T cells from the patient’s own T cells.
Zachary Roberts, Head of Research and Development and Chief Medical Officer at Allogene, has been working in the cell therapy space for 10 years.
Credit: Allogene Therapeutics, South San Francisco, CA
To make CAR T cells more readily available to patients with less time to wait, Allogene Therapeutics is one of several companies pioneering off-the-shelf CAR T cell products. Allogene achieves this by starting their manufacturing process with T cells from healthy donors — an allogeneic approach — rather than an autologous approach using the patient’s own cells. Zachary Roberts, Head of Research and Development and Chief Medical Officer at Allogene, said that this strategy allows for an enormous increase in the scale of accessible therapies. “We can make thousands of doses of CAR T cells, store them in a freezer, and then pull them out of the freezer just at the moment the patient needs them,” said Roberts.
He added that with their current manufacturing facility, they can produce between 20,000 to 60,000 doses each year, depending on the product. “We can produce in one year a number of doses that meets or exceeds all the patients treated with autologous products since the dawn of the CAR T era,” he said.
But given that allogeneic CAR T cells do not originate from the patient’s own cells, they’re at risk of being rejected by the patient’s immune system. To find out how Allogene’s products have been faring against this challenge, DDN spoke with Roberts about Allogene’s results so far across their pipeline, which now goes beyond oncology to include autoimmune diseases.
Beyond the quick and accessible nature of an allogeneic approach, what are other advantages as well as disadvantages of using CAR T cells from healthy donors?
By the time a patient has been treated with chemotherapy enough times to be eligible for CAR T cells, their immune cells are no longer normal. They've been beat up by chemotherapy and they’ve lived in a patient who has had cancer for months or years — so asking those cells to suddenly wake up and be healthy enough that, if made into CAR T cells, they are able to eradicate a tumor seems a little bit hard to do. Now, we’ve seen that it still works, but one of the main reasons to shift to an allogeneic setup is that you know what you're getting from young, healthy donors. So that's a very strong rationale on top of the fact that it’s so much easier to scale up production quickly and offer an off-the-shelf treatment to patients immediately.
The drawback is that the immune system is designed to recognize non-native cells as foreign. That's how they recognize the difference between an infectious virus and healthy tissue in our own bodies. So, if you take immune cells from an unrelated donor and you put them into the recipient, the patient’s immune system will reject those incoming CAR T cells. Therefore, the question at Allogene was: Can we create what we call a window of persistence — meaning that the cells can persist long enough in these unrelated recipients — to eradicate tumor cells? The fact that our Phase 1 data has shown consistent efficacy in three different realms of medicine — non-Hodgkin lymphoma, multiple myeloma and solid tumors — including looking at persistence itself, I think we've answered that question definitively as yes, we can do it, but it was very much an open question when the company was started.
What sets you apart from other companies also using an allogeneic approach?
The biggest thing is our experience. We've been at this for a long time, we have the greatest number of patients treated, and we really are leading the field in terms of showing our cells' ability to generate meaningful clinical remissions in oncology that compare well to the established bars set by the autologous programs. We've seen similar efficacy in multiple myeloma, lymphoma, and we have really the best data that's ever been shown in a solid tumor setting with our recent presentation at American Society of Clinical Oncology (ASCO) in our kidney cancer program.
Tell me more about what your recent data showed in kidney cancer.
That product was tested in our TRAVERSE clinical trial, where we manufactured CAR T cells to target CD70 (cluster of differentiation 70). CD70 is an interesting target because it's very highly expressed in clear cell renal cell carcinoma, the most common type of kidney cancer. We presented our Phase 1b update from our ongoing Phase 1 trial of ALLO-316 and the data was very exciting because it showed a 31 percent confirmed response rate in an extremely heavily pretreated group of patients — many of whom had already tried all available therapies for their metastatic kidney cancer. These results were specifically in patients who had a high CD70 expression on their tumor, so they were the ones most likely to respond to a CD70-directed therapy. Of these 16 patients, we saw five confirmed responders, four of whom are still in an ongoing response to the treatment, so they haven't yet experienced a relapse. The patient in the longest standing remission is out past a year now. All of these patients received a single dose of ALLO-316.
In this trial, we're now awaiting a little bit more durability of remission information. We expect to look at this data again later this year to see which of those patients remain in an ongoing remission. We're also communicating with the FDA about potential Phase 2 paths forward to registration, both in the third line setting, which is what we studied in the TRAVERSE trial, but potentially also in an earlier line study. And then we're also looking for opportunities to partner with large pharma to take this program forward into not just Phase 2 in kidney cancer, but potentially additional indications where CD70 is known to be highly expressed.
What have the ALPHA clinical trials that targeted CD19 shown in patients with relapsed/refractory large B-cell lymphoma?
The first and biggest takeaway from the ALPHA and ALPHA2 trials is that we showed efficacy that was comparable to the autologous CAR T cell data, which was one of the big questions in the field. The second key takeaway from that dataset was that the treatment was very well tolerated. And the third and final takeaway from that dataset was that the efficacy outcomes seemed to be better in patients who had low disease burden at the time of treatment. If we look specifically at the groups of patients whose tumor was at a low level when they received treatment, our complete remission rate was 80–100 percent.
The observation that it's relatively safe and it works really well in patients with low disease burden all fed into the design of ALPHA3, which is a novel clinical trial design. What we're doing is using our off-the-shelf CD19 product, and we're giving it to patients in a new and different way that CAR T cells have not been given to patients to date. What makes ALPHA3 different is that we identify patients for treatment based on our ability to detect what's called minimal residual disease, or MRD, in patients who have just completed frontline care for diffuse large-B cell lymphoma (DLBCL). The current standard of care for DLBCL is that everybody gets more or less the same regimen upfront, called R-CHOP. This regimen and a related regimen that incorporates an antibody-drug candidate called polatuzumab, is combined chemotherapy and targeted immunotherapy, and patients who receive these treatments generally do quite well with the majority achieving remission.
The problem is that many of these patients, up to a third of them, will eventually have their disease come back, sometimes called a relapse. So even though they look great at the end of R-CHOP, the performance of our current techniques in assessing disease response to treatment, namely PET and CT scans, is insufficient to accurately predict who will suffer a relapse in the future and who is cured. So instead, we are using an investigational molecular test looking at circulating tumor DNA called Foresight Clarity™. It's developed by our partner, Foresight Diagnostics. This is a blood test that is designed to detect residual disease and predict disease outcomes with much more sensitivity and specificity than PET or CT scans. ALPHA3 is currently enrolling patients who appear to be in remission based on PET and CT scans but have residual disease detected by this ultrasensitive blood test. The goal of ALPHA3 is to show that, by treating patients with allogeneic CAR T cells at the time that their disease burden is at its lowest level, we will be able to prevent ever having the patients experience a disease relapse .
What is novel about your approach to using CAR T cells to treat autoimmune disease?
When we launched this program about a year and a half ago now, we knew that some of the limitations of CAR T cell usage in oncology — such as the need for apheresis, which is the procedure needed to collect enough of a patient’s T cells to start the autologous CAR T manufacturing process, the need for manufacturing itself and the need for significant chemotherapy-based-conditioning, which is commonly given to all patients before they receive CAR T cells — these were all going to be very difficult to overcome in a rheumatology setting. That’s why when we designed our program, we did something unique to combine two CARs — one targeting CD19 and the other targeting CD70 — into a single product.
The reason we did that was because we believe the CD19 product works because it suppresses B cells, and that's where most of the data is already for autoimmune conditions. The inclusion of CD70 gives us two differentiated advantages in this field. First is that CD70, in addition to being expressed on kidney cancer cells and a few other cancer cells, is also expressed on activated T cells, and these activated T cells might actually be playing a pretty critical role in the pathogenesis of these autoimmune disorders. That means we are potentially the only company who has a targeted way of addressing the pathogenic T cells in addition to the B cells in these patients. The other piece we learned from the TRAVERSE trial is that as the recipient’s immune system is trying to reject the allogeneic CAR T cells, as we discussed earlier, those recipient T cells are turning on CD70 expression on their surface. So CD70 gets expressed on their surface, which then allows the CAR T cells to recognize and kill those alloreactive host T cells before they can reject the allogenic CAR T cells. And we've seen in the TRAVERSE trial, these CAR T cells actually are able to divide very robustly in patients and achieve high concentrations that last a long time. We have even seen these CD70 CAR T cells persist in kidney cancer patients without the need for intensive conditioning treatment before the CAR T cells are infused. We call this the Dagger effect and it’s based on our proprietary Dagger® technology.
Coming back to that last hurdle in the autoimmune population, these patients don't want to get a lot of chemotherapy. Our proprietary Dagger® technology is able to potentially reduce the requirement for chemotherapy-based lymphodepletion, and allow us to just give patients CAR T cells to achieve the desired therapeutic effect.
Our investigational product is thus differentiated in three major ways: it’s an off-the-shelf, dual-targeting CAR T product that will target both B and T cells, and potentially will do so with little to no lymphodepletion required. If even two of the three of those things turned out to be effective here, we will have a very differentiated product.
What do you find most exciting about working in this space?
The promise of a single infusion of an off-the-shelf product that could cure patients of their life-threatening disease, both in oncology and in autoimmune settings, is the thing that is most exciting about CAR T cells. This is not chronic therapy, and if you can tailor a product and its characteristics to the specific patient population, whether that's the ALPHA3 MRD-positive patient or the treatment-resistant lupus patient, and arrest their disease progression and put them into remission with a single cell infusion — especially if that can be done with relatively minimal toxicity — that's a game changer.
This interview has been condensed and edited for clarity.
