The Pulse sat down with Dr. Eric Schmidt, the CFO of Allogene Therapeutics, to learn about the cutting edge of CAR-T (chimeric antigen receptor T cell) therapies. CAR-T immunotherapies work by modifying T cells, a natural part of the body’s immune system, to recognize cancer cells and destroy them. Previously this was done autologously, where cells are taken from the patient, modified, then introduced back into the patient. Allogene is pioneering allogeneic CAR-T cells, where cells are instead sourced from healthy donors.

Dr. Eric Schmidt, CEO of Allogene Therapeutics

The Pulse: What is the current standard of care in CAR-T (chimeric antigen receptor T cell) therapy?

Eric Schmidt: The first generation of autologous CAR-T therapies have been truly revolutionary for patients with non-hodgkin lymphoma and acute lymphoblastic leukemia, two types of blood cancer. They have provided patients with a grim prognosis a real chance at a long-term favorable outcome. That is a tremendous advance in oncology, and you can’t overstate the benefit these cell therapies have brought.

These existing therapies use autologous CAR-T technology, not allogeneic. One major drawback of autologous techniques that many patients don’t have the time to wait for their own cells to be engineered, produced, and released before their cancers progress. In clinical trials for Yescarta and Kymriah, between 10-30% of patients were unable to get their cells back in time to receive treatment. The inability to treat all patients is a real shortcoming of the current treatment paradigm that we’re hoping to remedy.

The Pulse: Can you describe what advantages Allogene’s allogeneic CAR-T cells have over autologous CAR-T cells?

Eric Schmidt: Allogene is looking to build upon the foundational advances of first-generation CAR-T therapies by making them more convenient, accessible, and at a lower cost of production. Our goal is to enable many more patients to get treated with this transformative therapeutic modality.

We source allogeneic cells from healthy donors, engineer them to be used in any eligible cancer patient, and create an inventory of product that can be shipped upon demand. Because we’re able to dissociate the production process from the treatment process and manufacture allogeneic or “off-the-shelf” cells well in advance of patients being in need, we could in theory deliver those cells within days – not weeks or months – and provide cells to a broader population of patients, including those who just don’t have time to wait.

Another major advantage is the scale of production. At Allogene, a single manufacturing run produces enough cells to treat approximately one hundred patients. While each run is more expensive to manufacture than a run of autologous cells, we think we can operate at a much lower unit cost of production.

In addition, because we source our cells from healthy donors and not from elderly cancer patients who may have experienced repetitive cycles of chemotherapy, our cell starting material could potentially be of higher quality with less patient-to-patient variability. In theory, a more standardized cell starting-material be associated could potentially be associated with improved quality and function.

The Pulse: How will allogeneic CAR-T cells differ from autologous CAR-T cells in distribution and access?

Eric Schmidt: In order for cell therapy to reach a broader population, we need to create a supply chain that is more similar to the standard pharmaceutical delivery model. The current situation where an autologous therapy is custom-made for one specific patient presents all kinds of complexity and logistical bottlenecks for the health care system. If we can make a product that is more universally applicable, we can inventory those cells, ship them on demand, and use pharmaceutical channels that exist within the healthcare system. In part, I believe the adoption of autologous CAR-T therapies has been slowed by the need to create a new delivery channel that requires a unique chain of custody for each individual patient.

The Pulse: What types of cancer is Allogene looking to treat and why? Might it look to treat other diseases in the future?

Eric Schmidt: The majority of our efforts are focused on using allogeneic CAR-T therapy for cancer, specifically hematalogic malignancies. Blood cancers including lymphoma, leukemia and myeloma are good opportunities for Allogene because they’ve been de-risked in the autologous situation and because we know they express certain targets that can safely be addressed with very potent cell therapies. We are taking on some platform risk in moving from autologous to allogeneic therapy, so we don’t want to add additional biologic risk for the time being.

Next year we may expand into solid tumors and over time, we may choose to expand beyond oncology, perhaps into immunological diseases.

The Pulse: How do you approach manufacturing and quality control for this next-generation therapy?

Eric Schmidt: Great question. Manufacturing is extremely important in a complex and highly innovative field like gene or cell therapy. We are looking at bringing manufacturing in house and have assembled a large and experienced team focused on technical operations. Almost half of our workforce and half our spending is dedicated to the production of our cell therapies. At the end of the day, our cells are our products and if we don’t have the highest quality, most finely engineered cells, then we won’t have products with the best chances of succeeding in the clinic or commercially.

Today we’ve created a production process that we are deploying it at third party contract manufacturing organization. Simultaneously, we’re building our own large-scale manufacturing footprint in Newark, California, close enough to our headquarters to make sure we have free flowing tech transfer and ideas between research and manufacturing. We expect to be able to make GMP-grade material at our new facility in 2021. The end goal is to do all our manufacturing in-house and have capacity to commercialize multiple cell therapy products.

The Pulse: Since this therapy needs to be administered by a medical professional, how do you think about ensuring access across wide geographies?

Eric Schmidt: Everyone is hoping to eventually get to a point where these therapies are delivered in an outpatient setting. It may take more engineering and innovation, but that would be the holy grail – to truly have a cell therapy that could be not only delivered off-the-shelf, but in a setting where less medical support is required. I’m pretty optimistic that an allogeneic platform can eventually get us there. Because allogeneic cells can be made at scale, companies like Allogene can contemplate making additional gene edits to further increase the potency and improve the safety of CAR-T therapy. Additional gene engineering steps are likely to be cost-prohibitive in the autologous realm, so an allogeneic platform could be critical to bringing cell therapies to that next level.

The Pulse: In terms of long-term patient follow-up, is your team thinking about ways to address the fact that some patients who enter remission after CAR-T therapy eventually relapse or again? Is there potential for boosters or re-treatments?

Eric Schmidt: Our current Phase I protocol in lymphoma allows for some re-treatment, so we intend to get a sense of how that might be best integrated into the treatment paradigm. Again, this is something that should be more easily achieved with allogeneic therapy than autologous therapy. In fact, there’s even some proof of concept that this is feasible: in studies conducted by our partner Servier with UCART 19 in leukemia, three patients were re-treated upon disease progression and two of those three responded to a second course of therapy.

The Pulse: How do you think about pricing and reimbursement in a relatively new field with few benchmarks?

Eric Schmidt: Being a next generation player with allogeneic therapies, we have the benefit of watching as autologous players advance the field of cell therapy. Hopefully autologous therapies will overcome some of the anticipated hurdles, including reimbursement and physician education. I do think the reimbursement landscape, which is still being worked out for Yescarta and Kymriah, will be more standardized in the future. First generation autologous players are also doing the heavy lifting in growing health care provider familiarity with these very potent therapies. Hopefully by the time Allogene is in position to launch an allogeneic CAR-T therapy the wheels will have been greased a bit.

In terms of CAR-T pricing, the cost of therapy of Yescarta and Kymriah has generated a lot of headlines. I actually think the price of these first-generation drugs are a good deal for society relative to other cancer therapies. This is because CAR-T is a one and done therapy with the potential to induce dramatic, long-term medical benefit. Compared to other expensive cancer drugs that are used chronically, the system can receive meaningful value from a one-time transformative therapy.

The Pulse: What trends do you think the future of CAR-T and immunotherapy holds?

Eric Schmidt: Right now we’re focusing on oncology because we need to get our first few products over the goal line, but cell therapy is a new therapeutic modality that could potentially be deployed in an expansive array of medical indications. It’s a unique modality, unlike small molecules, biologics, or even gene therapy. Via gene editing and gene insertion technologies, living cells can be programmed to exhibit almost any desired biologic activity. So I’m pretty optimistic that in 10-15 years, because of advances in cell therapy, we’ll see big transformations in many other diseases beyond cancer.

Interviewed by Michele Dragoescu, December 2019