Allogene's Mission To Democratize CAR-T
By Tyler Menichiello, contributing editor
Plenty of companies are coming up with innovative solutions to address the issues of cost and accessibility for CAR-T therapy (with some going so far as to cut out the manufacturing process entirely). However, I often find that the conversation around cost and accessibility can turn into a debate between autologous and allogeneic CAR-T.
While all currently approved CAR-T products are autologous, there is growing interest in the allogeneic approach. The allogeneic, off-the-shelf model offers the potential to both reduce treatment wait times and expand CAR-T availability to treat more patients. Some also argue that sourcing cells from healthy donors provides healthier starting material than using a sick patient’s own cells.
One company that’s working to bring allogeneic CAR-T to patients is Allogene Therapeutics. I had the chance to speak with CEO and co-founder, David Chang, MD, Ph.D., about the challenges facing allogeneic CAR-T, as well as its potential to “democratize cell therapy.”
Scalable Manufacturing For Off-The-Shelf CAR-T
After all, a highly effective (potentially curative) cell therapy means very little if it can’t help patients in need. Currently approved autologous CAR-T products are restricted by a bespoke manufacturing process that not only delays treatment, but limits manufacturing capacity. Today, only about 20% of eligible patients receive CAR-T treatment. To truly democratize CAR-T, Chang says, the therapy needs to be readily available to patients, kept in stock like any other drug.
That’s the future allogeneic CAR-T developers dream about, and it’s not too far from becoming a reality.
The allogeneic model is centered around bulk manufacturing — shifting away from the bespoke, autologous model to one that’s significantly more scalable. This gets the product to patients faster without being delayed by the manufacturing process. It’s also beneficial for patients who may not have otherwise had any viable T cells to make an autologous product.
But exactly how scalable are we talking? From a single healthy donor’s peripheral blood mononuclear cells (PBMCs), Allogene can provide enough product to treat more than 100 patients, Chang says. This kind of scalability makes it possible to build an inventory of CAR-T products that are ready whenever patients need them. It can also help meet the demand of moving the modality into broader indications — e.g. for autoimmune diseases, which Allogene is preparing to study in the near future.
Editor’s Note: If you’re interested in hearing more about the company’s scalable approach to CAR-T, I highly recommend checking out this episode of the Cell & Gene podcast featuring Allogene’s CMO and EVP of R&D, Zachary Roberts, MD, Ph.D.
Meeting Challenges With Innovation
One historical challenge often associated with allogeneic CAR-T is graft-versus-host disease (GVHD), but that issue has more-or-less been taken care of by editing out T-cell receptors, Chang tells me.
“The allogeneic CAR T cells cannot go after targets other than the one that’s directed by the chimeric antigen receptor,” he says. The downside of that, however, is that the patient’s immune system may recognize the allogeneic cells as foreign and reject them.
“How to make sure cells can persist long enough to accomplish what they need to do is where a lot of the science and innovation is focused,” he says.
Allogene is working on two different approaches to overcome this problem. The first utilizes a proprietary anti-CD52 antibody, which Chang says has been shown to support CAR-T efficacy and demonstrate a similar response rate and durability to autologous CAR-Ts. The other utilizes the company’s “Dagger” technology to selectively kill the part of a patient’s immune system that would reject the CAR T cells.
“It’s a very targeted way of controlling the immune response of the patients,” Chang explains. So far, the data has shown that this approach allows the allogeneic CAR T cells to expand at a level that is possibly better than autologous CAR T cells.
Aside from controlling the rejection of allogeneic CAR T cells, the other area of innovation is focused on finding ways to make allogeneic CAR-Ts more potent. Theoretically, if developers can increase the potency of these cells, then the required dose decreases, meaning even more patients can be treated from a single manufacturing run.
Opportunities To Reduce Treatment Costs
Price is a common talking point for cell therapies, especially with CAR-T. However, according to Chang, we should consider these treatment costs with some perspective.
“The one-time aspect makes the pricing look so high, but when you look at a one-time treatment versus something where you require chronic treatment for 12 or 18 months, the numbers do not look that bad,” he says.
That doesn’t mean the industry should ignore opportunities to reduce the cost. One way to do so, he says, is by reducing the ancillary cost of treatment. A substantial portion of autologous CAR-T comes from pretreatment costs (e.g., leukapheresis and hospitalization), which are avoidable with allogeneic CAR-T.
Improving the safety of these products is another way the industry is trying to reduce costs, according to Chang. With improved safety, a patient could theoretically receive an allogeneic CAR T cell infusion as an outpatient procedure to avoid an expensive hospital stay.
Combining Diagnostics With Effective Therapy
If you ask Chang, the question isn’t about whether allogeneic CAR-T will replace autologous CAR-T, but rather which one will hold a majority share of the space.
“If allogeneic can do the same thing that autologous can do but more effectively and in a more scalable way, I think there will eventually be more use of allogeneic than autologous,” he says.
One way to increase share in the market is to simply treat more patients, which is exactly what Allogene is aiming to do with its ALPHA3 study. This study involves using a molecular minimum residual disease (MRD; Foresight Diagnostics) assay to identify the 30% of first-line large B-cell lymphoma (LBCL) patients at risk of relapsing after receiving standard R-CHOP chemotherapy or another standard regimen. Not only does this approach stand to improve the overall cure rate of patients with LBCL, but it marks a significant step forward for the industry by using CAR-T as a frontline treatment (it is traditionally given to patients who have already relapsed). If shown to be successful, this will likely expand CAR-T into greater patient populations.
Wherever you stand on the autologous versus allogeneic CAR-T debate, I think we can all agree: Treating patients sooner and preventing their risk of relapse is a win for the entire industry. Hopefully, companies like Allogene will continue working to bring allogeneic CAR-T therapies to market and usher in a future where cell therapies are widely available and truly democratized.