Commercial Off-the-Shelf CAR-T Still Years Away from the Clinic
A survey by market research firm InCrowd revealed that hematologists and oncologists considered chimeric antigen receptor T-cell therapies the most exciting new development in cancer treatment.
Sixty-five percent of respondents expressed the most excitement for autologous CAR T-cell therapies, whereas 60% viewed allogeneic, also known as “off-the-shelf,” CAR T-cell therapies as having the same level of promise.
Although these therapies generated similar levels of excitement among clinicians, fewer than half of respondents (45%) indicated they were very or extremely familiar with allogeneic CAR T-cell therapies, compared with 65% who reported that degree of familiarity with autologous CAR T-cell therapies.
The survey results may come as no surprise; so far, the FDA has approved only autologous CAR T-cell therapies. Nevertheless, there is accumulating research into off-the-shelf CAR T-cell therapy as a potentially more accessible and cost-effective alternative to the time-consuming, personally engineered process required by autologous therapies.
Cell Therapy Next interviewed experts with different perspectives on the development of off-the-shelf CAR T-cell therapies to discuss the latest research efforts and the anticipated arrival of these therapies for clinical practice.
Allo vs. Auto
Current FDA-approved CAR T-cell therapies, including tisagenlecleucel (Kymriah, Novartis) and axicabtagene ciloleucel (Yescarta; Kite, Gilead), are considered second-generation therapies. Research into third-generation CAR T-cell therapies includes development of molecules with multiple costimulatory domains to reduce toxicities, those that target multiple antigens to enhance efficacy, and allogeneic CAR-Ts that help bypass the personalized manufacturing process of autologous CAR T-cell therapy.
The Leukemia & Lymphoma Society is among the organizations the provide grants to investigators in the CAR T-cell therapy field, and it has been engaged in funding CAR-T research since the beginning, according to Gwen L. Nichols, MD, the organization’s chief medical officer. LLS has also supported CAR T-cell therapy research through its Therapy Acceleration Program, partnering directly with biotechnology company Kite Pharma. The rough funding total is in the $40 million range, Nichols told Cell Therapy Next. Many of the society’s latest CAR-T grants have been awarded for research into off-the-shelf therapies (see box).
“We supported the initial investments in CAR-T and now we’re looking at a variety of ways to make it applicable to more patients, safer, less expensive and less cumbersome,” she said.
Nichols asserted that the only way to make CAR T-cell therapy more cost effective is to make the entire process less cumbersome. An easier treatment process will lead to more effective options, and more options will lower prices, she said.
The Leukemia & Lymphoma Society gave out its first grants for CAR T-cell research in 1998, and it took nearly 2 decades for an FDA-approved product to be developed. Now that the technology has proved to be effective, the question is, how long will current research efforts take to refine the treatment and deliver it faster and cheaper?
A Work in Progress
Stephan A. Grupp, MD, PhD, director of the cancer immunotherapy program at Children’s Hospital of Philadelphia, is one of the pioneers of CAR T-cell therapy and was among the first to test it in a pediatric clinical setting. He co-authored a review published in Nature Reviews Drug Discovery on the current state of off-the-shelf therapies and the challenges of their development.
“The technology is in its infancy,” Grupp told Cell Therapy Next, adding that although patients have been successfully treated with allogeneic cell therapies in clinical trials, the number of patients who have been treated is relatively small. Meanwhile, many companies are jockeying to develop off-the-shelf therapies.
“They’re all looking at the same general technology, and even companies that have had the most experience in the area are still fairly limited,” Grupp said. “There’s a lot to learn at this stage of the game. We’re just learning the rules about how you develop these cells and trying to get a sense for how well they work.”
Grupp said allogeneic cell therapies appear to be effective in certain settings, but efficacy data are very limited. Furthermore, it remains unclear how long the therapies will last within the body, which is another aspect of ongoing investigation for both autologous and allogeneic cell therapies.
Despite the many allogeneic products being tested in academic and trial settings, Nichols agreed with Grupp’s timeline for the development of commercially viable treatments.
“The first steps are underway,” she said, “but I think we are a long way from a standardized cellular product.”
Nirav N. Shah, MD, assistant professor of hematology and medical oncology at Medical College of Wisconsin, has a wealth of experience in the field of CAR-T and cellular therapies. From a clinician’s perspective, Shah said he is excited about the tremendous potential of allogeneic cell therapies, but he believes FDA-approved products are not on the immediate horizon.
“We’re at least 5 years away from any sort of marketed therapy where we are able to order a drug and get it delivered,” he told Cell Therapy Next.
Although there are many potential advantages to allogeneic CAR T-cell therapy, Shah noted that any new off-the-shelf therapies would need to meet the current safety and efficacy standards of autologous CARs, and being just as good in this case may be good enough to receive FDA approval.
“We now have a standard, and the standard is autologous CAR,” Shah said, adding that allogeneic CARs will need to demonstrate equivalent or better efficacy and safety in large clinical trials.
“Those sorts of trials can take years before they can be developed,” Shah said.
Getting On the Shelf
Developing a clinically effective off-the-shelf cell therapy for cancer involves surpassing the standard set by currently available autologous therapies. Key to assessing new therapies will be the toxicity profile, which may differ for a treatment derived from donor cells. The barriers to overcome include those common to transplant situations.
“Whenever we give allogeneic products, we worry that [the donor’s] immune system could interact poorly with the recipient’s immune system and lead to a different side effect profile than we’re used to seeing with autologous CAR T cells,” Shah said.
The primary concern is graft-versus-host disease.
This concern stems from years of performing allogeneic stem cell transplants, which Shah describes as intense procedures that can be curative for certain types of hematologic malignancies. With this risk in mind, many novel allogeneic CARs are being designed specifically to avoid the severe effects of graft-versus-host disease, he added.
“But until there are enough patients treated, we won’t be able to truly understand the risk profile of this new way of delivering this drug,” Shah said.
Nichols highlighted the potential pitfalls of tradeoffs to avoid possible adverse immune system responses with allogeneic cell therapies. These include making use of other, less allo-reactive immune system cells, like natural killer cells. The challenge is knowing how to modify these cells so that they appropriately target cancer cells the way autologous modified CAR T cells do.
“There’s still an awful lot to understand about individual responses and how well an allogeneic product might work as opposed to an autologous product,” Nichols said.
Grupp is currently working on trials to investigate allogeneic cell therapies, and he confirmed that the process of translating them into human treatments is well underway, albeit in its early stages.
“We’re over the bar of determining whether it works at all — we know that it does,” Grupp said.
Nevertheless, he echoed the sentiments of Shah, and said that being clinically effective against a disease is not good enough in this case; off-the-shelf therapies will need to be equally or more effective than autologous CAR T-cell therapies to achieve approval and widespread use.
“Does it have to be exactly the same? No, it probably doesn’t. But it must be similar and there needs to be some prospect for this to be not just a short-term therapy, but to have some longer-term potential for disease control,” Grupp said.
This all needs to be determined through longer-term follow up in a greater number of patients, according to Grupp.
Considering the Benefits
In addition to treating previously untreatable cancers, the goal of off-the-shelf therapies is to improve on the current generation of engineered cell therapies by cutting down manufacturing time and making the products more effective against a broader range of cancer types. A less complex manufacturing process coupled with greater availability should bring down the price of what is currently an extremely costly treatment, according to Shah.
“For an allogeneic product to be approved, the bar is going to be high from a safety and efficacy standpoint,” he said.
If any of the allogeneic products in development achieve similar efficacy to autologous cell therapies, Grupp envisions off-the-shelf as having immediate cost and accessibility benefits. It also could give rise to the field of multiplex gene editing of CAR T cells.
“This is really opening the door to multiplex gene editing, and that has enormous potential,” he said.
Grupp explained that allogeneic CAR T cells have more than one genetic manipulation, and he predicted that we will see more multiplex gene editing over the next 3 to 4 years. “Multiplex gene editing is extremely exciting and way more feasible in the allogeneic CAR-T world than the in the autologous CAR-T world,” he added.
Nichols pointed to perhaps a more critical benefit from the perspective of patient care. Often a patient’s disease will progress while waiting for autologous CAR T cells to be manufactured, to such a point that they are no longer eligible for the therapy or the therapy would be likely ineffective given the late-stage disease burden. In other cases, engineering delays have postponed the start of treatment. These scenarios would be avoidable if clinically effective off-the-shelf therapies were available at the clinic or could be delivered within a few days.
“We’ve seen it firsthand at the [Leukemia & Lymphoma Society], and we get a lot of calls about concerns from patients not being able to wait the time required,” Nichols said.
Are We There Yet?
Off-the-shelf cell therapies have the potential to transform cancer therapy much as the current generation of CAR T-cell therapy has, and immune checkpoint inhibitors before it.
“This is a very exciting area of research and it could transform immune therapy, if successful, because it would change how we deliver these products from a time and cost standpoint,” Shah said.
The ability to order up a cell therapy like with conventional drugs, rather than having to endure a single-patient manufacturing process, could be a game changer for the field.
“All of these new things are coming through the pipeline, and with larger numbers of patients being treated with these newer technologies in clinical trials, we’ll get a better sense of whether or not this is an effective strategy,” Shah said. “At the very least, this could be an effective strategy for those patients for whom we’re not able to make CAR T cells.”
Grupp warned that enthusiasm for the possibilities of off-the-shelf cell therapy should be tempered by the volume of work that’s yet to be done in this area.
“I think that we’re just at the beginning — it’s really important to understand that,” Grupp said.
Access to off-the-shelf therapies is limited to clinical trials and none currently being tested is close to FDA approval, he added.
“This isn’t going to be part of a clinician’s armamentarium outside of a clinical trial for some period of time,” Grupp said. “The goal is to have an FDA-approved product ... but we are not there yet.” – by Drew Amorosi
- Depil S, et al. Nat Rev Drug Discov. 2020;doi.org:10.1038/s41573-019-0051-2.
- InCrowd Inc. New and Emerging Trends in Cancer Treatment: CAR-T. Sept. 9, 2019.
- For more information:
- Stephan A. Grupp, MD, PhD, can be reached at email@example.com.
- Gwen L. Nichols, MD, can be reached at 161 Fort Washington Ave., New York, NY 10032.
- Nirav N. Shah, MD, can be reached at firstname.lastname@example.org.
Disclosures: Grupp reports research and/or clinical trial funding from Kite, Novartis and Servier and consultant/scientific advisory board roles with Adaptimmune, Cellectis, Cure Genetics, Eureka, GlaxoSmithKline, Humanigen, Juno, Novartis, Roche, TCR2 and Vertex. Shah reports research support from Multani Biotech and advisory board roles with Celgene/Juno and Kite/Gilead. Nichols reports no relevant financial disclosures.