Off-the-shelf CAR T cells hold ‘huge’ promise for cancer treatment, but more data needed
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Speed matters when it comes to treatment of highly aggressive cancers.
This is especially true with chimeric antigen receptor T-cell therapies, which typically are administered with curative intent to individuals with advanced disease.
All commercially available CAR T-cell therapies are derived from a patient’s own cells, a labor-intensive and time-consuming process. Several studies have demonstrated a link between treatment delays and poorer outcomes.
Long before the first CAR T cell came to market, researchers have been exploring ways to manufacture these therapies faster, primarily with allogeneic approaches that use cells from healthy donors.
The result would be a CAR-T holy grail — an off-the-shelf therapy that could shorten the time between referral and infusion to days rather than weeks, or potentially even longer.
Despite dramatic advances in efficacy and safety of the treatment modality, delays in manufacturing of certain commercially approved autologous CAR T-cell therapies persist, according to Frederick L. Locke, MD, chair of the department of blood and marrow transplant and cellular immunotherapy at Moffitt Cancer Center.
Locke recalled one patient who recently waited more than 60 days to secure a manufacturing slot for CAR-T.
“I was ready to treat this patient, but we were looking at two-and-a-half months [until manufacturing could begin],” recalled Locke, a member of the Healio | Cell Therapy Next Peer Perspective Board. “That is not really a good situation to be in.”
Locke, who is heavily involved in research of allogeneic CAR-T, considers the technology promising.
“The bottom line is that if allogeneic CAR-T proves to be effective and earns FDA approval, then it would be a win for our patients,” Locke said. “If we can prove that these therapies work, then it allows us to treat patients faster.”
Healio spoke with experts in the field of allogeneic CAR T-cell therapy to learn more about the state of the technology, when a true off-the-shelf option might be available in the clinic, and whether shorter time to infusion would have an effect on treatment efficacy or safety.
Avoiding rejection
American Society for Transplantation and Cellular Therapy offered a webinar this fall that provided a comprehensive overview on the state of allogeneic CAR T-cell therapies, including the advantages and disadvantages of this approach compared with autologous options.
Aside from faster time to treatment, benefits of allogeneic CAR-T include the use of healthier donor T cells not exposed to previous toxic therapy, potential for reduced costs and greater control over the manufacturing process, according to speaker Matthew Cooper, PhD, chief scientific officer at Wugen and assistant professor of medicine in the division of bone marrow transplant at Washington University School of Medicine in St. Louis.
Cooper is working on developing next-generation allogeneic CAR-T that overcomes efficacy and safety challenges associated with previous iterations of the adoptive cell therapy.
“As with any drug, CAR-T has its limitations,” Cooper said.
Allogeneic CAR-T must perform as well as autologous therapies in terms of durability and persistence, he added.
“It is becoming clear that allogeneic cell therapies are being limited by rejection,” Cooper said. “Expansion and persistence of adoptive cell therapies are important to achieve both short- and long-term efficacy.”
More than 10 years of follow-up data have shown CAR-T persistence is associated with prolonged remissions, Cooper said.
He pointed to results from one of the first phase 1 allogeneic CAR-T studies examining UCART19 (Servier) for pediatric patients with B-cell acute lymphoblastic leukemia.
UCART19 uses TALEN-based gene editing engineered to delete a T-cell receptor to prevent graft-versus-host disease and CD52 for protection against alemtuzumab (Lemtrada, Sanofi) preconditioning. The construct also included insertion of a CD19-directed CAR.
Investigators reported a response rate of 67%, similar to that observed with comparable autologous CAR T cells. However, the allogeneic CAR T cells could not expand without the addition of alemtuzumab.
“The results highlight the importance of preventing host-mediated rejections to maximize allogeneic CAR-T activity,” Cooper said. “Strategies to mitigate allogeneic rejection are required to realize the full potential of allogeneic CAR T cells.”
Starting on familiar ground
Several allogeneic cell therapy approaches are being evaluated in phase 1 studies.
Some are testing a variety of preconditioning regimens and combination strategies, such as the phase 1/phase 2 ALPHA2 study for large B-cell lymphoma sponsored by Allogene.
Precision Bio is using enhanced lymphodepletion in concert with novel gene-editing techniques to mitigate GVHD, including a phase 1 study of PBCAR0191 for CD19-positive B-cell malignances.
Allogeneic CAR T cells must be equal to or better than their autologous counterparts to achieve any level of success, according to David B. Miklos, MD, PhD, clinical director of cancer cell therapy and professor in the department of medicine at Stanford University.
Allogeneic CAR-T technology must histocompatibility challenges to make an effective and commercially viable product, he said. Further, although allogeneic may be the fastest approach, it may not necessarily be the best, he added.
“We have so few published studies,” Miklos told Healio. “The results so far with allogeneics are fascinating, but companies conducting these trials need to show more data to convince me.”
Thus far, trial sponsors have published partial data sets on their allogeneic trials, and Miklos expressed frustration about the speed with which data from these studies is being released.
“We need to see the full data set,” he said. “Making announcements by press release is no way to advance the field.”
Still, Miklos — an active investigator in at least four clinical trials evaluating allogeneic CAR-T — said he believes in its potential.
“The promise of allogeneic CAR-T is huge,” he said. “I believe in the technology, and I believe that large B-cell lymphoma is the perfect place to test it because we have shown that short-term expression of CAR-T results in high rates of efficacy that persists.”
B-cell maturation antigen (BCMA)-directed multiple myeloma CAR-T also are a good focus for allogeneic therapies, he said. But large B-cell lymphoma appears to be the target of choice because both researchers and commercial sponsors have evidence of the cell therapy’s established track record as treatment for that disease.
Treatment durability through at least 6 months after infusion of CAR-T is the standard that must be achieved, Miklos said. However, follow-up on allogeneic trials exceeding the 6-month period is in short supply.
“If one of these trials can demonstrate efficacy at 6 months with an allogeneic CAR-T that is the same or better than what is seen with autologous ones, then you’ve got my attention and — quite simply — that therapy is ready for FDA approval,” Miklos said.
Locke agreed that large B-cell lymphoma is the likely starting point for development of allogeneic therapies due to the successes established by autologous treatments in this space.
“It’s been shown that CAR T cells are effective for large B-cell lymphoma, and that’s the largest patient population currently receiving CD19-directed CAR T cells,” he said. “Certainly, patients with multiple myeloma are benefiting from autologous BCMA-directed CAR T cells, and there’s data to support that use of allogeneic CAR T cells against either CD19 in lymphoma or BCMA in myeloma can be effective for inducing remissions.”
Safety considerations
Safety concerns related to use of allogeneic CAR T-cell therapy include cytokine release syndrome and neurotoxicity associated with the use of immune effector cells. However, the need for higher-dose or “enhanced” preconditioning has some worried that it could lead to increased infection risk due to prolonged immunosuppression.
“Additional lymphodepletion is likely necessary to achieve expansion of CAR T cells and have a better likelihood of response,” Locke said.
Some commercial-sponsored trials have combined allogeneic CAR-T with monoclonal antibodies rather than additional lymphodepleting chemotherapy, he added
“I don’t know that there’s one sure way to do it, but it does appear that, even with gene editing, allogeneic CAR T cells do not expand as robustly as autologous ones,” he said.
All CAR T-cell therapies carry risk for treatment-related toxicity, Locke said. And it is likely that the additional preconditioning therapy is needed to promote cell engraftment while leaving patients at a higher risk for infection, he added.
“I think that’s balanced out by lower toxicity in terms of cytokine release syndrome and neurotoxicity rates we have seen thus far with allogeneics compared with autologous CAR-T,” Locke said. “Until we do a pivotal trial with a lot of patients in a uniform fashion with the same lymphodepletion regimen and the same dose of CAR-T, it will remain very difficult to know the overall risk profile that allogeneic CAR-T will present in comparison to autologous CAR-T.”
Current chemotherapy-based immunosuppressive preconditioning may not be required for allogeneic cell engraftment, Miklos said. Some allogeneic CAR T cells, he added, already express cytokines, such as interleukin-15, to enhance CAR-T cell expansion without causing immune suppression.
Regardless, the field of cell therapy evolved in such a way that its use of fludarabine and cyclophosphamide to achieve cell engraftment has led to prolonged immunosuppression.
“In my opinion, we resorted to lymphodepletion as the way to create CAR-T expansion, but there should be a way to expand the CAR T cell without causing systemic immune suppression,” he said.
He agreed with Locke that ongoing studies are attempting to work out the best combination of preconditioning and allogeneic CAR-T dose or — in some cases — combination strategies that limit or eliminate preconditioning.
Miklos referred to the ongoing shortage of fludarabine as possibly a serendipitous moment that could point the way toward less toxic preconditioning for allogeneics purely out of necessity.
The shortage has resulted in some clinics turning to alternative agents for preconditioning regimens.
“[Clinics] have had to try other mechanisms to continue offering commercially available CAR-T,” Miklos said.
Some have turned to the use of bendamustine for preconditioning and — anecdotally — the results thus far show less immunosuppressive toxicity, but efficacy will require at least 6 months of clinical follow-up to evaluate. Alternative lymphodepletion regimens may also mitigate T-cell immune suppression as an added benefit, Miklos noted.
Timeline to market
ALLO-501A will be the first allogeneic CAR-T to be evaluated in a pivotal phase 2 study for consideration of commercial approval by the FDA, but there are many other promising allogeneic CAR therapies being developed that vary in lymphodepletion intensity and the type of immune cells used.
Miklos said he’s anxious to see if results show an effective CAR-T that eradicates all of a patient’s lymphoma cancer cells during allogeneic CAR-T peak expansion — the time during which CAR-T exerts its most potent effects at approximately day 14 to day 21 after infusion.
He is less concerned about long-term CAR-T persistence. Limited persistence of allogeneic CAR-T cells is almost a benefit, Miklos said.
“We want allogeneic CAR-T to be limited because if it persists, then we’ve just created an entirely new problem — the patient has an allogeneic lymphocyte causing B-cell aplasia and possible histocompatibility-related cytopenias,” he said. “If the magic is over after day 21, then it should be possible to create anti-tumor benefit with an allogeneic CAR-T that can be monitored to show that CAR T cells are expanding and reducing in number along with a reduction in the patient’s cancer.”
It’s too early to predict how well allogeneic CAR T cells will perform and when they may be ready for commercial use, Locke said. However, the move toward phase 2 studies is “an exciting development” that will answer questions regarding safety and efficacy, he said.
If an allogeneic therapy with acceptable toxicity and durability can be developed, researchers will have achieved a noteworthy success destined to save lives, Locke added.
He said “the data are clear” when it comes to treatment delays using current autologous CAR-T: Long waits lead to worse outcomes.
“The sooner we can get CAR T cells into patients, the better off they will be,” Locke said. “A number of allogeneic CAR T-cell products look really promising and could end up getting FDA approval, building momentum for the idea that allogeneic CAR-T could be a viable treatment strategy.”
Miklos — a self-proclaimed “believer in allogeneic CAR T-cell therapy” — agreed with the wait-and-see approach.
He also professed high expectations for the results.
“Allogeneic CAR-T should be able to create the same complete response rate as autologous CAR-T based on previous results in large B-cell lymphoma,” Miklos said. “And that’s the bar that I will hold it to.”
References:
- American Society for Transplantation and Cellular Therapy. Off the shelf CAR T: a deep dive (webinar). Available at: https://learn.astct.org/products/off-the-shelf-car-t-a-deep-dive#tab-product_tab_overview. Published Oct. 13, 2022. Accessed Nov. 4, 2022.
- Lekakis LJ, et al. Abstract 649. Presented at: ASH Annual Meeting and Exposition; Dec. 11-14, 2021; Atlanta.
- Qasim W, et al. Sci Transl Med. 2017;doi:10.1126/scitranslmed.aaj2013.
For more information:
David B. Miklos, MD, PhD, can be reached at dmiklos@stanford.edu.
Frederick L. Locke, MD, can be reached at frederick.locke@moffitt.org.
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