CAR T-Cell Research Surges

OncologyLive, Vol. 21/No. 21, Volume 21, Issue 21
Pages: 28-31

Hundreds of trials are under way, 3 CAR T-cell therapies for hematologic malignancies are on the market, and 2 new products may receive FDA approval in the next several months, including a BCMA–directed therapy that is poised to help transform treatment of multiple myeloma.

Research on chimeric antigen receptor (CAR) T-cell therapies has exploded since the first such treatment received approval in 2017. Hundreds of trials are under way, 3 therapies for hematologic malignancies are on the market, and 2 new products may receive FDA approval in the next several months, including a BCMA–directed therapy that is poised to help transform treatment of multiple myeloma (MM).

In the near term, the approved therapies will gradually gain more indications and move to earlier treatment stages, experts say. On a parallel track, an off-the-shelf allogeneic product that is less costly and time-consuming to produce could be approved within a few years, greatly expanding the number of patients benefit-ing from CAR T cells. Other new categories of cellular therapies, such as tumor-infiltrating lymphocytes (TILs) that treat solid tumors, are also moving through the development pipeline.

The recent surge in research has been accompanied by a diversification of development and manufacturing pathways for these complex, personalized immunotherapies. Big pharmaceutical companies, start-ups, medical centers, and government labs alike are producing CAR T cells. Decentralized point-of-care processing and improved “cell engineering in a box” technologies may eventually speed up production and bring cellular therapies to more sites closer to patients.

“There’s a lot of innovation happening and a lot investment, and it’s really exciting. Before there were a few labs, and now we have a whole set of industries,” CAR T-cell pioneer Carl H. June, MD, said in an interview with OncologyLive®. A 2015 Giants of Cancer Care® award winner, June is the Richard W. Vague Professor in Immunotherapy in the Department of Pathology and Laboratory Medicine and director of the Parker Institute for Cancer Immunotherapy, both at the University of Pennsylvania in Philadelphia.

The number of clinical trials evaluating CAR T-cell therapies has increased dramatically since 2015, when investigators counted a total of 78 studies registered on the ClinicalTrials.gov website. In June 2020, the site listed 671 trials, comprising 357 registered in China, 256 in the United States, and 58 in other countries (Table).1

Table. A Snapshot of the CAR T-Cell Therapy Landscape

The CD19–Directed Landscape

So far, the FDA has approved 3 CAR T-cell treatments, all directed at CD19. The first was tisagenlecleucel (tisa-cel; Kymriah), initially approved in August 2017 for refractory or relapsed B-cell acute lymphoblastic leuke-mia (R/R ALL) in patients up to 25 years old and later expanded to include adults with R/R large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma (FL). The approvals are based on research June and colleagues conducted.2,3

In October 2017, axicabtagene ciloleu-cel (axi-cel; Yescarta) gained approval for adults with R/R DLBCL, primary mediastinal B-cell lymphoma, and transformed FL. In July 2020, brexucabtagene autoleucel (brexu-cel; Tecartus) joined the roster with an accelerated approval for adults with R/R mantle cell lymphoma; continued approval may be contingent on a confirmatory trial.2

Another CD19-directed therapy for R/R large B-cell lymphoma, lisocabtagene maraleucel (liso-cel; JCAR017), was under FDA review at press time.4 The application is based on the phase 1 TRANSCEND-NHL-001 study (NCT02631044),5 whose results showed an objective response rate (ORR) of 73% (95% CI, 66.8%-78.0%), including a complete response (CR) rate of 53% (95% CI, 46.8%-59.4%) among 256 evaluable patients.6 Median duration of response (DOR) was not reached (NR; 95% CI, 8.6-NR) with 12.0 months of median follow-up. Median progression-free survival was 6.8 months (95% CI, 3.3-14.1), and the median overall survival was 21.1 months (95% CI, 13.3-NR).

Safety analysis showed 79% of patients in the safety population (n = 269) had grade 3 or higher treatment-emergent adverse effects (TEAEs), primarily cytopenias (neutropenia, 60%; anemia, 37%; thrombocytopenia, 27%). Cytokine release syndrome (CRS) and neurological events occurred in 42% and 30% of patients, respectively. These effects included grade 3 or higher CRS in 2% of patients and neurological events in 10%.6

Differences in trial design and patient cohorts make comparisons with other CAR T-cell therapies difficult, but liso-cel appears to have an impressive toxicity profile and good durability, said Andre H. Goy, MD. Goy is physician in chief at Hackensack Meridian Health Oncology Care Transformation Service, chairman and chief physician officer at John Theurer Cancer Center, Lydia Pfund Chair for Lymphoma, academic chairman oncology at Hackensack Meridian School of Medicine at Seton Hall University, and professor of medicine at Georgetown University in Washington, DC.

“Liso-cel’s impact is going to be significant because if it’s confirmed to be less toxic, as it looks like, and assuming there are no issues with the manufacturing process, this could definitely be a competitor. No question about that,” Goy, a leading investigator of brexu-cel7 and other CAR therapies, said in an interview.

Targeting BCMA

Also in late-stage development is idecabtagene vicleucel (ide-cel, bb2121), with an FDA decision expected by March 27, 2021. The biologics license application seeks approval for the BCMA-directed CAR therapy for the treatment of adult patients with MM who have received at least 3 prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody.8

The application is supported by data from the phase 2 KarMMA trial (NCT03361748) in heavily pretreated patients (N = 128) with refractory MM.8 Treatment with ide-cel resulted in an ORR of 73% (95% CI, 65.8%81.1%; P < .0001), meeting the trial’s primary end point, according to findings presented at the 2020 American Society of Clinical Oncology Virtual Scientific Program. The CR/stringent CR rate was 33% (95% CI, 24.7%-40.9%; P < .0001), the median DOR was 10.7 months (95% CI, 9.0-11.3), and median progression-free survival was 8.8 months (95% CI, 5.6-11.6).9

Grade 3 or higher CRS occurred in 5.5% of patients, and 1 death occurred because of a CRS event. Grade 3 neurotoxicity events occurred in 3.1% of patients. No grade 4 or 5 events were reported. Grade 3 or worse CRS or neurotoxicity events were reported in 6% or less of patients at the target dose of 450 x 106 CAR T cells. Any-grade CRS and neurotoxicity events occurred in 84% and 18% of patients, respectively.9

Therapies targeting BCMA are expected to have a significant impact on the treatment landscape in MM. The transmembrane glycoprotein is expressed at high levels on MM cells and on plasma cells but not on other normal tissue, making it a promising target.10 In August 2020, the FDA approved the first therapy targeting BCMA, the antibody-drug conjugate belantamab mafodotin-blmf (Blenrep), for patients with R/R MM who have received at least 4 prior therapies.2

Approval of ide-cel or another similar CAR T-cell therapy would be a “huge event” because it would fulfill a major unmet medical need and show that CARs work with targets other than CD19, according to June. “What the field definitely needs is curative therapy so patients aren’t on chronic treatment. It’s really exciting that that’s going to happen,” he said.

June added that he anticipates many trials will look at whether CAR treatments could replace stem cell transplants for patients with MM and, eventually, whether CARs can be used as frontline therapy for the disease.

Pending Studies

Studies are already under way on using other CARs earlier in treatment paradigms. The phase 3 ZUMA-7 trial (NCT03391466) is evaluating axi-cel versus standard-of-care secondline therapy for patients with R/R DLBCL, and the phase 2 ZUMA-12 trial (NCT03761056) is studying the therapy as a frontline treatment for high-risk large B-cell lymphoma. The phase 2 TRANSCEND-PILOT-017006 trial (NCT03483103) is testing liso-cel as a second-line therapy for patients with aggressive B-cell non-Hodgkin lymphoma (NHL) who are ineligible for stem cell transplant. “A lot of studies are investigating the best timing for CAR T,” Goy said. “We’re looking at shifting [CARs] to a better, earlier use because we know that although patients respond even if they have failed multiple lines of therapy, if they have [a large burden of] disease and are kind of beat up by the prior treatment or lymphoma, they don’t do as well.”

Renier J. Brentjens, MD, PhD, a leading CAR T-cell investigator, also sees opportunities to move the therapies forward. “In the arena of, for example, DLBCL, where there are a significant number of durable remissions, I would not be surprised if [a CAR T-cell therapy] becomes kind of a second-line drug as opposed to the drug of last resort,” said Brentjens, director of the Cellular Therapeutics Center at Memorial Sloan Kettering Cancer Center in New York, New York.

Investigators are also conducting trials of CD19-directed CAR T-cell therapies against new indications, such as B-cell ALL in adults and low-grade lymphomas such as FLs and chronic lymphocytic lymphoma. Kite Pharma has filed a supplemental biologics license application with the FDA to expand axi-cel’s indications by adding R/R FL and marginal zone lymphoma following 2 or more systemic therapies, based on data from the phase 2 ZUMA-5 trial (NCT03105336).11 Investigators are also studying existing CARs in combination with checkpoint inhibitors and other immunotherapy drugs.

Beyond liso-cel and ide-cel, dozens of enhanced CARs directed at CD19 and BCMA have shown promise and a few could be commercialized within 2 or 3 years. One is JNJ-4528, which is directed against 2 distinct BCMA epitopes. It was originally developed in China (where it is called ciltacabtagene autoleucel) and is now being developed through a collaboration between Legend Biotech and Janssen Biotech. The agent has shown positive results for patients with R/R MM in phase 1 and 2 trials and been granted breakthrough therapy designation in the United States and China, as well as PRIME status from the European Medicines Agency.12

A number of novel CARs with different targets and formulations are in trials, but when they might become widely available is unclear. These include innovations such as bispecific or dual CAR T-cell therapies targeting CD19-CD22 or BCMA-CD3, “armored CARs” that secrete cytokines, and CARs aimed at solid tumors.

The next major CAR development may instead be an allogeneic, off-the-shelf product that uses donor T cells.

Goy said allogeneic products are among the most promising of the next wave of CAR treatments. “They’re off-the-shelf by definition, and very fit T cells. It’s very early but so far the responses have been very impressive, based on small numbers of patients, and not very toxic. That will be potentially very important,” he said.

June called an allogeneic CAR a potential “game changer” because it can be manufactured in large batches and delivered to patients anywhere for immediate infusion, at a significantly lower cost than that of current CAR therapies. He said these therapies could arrive in as soon as 3 years.

“Once allogeneic cell [therapies] come out, they’ll be everywhere and have much deeper penetration into smaller centers, more rural areas where people have no access to CAR T cells right now. All the small practices can just order them. That will be the tipping point. Right now it will stay at the major centers for these autologous cells,” June said.

Among the more advanced allogeneic therapies are UCART19 and ALLO-501, anti-CD19 CARs that Allogene and partner firms are developing. The 2 agents are structurally identical but use different manufacturing processes and are paired with different lymphodepletion regimens.13

In pooled data from 2 phase 1 studies (CALM; NCT02746952 and PALL; NCT02808442), 82% (14 of 17) of patients with R/R B-ALL who received UCART19 and a lymphodepletion regimen containing fludarabine, cyclophosphamide, and alemtuzumab achieved CR or CR with incomplete hematologic recovery.14

In the phase 1ALPHA study (NCT03939026), ALLO-501 was administered after a lymphodepletion regimen of fludarabine, cyclophosphamide, and anti-CD52 the monoclonal antibody ALLO-647 to patients with previously treated R/R large B-cell lymphoma or FL. The ORR was 63% (95% CI, 38%-84%), including a CR of 37% (95% CI, 16%-62%) in 19 evaluable patients.15

The companies developing UCART19/ ALLO-501 have several allogeneic candidates, including an anti-BCMA MM therapy (ALLO-715). Meanwhile, Cellectis is trialing UCART123, a CD123-targeted therapy for R/R acute myeloid leukemia, in the phase 1 AMELI-01 study (NCT03190278).

Other allogeneic CAR T-cell therapies in trials include 3 from Precision BioSciences: a CD19-directed product (PBCAR0191) being studied for no-Hodgkin lymphoma (NHL) and ALL; a CD20-targeted therapy (PBCAR20A) for NHL, chronic lymphocytic leukemia, and small lymphocytic lymphoma; and an anti-BCMA therapy for MM (PBCAR269A).16 Caribou Biosciences’ CB-010, an anti-CD19 therapy for R/R B-cell NHL, is slated to launch the phase 1 ANTLER trial soon.17

Off-the-shelf CAR therapies will eventually coexist with the personalized autologous therapies, predicted Jason Bock, PhD, vice president of the Therapeutics Discovery division and head of biologics product development at The University of Texas MD Anderson Cancer Center in Houston. “It will be dramatically more accessible, dramatically less costly, and probably a little bit less efficacious. There will be a lot of investment in technology to figure out how to try to bridge that gap. What you’ll lose in terms of pure potency, you’ll probably gain in terms of consistency,” he said.

Bock and others said they look forward to someday seeing CARs for solid tumors, but investigators face several biological hurdles, and marketable products are at least 5 years away. However, other types of adoptive cell therapies for solid tumors will likely become available much sooner. Iovance Biotherapeutics expects to file an application during 2021 for lifileucel, a TIL therapy for metastatic melanoma that is also being studied in cervical cancer.18

As development of CARs and related therapies has mushroomed, research and manufacturing have moved from a small number of academic-industry partnerships into a variety of venues. Commercial T-cell products are manufactured at large pharmaceutical company hubs, and therapies for trials are being produced at those sites, at specialized contract labs, and at several major medical centers, such as Memorial Sloan Kettering, Dana-Farber Cancer Institute, MD Anderson, Stanford Medicine, and Moffitt Cancer Center.

Bock said MD Anderson recently added to its production capacity by purchasing a 60,000-square-ft cellular therapy manufacturing facility at Texas Medical Center in Houston. It will allow the organization to move therapies from the lab to the clinic quickly while assuring full access to data and firm control of the manufacturing process, which can significantly affect the quality of the product, he said.

“We wanted to be able to produce the product in such a way that if we had breakthrough products, and we didn’t have time to tech-transfer to a commercial facility, we wouldn’t have a delay in getting that product to patients. This facility can act as a launch facility,” Bock said in an interview. The facility could also potentially supply some niche products on an ongoing basis, such as a future cellular therapy for a rare tumor, he added.

Some physicians and patient advocates have argued that CAR T-cell products should be made at medical centers across the country rather than by industry because the centers can deliver the cells more quickly to their critically ill patients and at lower cost.19 Bock said he does not expect that to happen because of the complexity and tight federal regulation of cellular manufacturing processes. MD Anderson’s new facility will not be used for long-term manufacturing of commercialized CAR products, which is better left to pharmaceutical companies that are experts in large-scale production, distribution, and marketing, he said.

However, Bock and others said they can envision a time when fully enclosed, automated “cell engineering in a box” systems are perfected and installed at medical centers, allowing point-of-care CAR T-cell production. Technicians would essentially insert patient cells, viral vectors, and other supplies in one end and wait for a bag of engineered cells to come out the other for infusion. Investigators have experimented with such systems, using the Miltenyi CliniMACS Prodigy device to produce CAR T-cells and treating patients with hematological malignancies.20,21

Brentjens said there may not yet be enough published data to conclude that automated systems are feasible, and he does not know what training would be required of hospital staff. He also noted that the hospital would still have to purchase viral vectors from a pharmaceutical company to make the process work.

“It’s like cake mix. You can either buy a fully made cake, or in that paradigm you’re buying the cake mix and you’re cooking up the cake yourself,” he said. “But obviously, the cake mix costs a lot less than the cake.”

References

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  9. Munshi NC, Anderson LD, Shah N, et al; KarMMa Study Investigators. Idecabtagene vicleucel (ide-cel; bb2121), a BCMA-targeted CAR T-cell therapy, in patients with relapsed and refractory multiple myeloma (RRMM): Initial KarMMa results. J Clin Oncol. 2020;38(suppl 15):8503. doi:10.1200/JCO.2020.38.15_suppl.8503
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