Immuno-Oncology Resource Center

Immuno-Oncology Resource Center

Source:

Tasian SK. Traveling along the bench-to-bedside road of AML CAR T-cell immunotherapy. Presented at: Personalizing Pediatric Cancer Care Summit; March 10-11, 2022; Philadelphia.

Disclosures: Tasian reports advisory board roles with or research funding from Aleta Biotherapeutics, Gilead Sciences, Incyte and Kura Oncology.
March 25, 2022
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Next breakthrough for CAR T cells may come in acute myeloid leukemia

Source:

Tasian SK. Traveling along the bench-to-bedside road of AML CAR T-cell immunotherapy. Presented at: Personalizing Pediatric Cancer Care Summit; March 10-11, 2022; Philadelphia.

Disclosures: Tasian reports advisory board roles with or research funding from Aleta Biotherapeutics, Gilead Sciences, Incyte and Kura Oncology.
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Commercially available chimeric antigen receptor T cells for acute myeloid leukemia could be just a few years away, according to a presenter at the inaugural Personalizing Pediatric Cancer Care Summit.

Sarah K. Tasian, MD, chief of the hematologic malignancies program at Children’s Hospital of Philadelphia and associate professor of pediatrics at University of Pennsylvania’s Perelman School of Medicine, provided a positive-yet-tempered outlook for CAR-T in AML.

Risks versus benefits of standard chemotherapy for younger patients with AML.
Infographic derived from Tasian SK. Traveling along the bench-to-bedside road of AML CAR T-cell immunotherapy. Presented at: Personalizing Pediatric Cancer Care Summit; March 10-11, 2022; Philadelphia.

Tasian said she anticipates that cellular immunotherapy could be approved for commercial use in certain patients with AML based on the progress of clinical trials.

“We have been inspired by the success of CAR-T in B-cell [acute lymphoblastic leukemia] and the discovery of CD19 as a universal antigen target,” Tasian said during a presentation. “We are, however, probably 5 years or more behind where we would like to be for these therapies in AML.”

Translating CAR-T has proven more difficult for AML than other blood cancers because of the lack of a true universal target antigen, Tasian said. Antigen targets in clinical testing also are expressed on other tissues and, therefore, create challenges related to off-target treatment-related toxicities.

The underlying biologic, genetic and immunologic diversity of AML in younger patients means that multiple immunotherapeutic approaches — including combination therapies — may be necessary to improve treatments for patients with relapsed or refractory disease, she said.

Long-term durability of immunotherapy for patients with chemorefractory AML is unknown. Although CAR-T is moving toward becoming a replacement for hematopoietic stem cell transplant for some B-cell malignancies, “we are really not yet there for AML,” she said.

There are, however, a handful of CAR constructs already in phase 1 or moving into phase 2 clinical testing for AML.

Sarah K. Tasian, MD
Sarah K. Tasian

“If we can understand whether these targets work for CAR T cells in AML, or alternative cell therapies that include [natural killer] cells or CAR-NK cells, then I think commercialization opportunities could present themselves in the next 2 to 3 years,” Tasian told Healio. “Just about everything right now resides in academia, but I am hopeful that there will be commercialization opportunities — whether they be autologous cells or some of the promising allogeneic or ‘universal’ approaches also in development.”

AML’s ‘clinical albatross’

The pursuit of an immunotherapy for relapsed or refractory AML is necessary because chemotherapies are not effective for up to a third of patients. Those who relapse within a year of initial treatment are unlikely to benefit from further intensification or salvage chemotherapy, Tasian said.

“This is our clinical albatross and where we have focused a lot of our work in the laboratory, as well as in early phase clinical trials,” she said during her presentation.

“Many of these [patients] continue to die despite our best salvage efforts,” Tasian added. “This has inspired those of us in the laboratory and early-phase clinical trial domains to develop different therapies that have alternative mechanisms of action that we hope can overcome chemoresistance.”

Pediatric AML is the second most common leukemia among children, yet an effective and commercially available CAR T-cell therapy for younger patients with advanced, chemoresistant disease likely will take longer, Tasian said.

“First-in-human trials have required older adolescent and young adult patients to enroll first for safety considerations, and the pace of referrals in this age category has been slow at pediatric hospitals,” she told Healio. “This will remain a likely hurdle for new pediatric cell therapy phase 1 trials.”

Promising targets

Despite challenges overall and slower progress among younger patients, dozens of antigen targets have been theorized, with several being evaluated in clinical trials for AML.

The most advanced clinical testing programs are for CD33 and CD123 — two antigens expressed in most pediatric AML cases, Tasian said.

Furthest along in development are monoclonal antibody-based therapeutics for adults with relapsed or refractory AML.

Children’s Hospital of Philadelphia is a primary trial site for one NIH-led clinical trial (NCT03971799) evaluating a novel CD33-directed CAR-T for younger patients with relapsed or refractory AML who received at least two previous lines of therapy.

Patients with AML who express “bright levels” of CD33 are among those with the highest risk and have been associated with inferior disease-free and overall survival outcomes, Tasian said.

The multicenter phase 1 study opened approximately 2 years ago and seeks to determine safety and tolerability of the investigational therapy, with goals of finding a recommended phase 2 dose and identifying a potential early efficacy signal. The overall aim for patietns who respond to the therapy is to serve as a bridge to consolidative HSCT, Tasian said. Enrollment requires patients to have an identified transplant donor.

CD123 likely is enriched on leukemia-initiating cells and is thought to contribute to disease relapse. It is another promising AML target and presents “as close to universal expression as we can get in pediatric AML,” Tasian said.

The antigen is highly prevalent among patients with AML despite biological differences between age groups, with expression seen in 80% or more of patients regardless of age, she added.

“Preclinical and emerging clinical data demonstrate potent anti-AML activity of CD123-targeting immunotherapies, including bispecific antibodies, antibody-drug conjugates and — hopefully soon — CAR T cells,” she said during her presentation.

Younger patients are being enrolled as part of the CATCHAML trial (NCT04318678) to evaluate the safety and tolerability of an autologous CD123-directed CAR-T. The phase 1 study is being conducted at St. Jude Children’s Research Hospital and includes patients who have relapsed after at least two previous lines of standard therapy.

Another phase 1 trial (NCT04678336) of CD123-directed CAR-T for younger patients with AML is being conducted at Children’s Hospital of Philadelphia and University of Pennsylvania. The novel CAR construct is based on previous research by Tasian and colleagues that demonstrated safety and feasibility using an mRNA-based CD123 CAR T cell. The previous iteration of the CAR-T did not prove effective in its cancer-killing capabilities in adult patients but established a sufficient safety profile to allow for testing using a lentiviral-based product, Tasian said.

‘A completely different beast’

Approval of a CAR-T for patients with chemorefractory AML “would be truly marvelous,” Tasian told Healio.

“Anything that is effective — particularly for patients who relapse early — would be beneficial compared with intensive, yet-ineffective, salvage chemotherapy,” she said.

Even if CAR-T cannot achieve the high level of complete responses seen among patients with other B-cell malignancies, it could become a useful bridge to HSCT with the aim of achieving more durable remissions, she said.

“Multiple modalities will likely be needed to improve cure rates appreciably given the heterogeneity of childhood AML,” Tasian said. “Although the B-cell ALL paradigm has been incredibly inspiring, we have learned that successful development of CAR T-cell immunotherapy for AML is a completely different beast.”

For more information:

Sarah K. Tasian, MD, can be reached at Children’s Hospital of Philadelphia, 3501 Civic Center Blvd., Philadelphia, PA 19104; email: tasians@chop.edu.