Review Underscores Potential and Obstacles of Universal CAR T-Cell Therapy

Autologous chimeric antigen receptor (CAR) T-cell therapies have expanded the treatment landscape of certain cancer types in recent years, but a recent review deems universal CAR T-cell (UCART) therapy the “future of cell therapy.”

Autologous CAR T-cell therapy involves collecting a patient’s peripheral blood to engineer and reinfuse CAR T cells targeting specific tumor markers. It has shown promise in hematological malignancies, and 5 autologous CAR T-cell therapies are currently FDA approved for several cancer types. Autologous CAR T-cell therapy production has several limitations that may be mitigated by universal CAR T cells. However, producing universal CAR T cells does not come without challenges.

Because autologous CAR T cells are extracted and reinjected into the same patient, the process can take 2 to 3 weeks and requires perfect execution for the treatment to be usable. Additionally, some patients’ T cells, such as those affected by earlier chemotherapy, may not be sufficient for CAR T-cell therapy production. High costs are also a concern with autologous CAR T-cell production. These challenges limit CAR T-cell therapy uptake in real-world settings.

UCART therapy is inspired by allogeneic CAR T-cell therapy, which involves taking T cells from a donor and engineering them to use in a patient. The concept of UCART takes this basic strategy—a one-to-one, donor-to-patient model—and expands upon it. The treatment is “universal” due to the universal CAR and universal T cell used to create it. It is also cheaper than autologous CAR T-cell therapy.

Notably, graft versus host disease (GVHD) and poor CAR T-cell expansion are obstacles that have also been seen in allogeneic CAR T-cell therapy. With UCART, both GVHD and host versus graft reaction are serious safety concerns that also impact the treatment efficacy.

A CD19-targeted UCART product called UCART19, which uses the transcription activator-like nucleases (TALEN) gene editing method, was developed by Cellectis and led to complete remission when first used in a 1-year-old girl with relapsed B cell acute lymphoblastic leukemia (B-ALL). In a pair of phase 1 clinical trials including a total of 21 patients with B-ALL, 67% of patients experienced complete response (CR) or CR with incomplete hematological recovery within 28 days after infusion. The 6-month rate of progression-free survival was 27%, and the overall survival rate was 55%. The rate of cytokine release syndrome (CRS) was 91%, with 14% of those cases considered grade 3 or above. Two patient deaths were considered treatment related.

Another UCART targeting CD19, ALLO-501, was created by Cellectis and Allogene Therapeutics and has an updated manufacturing process. Among 46 patients total, the overall response rate (ORR) was 61.5% in patients with relapsed/refractory large B-cell lymphoma and 82.6% in patients with follicular lymphoma (FL) in a phase 1 trial. CR rates were 46.2% and 52.2%, respectively. This updated product showed no dose-limiting toxicity, GVHD, unmanageable CRS, or immune effector cell-associated neurotoxicity syndrome of grade 2 or higher. The overall ORR and CR were 50% in a study of ALLO-501A, a next-generation anti-CD19 UCART from Allogene Therapeutics.

UCART products targeting multiple markers are also being investigated, as are UCART products with potential for use in solid tumors. Safety is a chief concern and has been a challenge with CAR T-cell therapy and gene editing methods in general.

“With the advance of gene and non-gene editing technologies for knocking off T cell receptors on CAR-T cells, GVHD, which used to be a major challenge of UCART therapy, is no longer a predominant concern. However, gene editing methods introduce the risk of inserting mutations and disrupting functional genes,” the authors wrote.

For example, a bone marrow biopsy of a patient with advanced FL who developed secondary aplastic anemia after treatment with ALLO-501A found anti-CD19 CAR T cells with chromosomal abnormalities. A clinical hold was placed on Allogene Therapeutics’ allogeneic CAR-T products but was lifted after the chromosomal abnormality was not found to be correlated with gene editing. Still, the risks of gene editing are important to consider.

The need for lymphodepletion prior to UCART to prevent rejection after infusion is also a concern, as these treatments are myelosuppressive and increase the risk of bleeding and infection. Anti-infection prophylaxis and supportive treatment are therefore crucial.

Despite the obstacles and risks, the review authors conclude that UCART has potential to play a key role in cell therapy and mitigate some of the limitations associated with autologous CAR T-cell therapy.

“As it stands, the most likely start of UCART cells is as a complementary treatment of autologous CAR-T, then the possibility of advancing to the front line will be explored,” the authors wrote. “In this process, the upgrade of products along with the advances in life science technology is essential.”

Reference

Sun W, Jiang Z, Jiang W, Yang R. Universal chimeric antigen receptor T cell therapy - the future of cell therapy: a review providing clinical evidence. Cancer Treat Res Commun. Published online September 22, 2022. doi:10.1016/j.ctarc.2022.100638