With further research, allogeneic CAR T-cell therapy may help overcome the cost and production time barriers currently associated with autologous CAR T-cell therapy.
Chimeric antigen receptor (CAR) T-cell therapy has emerged as an effective type of immunotherapy, particularly in the treatment landscape surrounding hematological cancers. But harvesting autologous CAR T-cells to genetically modify and reinfuse—the typical manufacturing process—is notoriously expensive, tedious, and can be difficult in patients with high tumor burden and those who have had previous tumor-reductive treatment.
Allogeneic, aka off-the-shelf, CAR T-cell therapy using donor cells could potentially overcome some of the drawbacks of autologous CAR T-cell therapy, and a recent case study published in ImmunoMedicine showed that this method could be effective with manageable adverse effects, although the disease maintenance period was short.
Human leukocyte antigen (HLA) matched allogeneic CAR T cells currently hold the most promise in making CAR T-cell therapy more accessible, but only a small number of patients with B-cell malignancies have received treatment with donor-derived CAR T cells. This especially includes patients who relapsed post-transplantation, and most have achieved complete remission (CR) or partial remission (PR) and had relatively infrequent instances of graft-versus-host disease (GVHD) and other toxicities.
Study authors recruited a 53-year-old female patient who presented with relapsed/refractory acute B-cell lymphoblastic leukemia and had received a series of chemotherapies from October 2018 to August 2019. The patient’s tumor burden was as high as 85% at relapse. Given the likelihood of failure with manufacturing autologous CAR T cells due to low quantities, she was recruited to the authors’ clinical trial of HLA-matched allogeneic CAR-T cell therapy to avoid delays in treatment.
The patient received a cycle of hyperfractionated cyclophosphamide, vincristine, adriamycin, and dexamethasone (Hyper-CVAD Part A), followed by fludarabine and cyclophosphamide for lymphodepletion. Then, HLA-matched allogeneic anti-CD19 CAR T cells donated by her sister were infused at a dose of 3.3 × 106/kg.
Shortly after infusion, the patient developed recurrent fevers, severe headache, and elevated cytokine levels. CAR T cells and non–CAR T cells expanded exponentially. The symptoms were a result of Grade 2 cytokine release syndrome, which mostly resolved after 10 days of supportive care, antibiotics, and antifungal therapy. There were no symptoms of graft-versus-host disease (GVHD) or immune effector cell-associated neurotoxicity syndrome.
On day 10, cerebrospinal fluid (CSF) analysis confirmed central nervous system leukemia and cytokine levels higher than in blood samples. Flow cytometry analysis on day 10 showed effective CAR T-cell expansion in CSF. Antiemetic drugs and mannitol were added to the treatment regimen, and on day 14, CSF contained no leukemia cells. The patient was in CR and tested negative for minimal residual disease (MRD). She also tested negative for both the fusion gene BCR-ABL and T315I mutation.
Fifteen days post-infusion, the patient was discharged from the hospital and prepared for allogeneic hematopoietic stem cell transplantation. A bone marrow examination 35 days after CAR T-cell therapy infusion showed relapse and MRD level increase.
Despite the short remission period in this case study and the high relapse rate seen overall in allogeneic CAR T-cell therapy so far, the efficacy of the treatment and manageable toxicity are indicators that this manufacturing method is worth further study to overcome these hurdles.
“The inability of allogeneic T cells to maintain long-term immune surveillance might be attributed to the recognition and elimination by the host immune cells,” study authors wrote. “It might also associate with severe lymphopenia, the number of allogeneic CAR T cells, and the degree of HLA-matching.”
One potential route is using allogeneic CAR T-cell therapy to condition patients ahead of hematopoietic stem cell transplantation or using a combination of allogeneic and autologous CAR T cells in patients with high tumor burden whose disease is chemorefractory.
Overall, further research could make allogeneic CAR T-cell therapy a viable alternative to costly and time-consuming autologous CAR T-cells therapy manufacturing, the study authors conclude.
Huang Y, Tan Su Yin E, Wei G, et al. HLA-matched allogeneic anti-CD19 CAR-T therapy in treating a relapsed/refractory acute lymphoblastic leukemia patient with high tumor burden. ImmunoMedicine. Published online March 27, 2022. doi:10.1002/imed.1032