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 therapeutic landscape of hematological cancers. But harvesting autologous CAR T cells for genetic modification and re-injection – the typical manufacturing process – is notoriously expensive, time-consuming, and can be difficult in patients with high tumor burden and those who have already received tumor-reducing therapy. .
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 Posted in ImmunoMedicine showed that this method could be effective with manageable side effects, although the disease maintenance period was short.
Allogeneic human leukocyte antigen (HLA)-matched CAR T cells currently hold the most promise for making CAR T therapy more accessible, but only a small number of patients with B-cell malignancies have received treatment with cells. Donor-derived CAR T. This especially includes patients who relapsed after transplantation, and most achieved complete remission (CR) or partial remission (PR) and had relatively infrequent cases of graft versus host disease (GVHD) and other toxicities.
The study authors recruited a 53-year-old patient who had relapsed/refractory B-cell acute lymphoblastic leukemia and had received a course of chemotherapy from October 2018 to August 2019. The patient’s tumor burden was as high as 85% at relapse. Given the likelihood of failure to manufacture autologous CAR T cells due to low quantities, she was recruited for the authors’ clinical trial of allogeneic HLA-matched CAR-T cell therapy to avoid delays. 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, allogeneic HLA-compatible anti-CD19 CAR T cells donated by his sister were infused at a dose of 3.3 × 106/kg.
Shortly after the infusion, the patient developed recurrent fevers, severe headaches, and elevated cytokine levels. CAR T cells and non-CAR T cells grew exponentially. Symptoms were the 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 higher cytokine levels than in blood samples. Flow cytometry analysis at day 10 showed efficient expansion of CAR T cells in CSF. Antiemetic drugs and mannitol were added to the treatment regimen, and by day 14 the CSF contained no leukemic cells. The patient was in CR and tested negative for minimal residual disease (MRD). She also tested negative for the BCR-ABL fusion gene and the T315I mutation.
Fifteen days after the infusion, the patient was discharged from the hospital and prepared for an allogeneic hematopoietic stem cell transplant. Bone marrow examination 35 days after infusion of CAR T-cell therapy showed relapse and increased level of MRD.
Despite the short period of remission in this case study and the high relapse rate seen in all CAR T-cell allogeneic therapy to date, treatment efficacy and manageable toxicity are indicators that this method manufacturing process deserves further study to overcome these obstacles.
“The inability of allogeneic T cells to maintain long-term immune surveillance could be attributed to recognition and elimination by host immune cells,” the study authors wrote. “It might also be associated with severe lymphopenia, allogeneic CAR T cell counts, and degree of HLA matching.”
One potential avenue is to use allogeneic CAR T cell therapy to condition patients prior to hematopoietic stem cell transplantation or to use 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 making expensive and time-consuming autologous CAR T cell therapies, the study authors conclude.
Huang Y, Tan Su Yin E, Wei G, et al. Allogeneic HLA-matched anti-CD19 CAR-T therapy in the treatment of a patient with relapsed/refractory acute lymphoblastic leukemia with a high tumor burden. ImmunoMedicine. Published online March 27, 2022. doi:10.1002/imed.1032