Some of the most impressive data on chimeric antigen receptor (CAR) T-cell therapy have come from studies conducted in China. Attendees at the 2021 Pan Pacific Lymphoma Conference heard from one of the leading Chinese investigators, Peihua (Peggy) Lu, MD, of Lu Daopei Hospital, who described the progress being made in CAR T-cell therapy development in China, including two recent promising endeavors: the phase I study on synthetic T-cell antigen receptor (STAR-T) and FasT CAR T-cell therapy program.1 Dr. Lu trained at the University of Nebraska, which sponsored the Pan Pacific Lymphoma Conference.
Peihua (Peggy) Lu, MD
Chinese and U.S. Efforts
Some 10 years after the early days of CAR T-cell therapy in the United States, China entered the game and quickly became a research powerhouse. Although the United States has gained more CAR T-cell patents—7,977 vs China’s 1,506—China currently has doubled the number of ongoing registered clinical trials—433 vs 288. More than 50 CAR T-cell products from 28 domestic companies in China have been accepted as investigational new drugs; 31 of them are approved for next-stage clinical trials, the majority of which continue to target CD19, though novel targets are increasing.
Certainly, one difference between CAR T-cell therapies in the United States and those in China is cost, Dr. Lu emphasized. The one CAR T-cell product approved so far by China’s National Medical Products Administration—axicabtagene ciloleucel (for lymphoma)—costs around $185,000 (in U.S. dollars) vs $373,000 in the United States. Although axicabtagene ciloleucel is much less expensive in China, it is not covered by insurance in China, she added.
Improving Outcomes in Relapsed B-Cell ALL: Transplantation
Focusing on the field in general, Dr. Lu described the use of allogeneic hematopoietic stem cell transplantation (allo-HSCT) as an approach to improving long-term remission after CAR T-cell therapy in patients with B-cell acute lymphocytic leukemia (ALL). Although many patients achieve complete responses to CAR T-cell therapy, some 40% relapse. Allo-HSCT might improve upon those outcomes, although the data have been mixed, and the practice remains controversial, she said.
According to Dr. Lu, evidence for its benefit is mounting, including findings from a study at Fred Hutchinson Cancer Center and another from her own institution. In the first study, 45 of 53 patients achieved complete remission after CAR T-cell treatment and achieved measurable residual disease (MRD)-negative status, whereas 22 relapsed early.2 Of the 45 MRD-negative responders, 18 went on to transplantation, of whom 11 (61.1%) achieved complete remission, 3 (16.7%) relapsed, and 4 (22.2%) had transplant-related mortality. Of the 27 who did not undergo transplantation, 19 (70%) relapsed.
“The conclusion was that you really need to consider consolidation and allogeneic transplant in patients achieving complete remission from CAR T-cell therapy (especially high-risk patients), unless future randomized trials show no benefit,” Dr. Lu said.
In her own center’s study of 110 patients, 102 (93%) achieved complete remission or complete remission with incomplete hematologic recovery, and 96 responders achieved MRD-negative status.3 Of this group, 75 went on to allo-HSCT, after which, relapse occurred in 10% of MRD-negative patients and 50% of MRD-positive patients. Of the 27 who did not undergo transplantation, 48% relapsed.
“Our suggestion is to consider pursuing allo-transplant, even if the patient already achieved only an MRD-negative complete remission from CAR T-cell treatment,” she said.
These first studies demonstrate the superiority of STAR T-cell therapy in terms of antileukemia potency compared with conventional CAR T-cell therapy…— Peihua (Peggy) Lu, MD
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Clinical outcomes and safety profiles are similar whether patients undergo CAR T-cell therapy or chemotherapy before transplantation. In her center’s study, patients treated with CAR T-cell therapy developed more acute graft-vs-host disease but had the same risk for severe acute graft-vs-host disease, around 12%.4 Similarly, the incidence of chronic graft-vs-host disease was higher after CAR T-cell therapy than chemotherapy, but severe chronic graft-vs-host disease was no different, also around 12%. Both approaches yielded “excellent” 4-year leukemia-free and overall survival rates exceeding 70%. Achievement of MRD negativity was associated with the best outcomes.
Improving the CAR T-Cell Structure
The best way to boost long-term remissions, however, is probably to start with even more effective cell therapy. In collaboration with China Immunotech (Beijing) Biotechnology Company, Ltd, Dr. Lu and colleagues are testing a novel adoptive T-cell product: synthetic T-cell receptor (TCR) and antigen receptor (STAR).
STAR T-cell therapy incorporates the antigen-recognition domain of the antibody and constant regions of the TCR that engage endogenous CD3 signaling machinery. According to Dr. Lu, STAR T cells exhibit less susceptibility to dysfunction and proliferate better than traditional CAR T cells. By having higher antigen sensitivity than CAR T cells, they could potentially reduce the risk of antigen loss-induced tumor relapse. In murine models, anti-CD19 STAR T cells have prominently outperformed their CAR T-cell counterparts in antileukemic activity without displaying the typical exhaustion.
Dr. Lu and colleagues built upon the promising preclinical activity they observed by enrolling 18 patients, most with challenging characteristics, on a phase I trial.5 After STAR T-cell infusion, all (100%) achieved MRD-negative complete remission by day 14 (though one patient became MRD-positive on day 28).
After STAR T-cell infusion, 11 of the 18 were bridged to allo-HSCT without relapse, after a median of 105 days. Of seven without transplant, six remain in complete remission, and one patient with very-high–risk disease relapsed and died. About half the patients developed mild cytokine-release syndrome, and just 2 of 18 patients developed grade 3 neurotoxicity.
“These first studies demonstrate the superiority of STAR T-cell therapy in terms of antileukemia potency compared with conventional CAR T-cell therapy, with high complete remission rates and low toxicity in relapsed or refractory B-cell ALL,” she said. “Given that this is a TCR complex–based CAR and a dual- or multiple-target construct, we see a potential for future development also in solid tumors.” 6
Further Improvements: FasT CAR T-Cell Therapy
Additional advantages are seen with novel FasT CAR T-cell products being developed by Dr. Lu and colleagues. To manufacture these products, purified T cells are activated with CD3/CD28 and transduced with a lentiviral vector carrying a CD19 scFv-CD28-CD3z CAR construct.
We already know that we need to give patients only a very low dose to see the [FasT CAR T cells] proliferate amazingly in vivo.— Peihua (Peggy) Lu, MD
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“Conventional CAR T cells require at least 9 to 14 days of manufacturing time. For our FasT CAR T cells, you need only 1 day [for manufacture]. Preclinical studies show superior expansion, younger phenotype, less exhaustion, and more infiltration into the bone marrow and, in animal models, more potent antileukemia activity vs conventional CAR T cells,” she explained.
These encouraging findings led to a phase I trial of 20 high-risk patients.7 Several doses were evaluated, the lowest one being 5 × 104. All 20 patients achieved complete remission or complete remission with incomplete hematologic recovery by day 28, and 90% achieved MRD negativity. A total of 12 patients were bridged to transplantation. At a median follow-up of 92 days, all have remained in complete remission and are doing well, except for one patient who developed an infection after transplantation.
Cytokine-release syndrome was grade 2 or 3 for four patients (20%). Grade 3 neurotoxicity occurred in two patients (10%).
“These cells are amazing with clear differences over conventional CAR T cells,” Dr. Lu said. “Certainly, over the long term, we need to see the duration of remission, and for that we need more time for observation. However, we already know that we need to give patients only a very low dose to see the cells proliferate amazingly in vivo. They also have good persistence. We are very excited about our FasT CAR data.”
CAR T Cells Move Beyond T Cells and Cancer
Looking to the future, Dr. Lu presented an intriguing list of emerging CAR T-cell products beyond T cells and uses for CAR T-cell therapy beyond cancer. Research has been published on these compounds:
- CAR natural killer cells
- CAR macrophages
- CAR derived from induced pluripotent stem cells
- CAR T-cell therapy for HIV/AIDS
- CAR T-cell therapy for autoimmune disorders and organ transplantation
- CAR T-cell therapy for cardiac fibrosis
- CAR T-cell therapy for aging cells.
DISCLOSURE: Dr. Lu reported no conflicts of interest.
REFERENCES
1. Lu P: CAR T-cell therapy in China. 2021 Pan Pacific Lymphoma Conference. Presented August 10, 2021.
2. Hay KA, Gauthier J, Hirayama AV, et al: Factors associated with durable event-free survival in adult B-cell ALL patients achieving MRD-negative complete remission after CD19 CAR T-cell therapy. Blood 133:1652-1663, 2019.
3. Zhang X, Lu XA, Yang J, et al: Efficacy and safety of anti-CD19 CAR T-cell therapy in 110 patients with B-cell acute lymphoblastic leukemia with high-risk features. Blood Adv 4:2325-2338, 2020.
4. Zhao YL, Liu DY, Sun RJ, et al: Integrating CAR T-cell therapy and transplantation: Comparisons of safety and long-term efficacy of allogeneic hematopoietic stem cell transplantation after CAR T-cell or chemotherapy-based complete remission in B-cell acute lymphoblastic leukemia. Front Immunol 12:605766, 2021.
5. Zhang X, Wang J, Liu Y, et al: Feasibility and safety study of a novel CD19-directed synthetic T-cell receptor and antigen receptor (STAR) T-cell therapy for refractory and relapsed B cell acute lymphoblastic leukemia. 2020 ASH Annual Meeting & Exposition. Abstract 270. Presented December 5, 2020.
6. Liu Y, Liu G, Wang J, et al: Chimeric STAR receptor using TCR machinery mediate robust responses against solid tumors. Sci Transl Med 13:eabb5191, 2021.
7. Yang J, He J, Zhang X, et al: A feasibility and safety study of a new CD19-directed FasT CAR-T therapy for refractory and relapsed B-ALL. Blood 134:825, 2019.
