乌鸦传媒視頻

Donor-derived anti-CD7 chimeric antigen receptor (CAR) T-cell therapy led to complete responses in 18 of 20 patients with relapsed or refractory (r/r) T-cell acute lymphoblastic leukemia (ALL), a first-in-human clinical trial showed.

After a median follow-up of 6.3 months, 15 of the 18 responding patients remained in remission, and seven patients had undergone stem-cell transplantation (SCT). All patients developed cytokine release syndrome (CRS), which was grade 1/2 in most instances. Because the therapy involved unmanipulated T cells, a majority of patients developed graft-versus-host disease (GVHD), grade 1/2 severity in all cases. All of the patients developed severe cytopenias, which were manageable.

The results provided the basis for an ongoing phase II trial of the donor-derived anti-CD7 therapy, reported Jing Pan, MD, of the State Key Laboratory of Experimental Hematology and Beijing Boren Hospital in China, and colleagues in the .

"Our study suggests that donor-derived CD7 CAR T-cell therapy is feasible and beneficial for patients with r/r ALL," they concluded. "AEs [adverse events], such as CRS, GVHD, and T-cell aplasia can be severe but are manageable. This intervention might be administered for those who have undergone previous SCT and those who are eligible for SCT and have potential donors."

The study, along with previously reported data from another Chinese group, has demonstrated proof of principle for targeting CD7 in T-cell ALL, said John DiPersio, MD, of Washington University in St. Louis. Additionally, investigators in his lab separately developed a to produce CD7-targeted CAR T-cell therapy for T-cell leukemias and possibly lymphomas, and clinical trials will likely begin before the end of the year.

"Almost all of the patients treated with these CAR T cells directed to CD7 have benefited, and by that I mean a complete response, and the majority also had MRD [minimal residual disease]-negative disease," DiPersio told 乌鸦传媒視頻. "Amazingly, only one patient relapsed, which is hard to believe, because this represents a level of efficacy that we haven't seen with any other CAR T-cell product or any other disease."

Despite the impressive results, albeit in a small number of patients, the study raised some questions, DiPersio continued. Wild-type T cells express CD7. Laboratory studies suggested that introducing a CD7-targeted CAR would lead to T-cell fratricide, reducing the potential clinical benefit. Laboratories in the U.S. and England, for example, use gene editing to remove the T-cell receptor from donor T cells to eliminate the potential for alloreactivity and GVHD and also remove the CD7 antigen to prevent fratricide.

"It turns out that the graft-versus-host disease [in the Chinese study] didn't seem to be a lethal event," said DiPersio. "That's kind of curious, and I can't understand why that would be. Despite that, 60% of the patients developed some graft-versus-host disease, which is a really worrisome side effect of this infusion."

Pan and colleagues reported findings from a phase I trial using donor T cells from eight new donors and 12 individuals who previously had donated T cells for transplantation. The patients with ALL had a median age of 11 years (range of 2 to 43) and a treatment history that included a median of three prior lines of systemic therapy. Twelve of the patients had previously undergone SCT.

Patients who received T cells from prior donors underwent standard lymphodepletion, whereas those who received cells from new donors underwent intensified lymphodepletion. Each patient received a single infusion of 5 × 10⁵ or 1 × 10⁶ cells. Safety was the primary endpoint, and efficacy was secondary.

Two patients developed grade 3/4 CRS and the rest developed grade 1/2 CRS, which had a median time to onset of 1 day and median duration of 7 days. Fever and hypoxia were the most common symptoms associated with CRS. Three patients developed grade 1 neurotoxicity, which had a median duration of 3 days. Frequency and severity of CRS and neurotoxicity did not differ by donor type, the authors stated.

Cytopenias were expected, as a majority of the patients had a history of grade ≥3 cytopenias prior to enrollment, including lymphocytopenia, anemia, thrombocytopenia, and neutropenia. The median time from infusion to recovery of absolute neutrophil count was 60 days and 50 days for platelet-count recovery.

GVHD was grade 1 in 11 of 12 patients who developed the condition. Median time to onset was 14 days after infusion and median duration was 3 days. All but one of the patients received methylprednisolone and/or ruxolitinib (Jakafi), which relieved symptoms in all cases.

All but one patient achieved an objective response to CAR T-cell therapy, and 18 of 19 responses were complete remissions. The authors reported that 17 of 18 complete responses were associated with MRD negativity.

Six of seven patients who underwent SCT remained in remission, and the seventh died of engraftment syndrome 14 days after transplantation. Eleven patients received no additional leukemia treatment, and nine remained in remission during a median follow-up of 7.0 months. One patient died after 5.5 months and one had a CD7-negative symptomatic relapse after 4 months.

Comment