Donor-derived CAR T cells show encouraging efficacy for advanced T-cell ALL
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Ninety-five percent of patients with relapsed or refractory T-cell acute lymphoblastic leukemia responded to therapy with donor-derived chimeric antigen receptor T cells, according to results of a phase 1 study.
The data — presented during the virtual ASCO Annual Meeting — also showed 85% of patients achieved minimal residual disease (MRD)-negative status after a single infusion of the investigational therapy, which demonstrated manageable toxicity.
“Patients with relapsed or refractory T-cell ALL have limited treatment options,” Jing Pan, MD, director of the department of hematology at Beijing Boren Hospital in China, said during a presentation. “CAR T-cell therapy is a milestone for patients with B-cell malignancies, but there are obstacles that limit the use of CAR T-cell therapy for patients with T-cell ALL.”
Those obstacles include CAR T-cell fratricide — or mutual killing — that can occur during the manufacturing process when using a T-cell lineage antigen, such as CD7 or CD5, as the CAR target, Pan said.
Other impediments include difficulty harvesting enough healthy T cells from heavily pretreated patients and the rapid onset of T-cell immunodeficiency — known as T-cell aplasia — related to treatment that occurs after infusion.
Pan and colleagues used a novel allogeneic, gene-edited, CD7-directed CAR T-cell therapy derived from matched donors. The therapy was created with IntraBlock proprietary technology that uses an intracellular organelle-anchoring domain that retains CD7 to endoplasmic reticulum with the aim of preventing T-cell fratricide during the manufacturing process.
The single-center, phase 1 trial included 20 patients (median age, 11 years; range, 2-43; 80% male) treated with CD7 CAR T cells between July 18 and Dec. 21, 2020. Patients received a median three (range, 2-4) lines of previous therapy, and 12 (60%) had a previous hematopoietic stem cell transplant.
CAR T cells were manufactured using new HLA-matched or haploidentical donor T cells or donor-derived T cells reserved from the patient’s previous HSCT. Sixteen patients received lymphodepletion chemotherapy followed by a single infusion at a target dose of 1 × 106 (± 30%) CD7 CAR T cells per kilogram of body weight, with the remaining four patients receiving a lower dose of 5 × 105 (± 30%) cells/kg.
Safety, including treatment-related adverse events, served as the study’s primary endpoint. Secondary endpoints included measurement of short-term efficacy.
Median follow-up was 6.3 months (range, 4-9.2).
Safety results showed no dose-limiting toxicities. All study participants had cytokine release syndrome, with 90% experiencing grade 1 or grade 2 CRS and one case each of grade 3 and grade 4 CRS.
Median time to CRS onset was 1 day (range, 0-9), with a median duration of 7 days (range, 1-30).
Three patients (15%) experienced immune effector cell-associated neurotoxicity syndrome (ICANS). All had grade 1 ICANS and high leukemia burden in their central nervous system at the time of CAR T-cell infusion, according to the researchers.
Twelve patients (60%) experienced graft-versus-host disease — mostly skin manifestations — within 45 days of infusion. No patient had grade 3 or higher GVHD, and 10 patients required intervention with either ruxolitinib (Jakafi, Incyte; n = 2) or ruxolitinib combined with methylprednisolone (n = 8).
Grade 3 or grade 4 cytopenia occurred in all patients after infusion with CD7 CAR T cells and in 80% of patients before trial enrollment.
One patient died of a pulmonary hemorrhage while experiencing fungal pneumonia 5.5 months after infusion. Four patients (20%) had asymptomatic virus reactivations after infusion.
“Adverse events, such as CRS, GVHD and T-cell immunodeficiency, can be severe but manageable,” Pan said.
Only one patient failed to respond to therapy within 30 days of infusion, for an overall response rate of 95%. Seventeen patients (85%) had an MRD-negative complete response to therapy by day 30. Two patients had a partial response, one of whom discontinued the trial to pursue other treatment.
Seven patients received subsequent HSCT. Six of them, as well as nine of the 11 other study participants who had an initial complete response to therapy, remained alive and disease free as of last follow-up.
Pan said the results thus far are encouraging, but he noted the small sample size and brief follow-up time and said further study will be necessary.
“This therapy can be applied to patients who had a prior [HSCT] or for patients who are eligible for HSCT and have an available donor,” he added. “Our study demonstrates that donor-derived CD7 CAR T-cell therapy is feasible and may benefit patients with relapsed or refractory T-cell ALL.”
Perspective
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Elizabeth L. Budde, MD, PhD
Despite being an early phase 1 trial, the results of this study are nonetheless encouraging and the therapy appears to be quite safe. CD7 has become a novel research target for CAR T-cell therapy, and we have seen reports with this approach at last year's ASH Annual Meeting and continue to get more data with these findings.
The interesting aspect of the researchers’ approach in this study is that they developed the CAR T cells from donor cells that were previously used for HSCT or, when those were not available, from another matched donor. This approach also appeared to be safe.
The results thus far are impressive, although efficacy is not the primary endpoint of this phase 1 study. The CAR T cells appear to be quite potent in these patients based on the results presented by Pan and colleagues.
What is not clear from these results is how the researchers edited their cells. But regardless of how it was done, it appears that CD7 is a valid target for CAR T-cell therapy, as this and other groups have demonstrated success with this approach.
These results are too early to determine the durability of CD7-targeted treatment or whether it may serve as a bridge to subsequent HSCT. However, options to treat T-cell ALL are limited, and this is the type of treatment that can provide hope and an additional choice for patients with this disease, much in the same way that patients with B-cell malignancies have experienced using CD19-directed CAR-T.
Perspective
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Rayne H. Rouce, MD
The difficulty in developing a CAR T-cell therapy for T-cell malignancies starts with shared antigens between the CAR, normal T cells and malignant T cells. CARs can be successfully generated, but because the target antigen is present on all these cells it can lead to fratricide — or CAR T cells targeting each other — and T-cell aplasia.
Pan and colleagues chose CD7 as their target mainly because it is largely expressed on most immature T-cell malignancies; it is also expressed on the majority of mature T cells. The results they presented with their donor-derived CAR T cells demonstrated remarkable efficacy in a heavily pretreated, treatment-refractory population.
Despite the small number of patients in this study, responses to therapy did not appear to be dependent on dose. This therapy appears to be an effective bridge to allogeneic HSCT, with evidence of longer-term DFS related to the persistence of CAR T cells in nine patients.
GVHD stands out as one of the problems with this approach going forward. Although the safety profile was consistent with what we are accustomed to seeing for CAR T cells for B-cell malignancies, some patients experienced low-grade GVHD that resolved with treatment.
The therapy evaluated by Pan and colleagues showed robust antitumor activity by killing malignant T cells and did result in T-cell aplasia. Using allogeneic donor cells removed some of the patient-specific T-cell factors, including quantitative and qualitative T-cell dysfunction that is often seen when using autologous T cells in heavily pretreated patients.
On-target/off-tumor toxicity with this approach remains an issue, raising the question of whether allogeneic HSCT will remain the primary approach to rescue therapy. Other questions include the impact of heterogeneous antigen expression, which appeared small in this study despite the limited number of patients treated. Finally, will antigen escape become a limiting factor, and will CAR-T for T-cell malignancies need to move toward targeting multiple antigens, as has occurred in the treatment of B-cell malignancies?
Baylor College of Medicine
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Pan J, et al. Abstract 10001. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
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