Experimental CAR-T safe, ‘highly effective’ for certain patients with T-cell malignancies
Click Here to Manage Email Alerts
NEW ORLEANS — A novel chimeric antigen receptor T-cell therapy conferred a 78% complete response rate in patients with heavily pretreated T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma, study results showed.
Data from the phase 1/phase 2 study presented at ASH Annual Meeting and Exposition revealed less robust survival results for those with certain genomic alterations.
Background
“Effective treatments are still lacking for refractory or relapsed T-cell acute lymphoblastic leukemia or T-cell lymphoblastic lymphoma,” Peihua “Peggy” Lu, MD, medical executive president of Lu Daopei Hospital and Beijing Lu Daopei Institute of Hematology, told Healio. “Once relapsed, the majority of patients only have a slim chance of long-term survival.”
Lu and colleagues looked to apply the success of CAR T-cell therapy seen among patients with B-cell ALL to those with T-cell disease. The investigators chose CD7 — an antigen known to be highly expressed on T cells — as the target for their experimental therapy.
CD7 presents issues as a therapeutic target because it is expressed on both healthy and cancerous T cells and is susceptible to T-cell fratricide.
“We have developed a novel fratricide-resistant approach to derive naturally selected anti-CD7 CAR T cells using lentiviral transduction of peripheral T cells that can overcome CD7-directed fratricide without additional genetic modifications,” she said. “Anti-CD7 CAR T cells remain CD7-positive but minimize the available surface CD7 antigen via CAR-mediated CD7 epitope masking or by intracellular sequestration of the CD7 protein, thus precluding major T-cell fratricide.”
Lu said they successfully manufactured anti-CD7 CAR T-cells (NS7CAR) from both study participants’ peripheral blood samples and hematopoietic stem cell transplantation donors.
Methodology
Lu and colleges enrolled 65 patients as part of a phase 1/phase 2 study to assess the efficacy and safety of NS7CAR in patients with relapsed or refractory CD7-positive T-cell malignancies.
The analysis included 60 patients (median age, 19 years; range, 2-47) with either T-cell ALL (n = 35) or T-cell lymphoblastic lymphoma (n = 25) who received a subsequent infusion of NS7CAR.
Thirty-one patients (52%) had extramedullary disease.
All study participants received fludarabine and cyclophosphamide as preconditioning therapy prior to infusion with NS7CAR, and 48 patients received bridging chemotherapy to control disease progression before CAR-T.
Patients received a single IV infusion of NS7CAR at one of three dose levels: low-dose (5 × 105 cells/kg; n = 25), medium dose (1-1.5 × 106 cells/kg; n = 34) or high dose (2 × 106 cells/kg; n = 1).
Median follow-up was 221.5 days (range, 23-621), with a data cutoff date of Aug. 31.
Key findings
Forty-seven patients (78.3%) had a complete response to therapy.
The 28-day post infusion evaluation showed 51 of 54 patients (94.4%) achieved minimal residual disease-negative status in bone marrow or peripheral blood.
Investigators reported an 81% overall response rate among 31 patients with extramedullary disease, including 18 patients (58%) who had a complete response to therapy.
Further analysis showed an 18-month OS rate of 72% for the entire study population, in addition to a 55% PFS rate.
Patients who had a complete response to CAR-T and received subsequent consolidation therapy with HSCT had significantly longer 18-month PFS compared with those who did not receive consolidation transplant (61% vs. 30%; P = .0003).
Investigators noted a significantly lower 18-month PFS rate among six patients with STIL::TAL1 alterations compared with the rest of the study population (17% vs. 59%; P = .0002). Additionally, the subgroup with TP53 alterations had a significantly lower OS rate (31% vs. 77%; P = .0164).
Most patients (88%) experienced low-grade cytokine release syndrome. Grade 3 CRS occurred in six patients (7%), with only one case of grade 4 events reported.
Neurotoxicity rarely occurred during the study, with most patients (93%) reporting no symptoms. Two patients had reported grade 1 immune effector cell-associated neurotoxicity syndrome, whereas another patient had grade 4 symptoms.
Clinical implications
The results suggest that NS7CAR is “safe and highly effective” in patients with heavily pretreated CD7-positive T-cell malignancies, according to Lu, especially in patients with extramedullary disease and a history of previous allogeneic HSCT.
“However, patients with high-risk subtypes [and] complex cytogenetics tend to have poorer overall survival or progression-free survival,” she told Healio.
Despite this limitation, Lu said CD7 is an attractive target for T-cell malignancy treatments and that experimental cellular therapies like the one being evaluated by her group could offer an effective option for patients with relapsed or refractory disease.
Perspective
Back to TopNoam Kopmar, MD, and Ryan Cassaday, MD
The CD7-directed CAR-T product that Lu and colleagues developed is described as “naturally selected” from bulk T cells for “fratricide resistance,” where the cells comprising the infused product are those that were not eliminated by other cells in culture. These CAR-T cells yielded high response rates (complete remission rate of 94%, with most being MRD-negative), favorable survival and infrequent severe toxicity. High-risk subgroups of T-cell ALL — like those harboring TP53 mutations — had the worst outcomes.
Although the results are exciting, the data raise questions about the reproducibility of the approach. For example, Lu and colleagues report only five patients (8%) were excluded during screening. In comparison, the multicenter international trials that led to the approvals of tisagenlecleucel (Kymriah, Novartis) and brexucabtagene autoleucel (Tecartus, Kite Pharma) had a screen-fail rate of about 25%. Lu and colleagues also observed a 98% manufacturing success rate, enviable compared to available approaches.
These results — albeit preliminary — provide a glimpse of the future for patients with relapsed or refractory T-cell ALL. Despite the advances for B-cell ALL, therapeutic options for T-cell ALL remain limited: nelarabine is the only specific FDA-approved therapy, and outcomes for these patients are generally dismal. Therefore, the excitement from the results with CD7-targeted CAR-T cells described by this group and others should not be understated. Longer follow-up will be needed to fully assess the durability of these responses and to assess for any long-term safety signals. It will also be critical to ensure their results can be reproduced in other settings.
References:
Lu P, et al. Blood. 2022;doi:10.1182/blood.2021014498.
Maude SL, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1709866.
Shah BD, et al. Lancet. 2021;doi:10.1016/S0140-6736(21)01222-8.
Pan J, et al. J Clin Oncol. 2021;doi:10.1200/JCO.21.00389.
Collapse
Zhang X, et al. Abstract 980. Presented at: ASH Annual Meeting and Exposition; Dec. 10-13, 2022; New Orleans.
Click Here to Manage Email Alerts