Clinical outcomes for children and adolescents/young adults (AYAs) with T-acute lymphoblastic leukemia (T-ALL) and lymphoma (T-LL) have improved markedly in recent decades, with current five-year event-free survival (EFS) and overall survival (OS) rates exceeding 85% and 90%, respectively.1–3 These achievements are directly related to improvements in biologic and genetic characterization of T-ALL subtypes4, 5 and the results of landmark phase III clinical trials conducted by international pediatric oncology consortia, which have demonstrated the importance of dexamethasone- versus prednisone-based regimens and intercalation of asparaginase, nelarabine, and/or bortezomib for relevant cases.6–10 However, the prognosis of relapsed T-ALL/LL among children and AYAs is quite poor, with frequent inability to induce second complete remission (CR2) and EFS and OS rates less than 25%.11
Comprehensive clinical trials have investigated various salvage chemotherapy regimens and/or relevant targeted inhibitors in children and AYAs with relapsed T-ALL/LL, including BCL-2 and BCL-XL inhibitors, cyclin-dependent kinase inhibitors, gamma secretase inhibitors, PI3K/mTOR pathway inhibitors, proteasome inhibitors, and Src family kinase inhibitors.12 Such approaches have been incompletely effective to date, highlighting a persistent scientific knowledge gap and unmet medical need.2 The paradigm-shifting achievements of CD19- and CD22-directed chimeric antigen receptor (CAR) T-cell immunotherapies for patients with relapsed/refractory B-ALL during the past decade have inspired similar hope for successful approaches for T-ALL. However, early efforts to develop CAR T-cell immunotherapies were limited by issues of on-target/off-tumor “fratricide” given T-ALL antigen expression also present on normal T cells from which CAR T cells are derived.13 These obstacles have largely been overcome in recent preclinical studies via sophisticated cell surface target protein expression downregulation/blockade or genome editing strategies.14–17 Early-phase clinical trials throughout the world are now exploring the safety and preliminary activity of autologous or allogeneic (hematopoietic stem cell transplant [HSCT] donor-derived or universal/”off-the-shelf” gene-edited) CAR T-cell immunotherapies targeting CD5, CD7, or CD38 for children and/or adults with relapsed/refractory T-ALL/LL. Whether such approaches will ultimately succeed is not yet known.
In a remarkable brief report, Robert Chiesa, MD, and colleagues of the Base Edited CAR T Group based primarily at the University College London describe interim results of a phase I clinical trial testing base-edited CD7-targeting CAR (BE-CAR7) T cells in three pediatric patients with multiply relapsed T-ALL. The BE-CAR7 T cells were created via CRISPR gene editing of normal healthy donor T cells using single-guide RNAs against TRBC1 and TRBC2, CD7, and CD52 with a goal of eliminating allogeneic graft-versus-host effects when cells are infused into patients.18 The investigators first detected ~60% transduction efficiency of the BE-CAR7 T cells, depleted remaining ab-T cell receptor+ cells, and confirmed lack of CD7 and CD52 expression in 99% and 92% of the final BE-CAR7 T-cell clinical product, respectively. Importantly, morphologic remission of T-ALL was achieved in all three treated children (two measurable residual disease [MRD] negative and one MRD positive by flow cytometry) with detection of BE-CAR7 transcripts in peripheral blood. One patient died of invasive pulmonary fungal infection in the setting of prolonged pancytopenia approximately one month after infusion of BE-CAR7 T cells. The remaining two patients were able to proceed to subsequent allogeneic HSCT following total body irradiation, etoposide, and anti-thymocyte globulin conditioning. One child experienced subsequent CD7+ medullary relapse at four months post-HSCT. Expected sequelae of CAR T-cell immunotherapy occurred in all patients, including high-grade cytokine release syndrome with associated hyperinflammatory biomarkers and immune effector cell-associated neurologic syndrome. Other observed issues included generalized rash of unclear etiology and post-infusion bone marrow hypocellularity.
These noteworthy early results demonstrating relative safety of BE-CAR7 T-cell immunotherapy and initial remission induction in three children with relapsed, highly chemorefractory T-ALL that facilitated consolidative HSCT in two patients provide critical clinical feasibility. Actualization of allogeneic “off-the-shelf” cellular immunotherapy is of particular interest for heavily myelosuppressed patients from whom autologous T cells are of insufficient quantity or quality for successful CAR T-cell manufacturing. Universal CAR T-cell strategies are also attractive given their ready availability for infusion without the need to wait for patient-specific autologous T-cell manufacturing (particularly in the setting of rapid disease progression), as well as potential dosing efficiency and cost efficacy with multiple patients able to be treated from a single normal T-cell donor manufacturing process. This exciting study thus provides robust rationale for further clinical investigation of allogeneic cellular immunotherapies for patients with relapsed/refractory T-ALL/LL and other high-risk acute leukemias.
Dr. Tasian indicated no relevant conflicts of interest.