Chiesa
R
,
Georgiadis
C
,
Syed
F
, et al
.
Base-edited CAR7 T cells for relapsed T-cell acute lymphoblastic leukemia
.
N Engl J Med
.
2023
;
389
(
10
):
899
910
.

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.13  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.610  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.1417  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.

1
Raetz
EA
,
Bhojwani
D
,
Devidas
M
, et al
.
Children’s Oncology Group blueprint for research: Acute lymphoblastic leukemia
.
Pediatr Blood Cancer
.
2023
;
70
Suppl 6
:
e30585
.
2
Si Lim
SJ
,
Ford
JB
,
Hermiston
ML
.
How I treat newly diagnosed and refractory T-cell acute lymphoblastic lymphoma in children and young adults
.
Blood
.
2023
;
141
(
25
):
3019
3030
.
3
Teachey
DT
,
O’Connor
D
.
How I treat newly diagnosed T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma in children
.
Blood
.
2020
;
135
(
3
):
159
166
.
4
Chen
Xu J
,
Vincent
C
TL, et al
.
Progenitor sub-populations in treatment resistant T-ALL
.
Blood
.
2022
;
140
(
Suppl 1
):
1724
1726
.
5
Pölönen
P
,
Elsayed
A
,
Di Giacomo
D
, et al
.
Comprehensive genome characterization of childhood T-ALL links oncogene activation mechanism and subtypes to prognosis
.
Blood
.
2022
;
140
(
Suppl 1
):
1727
1729
.
6
Dunsmore
KP
,
Winter
SS
,
Devidas
M
, et al
.
Children’s Oncology Group AALL0434: A phase III randomized clinical trial testing nelarabine in newly diagnosed T-cell acute lymphoblastic leukemia
.
J Clin Oncol
.
2020
;
38
(
28
):
3282
3293
.
7
Winter
SS
,
Dunsmore
KP
,
Devidas
M
, et al
.
Improved survival for children and young adults with T-lineage acute lymphoblastic leukemia: Results From the Children’s Oncology Group AALL0434 Methotrexate Randomization
.
J Clin Oncol
.
2018
;
36
(
29
):
2926
2934
.
8
Petit
A
,
Trinquand
A
,
Chevret
S
, et al
.
Oncogenetic mutations combined with MRD improve outcome prediction in pediatric T-cell acute lymphoblastic leukemia
.
Blood
.
2018
;
131
(
3
):
289
300
.
9
Vora
A
,
Goulden
N
,
Mitchell
C
, et al
.
Augmented post-remission therapy for a minimal residual disease-defined high-risk subgroup of children and young people with clinical standard-risk and intermediate-risk acute lymphoblastic leukaemia (UKALL 2003): A randomised controlled trial
.
Lancet Oncol
.
2014
;
15
(
8
):
809
818
.
10
Teachey
DT
,
Devidas
M
,
Wood
BL
, et al
.
Children’s Oncology Group Trial AALL1231: A phase III clinical trial testing bortezomib in newly diagnosed t-cell acute lymphoblastic leukemia and lymphoma
.
J Clin Oncol
.
2022
;
40
(
19
):
2106
2118
.
11
Hunger
SP
,
Raetz
EA
.
How I treat relapsed acute lymphoblastic leukemia in the pediatric population
.
Blood
.
2020
;
136
(
16
):
1803
1812
.
12
McMahon
CM
,
Luger
SM
.
Relapsed T cell ALL: Current Approaches and new directions
.
Curr Hematol Malig Rep
.
2019
;
14
(
2
):
83
93
.
13
Alcantara
M
,
Tesio
M
,
June
CH
, et al
.
CAR T-cells for T-cell malignancies: Challenges in distinguishing between therapeutic, normal, and neoplastic T-cells
.
Leukemia
.
2018
;
32
(
11
):
2307
2315
.
14
Png
YT
,
Vinanica
N
,
Kamiya
T
, et al
.
Blockade of CD7 expression in T cells for effective chimeric antigen receptor targeting of T-cell malignancies
.
Blood Adv
.
2017
;
1
(
25
):
2348
2360
.
15
Cooper
ML
,
Choi
J
,
Staser
K
, et al
.
An “off-the-shelf” fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies
.
Leukemia
.
2018
;
32
(
9
):
1970
1983
.
16
Diorio
C
,
Murray
R
,
Naniong
M
, et al
.
Cytosine base editing enables quadruple-edited allogeneic CART cells for T-ALL
.
Blood
.
2022
;
140
(
6
):
619
629
.
17
Gomes-Silva
D
,
Srinivasan
M
,
Sharma
S
, et al
.
CD7-edited T cells expressing a CD7-specific CAR for the therapy of T-cell malignancies
.
Blood
.
2017
;
130
(
3
):
285
296
.
18
Qasim
W
.
Genome-edited allogeneic donor “universal” chimeric antigen receptor T cells
.
Blood
.
2023
;
141
(
8
):
835
845
.