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Nature Medicine Jul 2023In the context of relapsed and refractory childhood pre-B cell acute lymphoblastic leukemia (R/R B-ALL), CD19-targeting chimeric antigen receptor (CAR)-T cells often...
In the context of relapsed and refractory childhood pre-B cell acute lymphoblastic leukemia (R/R B-ALL), CD19-targeting chimeric antigen receptor (CAR)-T cells often induce durable remissions, which requires the persistence of CAR-T cells. In this study, we systematically analyzed CD19 CAR-T cells of 10 children with R/R B-ALL enrolled in the CARPALL trial via high-throughput single-cell gene expression and T cell receptor sequencing of infusion products and serial blood and bone marrow samples up to 5 years after infusion. We show that long-lived CAR-T cells developed a CD4/CD8 double-negative phenotype with an exhausted-like memory state and distinct transcriptional signature. This persistence signature was dominant among circulating CAR-T cells in all children with a long-lived treatment response for which sequencing data were sufficient (4/4, 100%). The signature was also present across T cell subsets and clonotypes, indicating that persisting CAR-T cells converge transcriptionally. This persistence signature was also detected in two adult patients with chronic lymphocytic leukemia with decade-long remissions who received a different CD19 CAR-T cell product. Examination of single T cell transcriptomes from a wide range of healthy and diseased tissues across children and adults indicated that the persistence signature may be specific to long-lived CAR-T cells. These findings raise the possibility that a universal transcriptional signature of clinically effective, persistent CD19 CAR-T cells exists.
Topics: Humans; Antigens, CD19; Immunotherapy, Adoptive; Leukemia, Lymphocytic, Chronic, B-Cell; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Antigen, T-Cell; Remission Induction; T-Lymphocytes
PubMed: 37407840
DOI: 10.1038/s41591-023-02415-3 -
Blood Jan 2021CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T-cell therapy has shown significant efficacy for relapsed or refractory (R/R) B-cell malignancies. Yet,...
CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T-cell therapy has shown significant efficacy for relapsed or refractory (R/R) B-cell malignancies. Yet, CD19 CAR T cells fail to induce durable responses in most patients. Second infusions of CD19 CAR T cells (CART2) have been considered as a possible approach to improve outcomes. We analyzed data from 44 patients with R/R B-cell malignancies (acute lymphoblastic leukemia [ALL], n = 14; chronic lymphocytic leukemia [CLL], n = 9; non-Hodgkin lymphoma [NHL], n = 21) who received CART2 on a phase 1/2 trial (NCT01865617) at our institution. Despite a CART2 dose increase in 82% of patients, we observed a low incidence of severe toxicity after CART2 (grade ≥3 cytokine release syndrome, 9%; grade ≥3 neurotoxicity, 11%). After CART2, complete response (CR) was achieved in 22% of CLL, 19% of NHL, and 21% of ALL patients. The median durations of response after CART2 in CLL, NHL, and ALL patients were 33, 6, and 4 months, respectively. Addition of fludarabine to cyclophosphamide-based lymphodepletion before the first CAR T-cell infusion (CART1) and an increase in the CART2 dose compared with CART1 were independently associated with higher overall response rates and longer progression-free survival after CART2. We observed durable CAR T-cell persistence after CART2 in patients who received cyclophosphamide and fludarabine (Cy-Flu) lymphodepletion before CART1 and a higher CART2 compared with CART1 cell dose. The identification of 2 modifiable pretreatment factors independently associated with better outcomes after CART2 suggests strategies to improve in vivo CAR T-cell kinetics and responses after repeat CAR T-cell infusions, and has implications for the design of trials of novel CAR T-cell products after failure of prior CAR T-cell immunotherapies.
Topics: Adult; Aged; Antigens, CD19; Cell Proliferation; Cyclophosphamide; Cytokine Release Syndrome; Female; Humans; Immunotherapy, Adoptive; Leukemia, B-Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Male; Middle Aged; Multivariate Analysis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Progression-Free Survival; T-Lymphocytes; Treatment Outcome; Vidarabine
PubMed: 32967009
DOI: 10.1182/blood.2020006770 -
British Journal of Haematology Jul 2019While survival in paediatric acute lymphoblastic leukaemia (ALL) is excellent, survival following relapse is poor. Previous studies suggest proteasome inhibition with... (Clinical Trial)
Clinical Trial
While survival in paediatric acute lymphoblastic leukaemia (ALL) is excellent, survival following relapse is poor. Previous studies suggest proteasome inhibition with chemotherapy improves relapse ALL response rates. This phase 2 Children's Oncology Group study tested the hypothesis that adding the proteasome inhibitor bortezomib to chemotherapy increases complete response rates (CR2). Evaluable patients (n = 135, 103 B-ALL, 22 T-ALL, 10 T-lymphoblastic lymphoma) were treated with reinduction chemotherapy plus bortezomib. Overall CR2 rates were 68 ± 5% for precursor B-ALL patients (<21 years of age), 63 ± 7% for very early relapse (<18 months from diagnosis) and 72 ± 6% for early relapse (18-36 months from diagnosis). Relapsed T-ALL patients had an encouraging CR2 rate of 68 ± 10%. End of induction minimal residual disease (MRD) significantly predicted survival. MRD negative (MRDneg; MRD <0·01%) rates increased from 29% (post-cycle 1) to 64% following cycle 3. Very early relapse, end-of-induction MRDneg precursor B-ALL patients had 70 ± 14% 3-year event-free (EFS) and overall survival (OS) rates, vs. 3-year EFS/OS of 0-3% (P = 0·0001) for MRDpos (MRD ≥0·01) patients. Early relapse patients had similar outcomes (MRDneg 3-year EFS/OS 58-65% vs. MRDpos 10-19%, EFS P = 0·0014). These data suggest that adding bortezomib to chemotherapy in certain ALL subgroups, such as T-cell ALL, is worthy of further investigation. This study is registered at http://www.clinical.trials.gov as NCT00873093.
Topics: Adolescent; Adult; Bortezomib; Child; Child, Preschool; Disease-Free Survival; Female; Humans; Infant; Male; Neoplasm, Residual; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Survival Rate; Time Factors
PubMed: 30957229
DOI: 10.1111/bjh.15919 -
Blood Jul 2021Chimeric antigen receptor (CAR)-T-cell therapeutic efficacy is associated with long-term T-cell persistence and acquisition of memory. Memory-subset formation requires...
Chimeric antigen receptor (CAR)-T-cell therapeutic efficacy is associated with long-term T-cell persistence and acquisition of memory. Memory-subset formation requires T-cell factor 1 (TCF-1), a master transcription factor for which few regulators have been identified. Here, we demonstrate using an immune-competent mouse model of B-cell acute lymphoblastic leukemia (ALL; B-ALL) that Regnase-1 deficiency promotes TCF-1 expression to enhance CAR-T-cell expansion and memory-like cell formation. This leads to improved CAR-T-mediated tumor clearance, sustained remissions, and protection against secondary tumor challenge. Phenotypic, transcriptional, and epigenetic profiling identified increased tumor-dependent programming of Regnase-1-deficient CAR-T cells into TCF-1+ precursor exhausted T cells (TPEX) characterized by upregulation of both memory and exhaustion markers. Regnase-1 directly targets Tcf7 messenger RNA (mRNA); its deficiency augments TCF-1 expression leading to the formation of TPEX that support long-term CAR-T-cell persistence and function. Regnase-1 deficiency also reduces exhaustion and enhances the activity of TCF-1- CAR-T cells. We further validate these findings in human CAR-T cells, where Regnase-1 deficiency mediates enhanced tumor clearance in a xenograft B-ALL model. This is associated with increased persistence and expansion of a TCF-1+ CAR-T-cell population. Our findings demonstrate the pivotal roles of TPEX, Regnase-1, and TCF-1 in mediating CAR-T-cell persistence and recall responses, and identify Regnase-1 as a modulator of human CAR-T-cell longevity and potency that may be manipulated for improved therapeutic efficacy.
Topics: Animals; Antigens, CD19; Cell Line, Tumor; Cellular Reprogramming; Disease Models, Animal; Epigenesis, Genetic; Humans; Immunocompetence; Immunologic Memory; Immunotherapy, Adoptive; Mice, Inbred C57BL; Mice, Transgenic; Phenotype; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Ribonucleases; T Cell Transcription Factor 1; T-Lymphocytes; Mice
PubMed: 33690816
DOI: 10.1182/blood.2020009309 -
Asian Pacific Journal of Cancer... Jul 2020To investigate the use of glutamine administered orally during Methotrexate chemotherapy to prevent oral mucositis and reduce hospital costs in children with acute... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To investigate the use of glutamine administered orally during Methotrexate chemotherapy to prevent oral mucositis and reduce hospital costs in children with acute lymphoblastic leukemia (ALL).
METHODS
Twenty-four children received oral glutamine (400 mg/kg body weight per day) and twenty four received placebo on days of chemotherapy administration and for at least 14 additional days. Oral mucositis was graded daily at each day of treatment till completion of therapy. The study groups were compared for the oral mucositis development using the WHO scale.
RESULTS
Oral mucositis occurred in 4.2 % of the glutamine group and 62.5% in the placebo group. The use of glutamine was directly associated with prevention of oral mucositis than placebo (OR 0,026; 95% CI: 0,003-0,228). The duration of length hospital stay was lower in the glutamine group than in the placebo group ((8 vs 12 days); p = 0,005). Hospital cost per day for glutamine group was 40 USD per day while placebo group was 48 USD per day.
CONCLUSIONS
There was significant difference in the prevention of oral mucositis by oral glutamine vs placebo. The hospital cost for glutamine supplementation was lower than control group.
Topics: Administration, Oral; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Case-Control Studies; Child; Child, Preschool; Female; Follow-Up Studies; Glutamine; Hospital Costs; Humans; Infant; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Stomatitis
PubMed: 32711440
DOI: 10.31557/APJCP.2020.21.7.2117 -
The Lancet. Haematology Oct 2021CNS relapse of acute lymphocytic leukaemia is difficult to treat. Durable remissions of relapsed or refractory B-cell acute lymphocytic leukaemia have been observed... (Clinical Trial)
Clinical Trial
CD19-targeted chimeric antigen receptor T-cell therapy for CNS relapsed or refractory acute lymphocytic leukaemia: a post-hoc analysis of pooled data from five clinical trials.
BACKGROUND
CNS relapse of acute lymphocytic leukaemia is difficult to treat. Durable remissions of relapsed or refractory B-cell acute lymphocytic leukaemia have been observed following treatment with CD19-directed chimeric antigen receptor (CAR) T cells; however, most trials have excluded patients with active CNS disease. We aimed to assess the safety and activity of CAR T-cell therapy in patients with a history of CNS relapsed or refractory B-cell acute lymphocytic leukaemia.
METHODS
In this post-hoc analysis, we included 195 patients (aged 1-29 years; 110 [56%] male and 85 [44%] female) with relapsed or refractory CD19-positive acute lymphocytic leukaemia or lymphocytic lymphoma from five clinical trials (Pedi CART19, 13BT022, ENSIGN, ELIANA, and 16CT022) done at the Children's Hospital of Philadelphia (Philadelphia, PA, USA), in which participants received CD19-directed CAR T-cell therapy between April 17, 2012, and April 16, 2019. The trials required control of CNS disease at enrolment and infusion and excluded treatment in the setting of acute neurological toxic effects (>grade 1 in severity) or parenchymal lesions deemed to increase the risk of neurotoxicity. 154 patients from Pedi CART19, ELIANA, ENSIGN, and 16CT022 received tisagenlecleucel and 41 patients from the 13BT022 trial received the humanised CD19-directed CAR, huCART19. We categorised patients into two strata on the basis of CNS status at relapse or within the 12 months preceding CAR T-cell infusion-either CNS-positive or CNS-negative disease. Patients with CNS-positive disease were further divided on the basis of morphological bone marrow involvement-either combined bone marrow and CNS involvement, or isolated CNS involvement. Endpoints were the proportion of patients with complete response at 28 days after infusion, Kaplan-Meier analysis of relapse-free survival and overall survival, and the incidence of cytokine release syndrome and neurotoxicity.
FINDINGS
Of all 195 patients, 66 (34%) were categorised as having CNS-positive disease and 129 (66%) as having CNS-negative disease, and 43 (22%) were categorised as having isolated CNS involvement. The median length of follow-up was 39 months (IQR 25-49) in the CNS-positive stratum and 36 months (18-49) in the CNS-negative stratum. The proportion of patients in the CNS-positive stratum with a complete response at 28 days after infusion was similar to that in the CNS-negative stratum (64 [97%] of 66 vs 121 [94%] of 129; p=0·74), with no significant difference in relapse-free survival (60% [95% CI 49-74] vs 60% [51-71]; p=0·50) or overall survival (83% [75-93] vs 71% [64-79]; p=0·39) at 2 years between the two groups. Overall survival at 2 years was significantly higher in patients with isolated CNS involvement compared with those with bone marrow involvement (91% [82-100] vs 71% [64-78]; p=0·046). The incidence and severity of neurotoxicity (any grade, 53 [41%] vs 38 [58%]; grade 1, 24 [19%] vs 20 [30%]; grade 2, 14 [11%] vs 10 [15%]; grade 3, 12 [9%] vs 6 [9%], and grade 4, 3 [2%] vs 2 [3%]; p=0·20) and cytokine release syndrome (any grade, 110 [85%] vs 53 [80%]; grade 1, 12 [9%] vs 2 [3%]; grade 2, 61 [47%] vs 38 [58%]; grade 3, 18 [14%] vs 7 [11%] and grade 4, 19 [15%] vs 6 [9%]; p=0·26) did not differ between the CNS-negative and the CNS-positive disease strata.
INTERPRETATION
Tisagenlecleucel and huCART19 are active at clearing CNS disease and maintaining durable remissions in children and young adults with CNS relapsed or refractory B-cell acute lymphocytic leukaemia or lymphocytic lymphoma, without increasing the risk of severe neurotoxicity; although care should be taken in the timing of therapy and disease control to mitigate this risk. These preliminary findings support the use of these CAR T-cell therapies for patients with CNS relapsed or refractory B-cell acute lymphocytic leukaemia.
FUNDING
Children's Hospital of Philadelphia Frontier Program.
Topics: Adolescent; Adult; Antigens, CD19; Central Nervous System Neoplasms; Child, Preschool; Female; Humans; Immunotherapy, Adoptive; Infant; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Chimeric Antigen; Recurrence; Young Adult
PubMed: 34560014
DOI: 10.1016/S2352-3026(21)00238-6 -
Journal of Hematology & Oncology Mar 2021Acute lymphoblastic leukemia (ALL) is a hematological malignancy characterized by the malignant clonal expansion of lymphoid hematopoietic precursors. It is regulated by... (Review)
Review
Acute lymphoblastic leukemia (ALL) is a hematological malignancy characterized by the malignant clonal expansion of lymphoid hematopoietic precursors. It is regulated by various signaling molecules such as cytokines and adhesion molecules in its microenvironment. Chemokines are chemotactic cytokines that regulate migration, positioning and interactions of cells. Many chemokine axes such as CXCL12/CXCR4 and CCL25/CCR9 have been proved to play important roles in leukemia microenvironment and further affect ALL outcomes. In this review, we summarize the chemokines that are involved in ALL progression and elaborate on their roles and mechanisms in leukemia cell proliferation, infiltration, drug resistance and disease relapse. We also discuss the potential of targeting chemokine axes for ALL treatments, since many related inhibitors have shown promising efficacy in preclinical trials, and some of them have entered clinical trials.
Topics: Animals; Antineoplastic Agents; Chemokine CXCL12; Chemokines; Disease Progression; Drug Discovery; Humans; Molecular Targeted Therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Receptors, CXCR4; Tumor Microenvironment
PubMed: 33743810
DOI: 10.1186/s13045-021-01060-y -
International Braz J Urol : Official... 2022
Topics: Child; Humans; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Testicular Neoplasms
PubMed: 36037260
DOI: 10.1590/S1677-5538.IBJU.2022.0318 -
International Journal of Molecular... Mar 2024Infant acute lymphoblastic leukemia (Infant ALL) is a kind of pediatric ALL, diagnosed in children under 1 year of age and accounts for less than 5% of pediatric ALL. In... (Review)
Review
Infant acute lymphoblastic leukemia (Infant ALL) is a kind of pediatric ALL, diagnosed in children under 1 year of age and accounts for less than 5% of pediatric ALL. In the infant ALL group, two subtypes can be distinguished: -rearranged ALL, known as a more difficult to cure form and - non-rearranged ALL with better survival outcomes. As infants with ALL have lesser treatment outcomes compared to older children, it is pivotal to provide novel treatment approaches. Progress in the development of molecularly targeted therapies and immunotherapy presents exciting opportunities for potential improvement. This comprehensive review synthesizes the current literature on the epidemiology, clinical presentation, molecular genetics, and therapeutic approaches specific to ALL in the infant population.
Topics: Infant; Humans; Child; Adolescent; Immunotherapy; Molecular Targeted Therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 38612531
DOI: 10.3390/ijms25073721 -
Best Practice & Research. Clinical... Dec 2022Quantification of measurable residual disease (MRD) in acute lymphoblastic leukemia (ALL) is a well-established clinical tool used to risk stratify patients during the... (Review)
Review
Quantification of measurable residual disease (MRD) in acute lymphoblastic leukemia (ALL) is a well-established clinical tool used to risk stratify patients during the course of chemotherapy, immunotherapy, and/or transplant therapy. As technologies evolve, the sensitivity for quantifying exceptionally low disease burden using either next generation sequencing (NGS) or next generation flow cytometry (NGF) has improved. It is now possible to detect MRD and quantify it precisely in patients who would previously have been deemed MRD negative by older, lower sensitivity methods. Persistence or recurrence of ALL disease burden above 10 (0.01%) is accepted as the minimum threshold for making clinical decisions, but with NGS and NGF, clinicians now confront decision-making with disease burdens sometimes quantified to as low as 10 (0.0001%, or one leukemia cell in a million leukocytes). Emerging data suggest these higher sensitivity methods are superior for identifying patients at lowest risk for relapse, but it remains controversial whether to institute therapies such as blinatumomab or chimeric antigen receptor (CAR)-T cells or move patients to allogeneic hematopoietic cell transplant (alloHCT) when they have quantifiable disease burden less than 10. With additional evidence to facilitate integration of highly sensitive MRD quantification into clinical care and to contextualize MRD within the genotype of individual patients, it will likely be increasingly possible to identify patients able to avoid alloHCT and potentially even de-escalate therapy.
Topics: Humans; Hematopoietic Stem Cell Transplantation; High-Throughput Nucleotide Sequencing; Neoplasm, Residual; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 36517126
DOI: 10.1016/j.beha.2022.101407