Emerging and Future Targeted Therapies for Pediatric Acute Myeloid Leukemia: Targeting the Leukemia Stem Cells
Abstract
:1. Introduction
2. Discovery and Evolving Knowledge of Stem Cells in Adult AML
2.1. Functional Definitions and Immunophenotype
2.2. LSC Transcriptional Signatures
2.3. LSC Metabolism, Microenvironment, and Drug Resistance
3. LSC Biology in Pediatric Myeloid Disease
3.1. Immunophenotype
3.2. LSC Transcriptional Signatures
3.3. LSC Metabolism, Microenvironment, and Drug Resistance
4. Immunotherapies
4.1. CD33
4.2. CD123
4.3. Checkpoint Inhibitors
4.4. CD47
4.5. Folate Receptor 1/Folate Receptor-Alpha
5. Other Novel Agents
5.1. FLT3 Inhibitors
5.2. Menin Inhibitors
5.3. Venetoclax
5.4. PARP Inhibitors
5.5. Epigenetic Modifiers
5.6. Selinexor
5.7. Niclosamide
5.8. Uproleselan
5.9. Enasidenib
5.10. Pevonedistat
6. Future Targets
6.1. Immunotherapies
- CD70 is a tumor necrosis factor receptor ligand that is not normally expressed in normal tissues or on HSCs during hematopoiesis. It is upregulated on immune cells upon activation but not on resting B or T lymphocytes [217]. It has been demonstrated that CD34+ AML cells and LSCs express CD70 and its receptor CD27, that CD70/CD27 signaling in AML cells activates stem cell expression programs, and that the promoter for CD70 is sensitive to methylation [218,219]. For these reasons, blocking CD70/CD27 signaling in conjunction with hypomethylating agents is being considered as a potential treatment concept for AML. Currently, a CD70-targeting antibody, cusatuzumab, in combination with azaciditine or venetoclax, remains under clinical investigation with promising initial responses but short follow-up of treated patients to date [220].
- Surface expression of CD69 was enriched on LSCs from patients whose disease proved chemoresistant in one study, and CD69 expression in transcriptional data from large retrospective cohorts of pediatric patients correlated with poor outcomes [66]. Therefore, CD69 could represent a future LSC-targeting strategy for pediatric AML, although CD69 expression on regulatory T cells and other specialized T cell subsets may indicate unwanted side effects of immune dysregulation with CD69-targeting [221].
6.2. Other Novel Agents
- A 2021 study evaluated AML transcriptional data from 284 pediatric patients and found that high expression of calcitonin receptor-like receptor (CALCRL), a G-protein coupled receptor with roles in proliferation, apoptosis, and inflammation, was associated with inferior 5-year EFS and OS compared to those with low expression of CALCRL [222]. Antibody- or small molecule-based targeting of the CALCRL ligand calcitonin gene-related peptide (CGRP) are currently being investigated for migraine (NCT03432286, NCT05217927) and may warrant investigation as novel agents for both adult and pediatric AML. As noted above, given the association of LSCs with alternative splicing and exon skipping [59], a splicing modulator such as rebecsinib might be of future clinical interest in pediatric AML, particularly combined with anti-CD47 agents and/or pro-apoptotic agents such as venetoclax.
- Telomerase activity has been postulated to be a dependency in adult LSCs, and genetic deletion of an RNA template subunit (TERC) in mouse models of leukemia significantly impaired LSC functionality [223]. While children with AML tend to have lower telomerase activity on average than adults, those with higher telomerase activity had worse outcomes in a retrospective analysis [224]. Pre-treatment of six pediatric patient-derived xenograft (PDX) samples with the telomerase inhibitor imetelstat, alone or in combination with azacytidine- or cytarabine-based chemotherapy, reduced LSC viability, prolonged survival in primary murine recipients, and reduced engraftment into secondary recipients [225]. These data suggest that imetelstat could be an LSC-targeting therapy that should be prioritized for combination regimens. There is currently an ongoing clinical trial for adult MDS and AML that is enrolling participants at multiple Australian sites (NCT05583552).
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Class/Target | Agent | Study Population | Details | NCT # | Phase | Enrolling? |
---|---|---|---|---|---|---|
CD33 ADC | Gemtuzumab ozogamicin | ND secondary or R/R | + Liposomal Daunorubicin and Cytarabine | NCT04915612 | I | Yes |
ND | COG AAML1831; + SOC chemo or CPX-351 + GO | NCT04293562 | III | Yes | ||
CD33 CAR T cells | CD33CART | R/R | Lymphodepletion with Fludarabine and Cyclophosphamide | NCT03971799 | I/II | Yes |
SC-DARIC33 CAR T cells | R/R | Intermittent oral rapamycin which activates DARIC | NCT05105152 | I | Yes | |
CD123-toxin fusion protein | Tagraxofusp | R/R & CD123+ | monotherapy or + Fludarabine/Cytarabine or + Dexamethasone/Vincristine or + Azacitidine | NCT05955261 | I | Yes |
R/R | + Gemtuzumab Ozogamicin | NCT05716009 | I | Pending | ||
CD123xCD3 DART | Flotetuzumab | R/R | COG PEPN1812 | NCT04158739 | I | Completed |
CD123/NK cell engager | SAR443579 | R/R | Monotherapy; B-ALL and high-risk MDS also eligible | NCT05086315 | I/II | Yes |
CD123 CAR T cells | CD123-CAR T | R/R & CD123+ | Lymphodepletion with Fludarabine and Cyclophosphamide | NCT04318678 | I | Active, not recruiting |
CART123 | R/R | Lymphodepletion with Fludarabine and Cyclophosphamide | NCT04678336 | I | Active, not recruiting | |
Checkpoint inhibitors | Nivolumab | R/R | + Azacitidine | NCT03825367 | I/II | Active, not recruiting |
FOLR1-CDC | ELU001 | R/R & CBFA2T3::GLIS2+ | Monotherapy | NCT05622591 | I | Pending |
Class/Target | Agent | Study Population | Details | NCT # | Phase | Enrolling? |
---|---|---|---|---|---|---|
FLT3 Inhibitors | Gilteritinib | ND | COG AAML1831; + SOC chemo or CPX-351 + GO | NCT04293562 | III | Yes |
Gilteritinib | R/R | + FLAG | NCT04240002 | I/II | Yes | |
Quizartinib | R/R | + Fludarabine/Cytarabine/Etoposide | NCT03793478 | I/II | Yes | |
Pexidartinib | R/R | Monotherapy (National Cancer Institute) | NCT02390752 | I | Yes | |
MRX-2843 | R/R | Monotherapy | NCT04872478 | I | Yes | |
Menin Inhibitors | Revuminib | R/R, KMT2A-r | + chemo (FLAG for AML) | NCT05761171 | II | Pending |
R/R | + decitabine/cedazuridine (ASTX727) + venetoclax (SAVE trial, MD Anderson) | NCT05360160 | I/II | Yes | ||
R/R, KMT2A-r, NPM1-m | monotherapy | NCT04065399 | I/II | Yes | ||
Ziftomenib | R/R | expanded access on case-by-case basis | NCT05738538 | n/a | Available | |
JNJ-75276617 | R/R, KMT2A-r, NPM1-m, NUP98-r | + chemo (FLAG for AML), orally bioavailable | NCT05521087 | I | Pending | |
BCL2 Inhibitors | Venetoclax | ND | + conventional chemo (AML23, St. Jude) | NCT05955261 | II | Yes |
R/R | + FLA + GO; azacitidine (HMA) or ven/aza maintenance if unable to proceed to HSCT (PedAL/EuPAL) | NCT05183035 | III | Yes | ||
R/R | + idasanutlin (or idasanutlin + chemo) | NCT04029688 | I/II | Yes | ||
R/R | + azacitidine (HMA) + vorinostat (HDACi) + Fludarabine/Cytarabine/G-CSF | NCT05317403 | I | Yes | ||
R/R | + Selinexor (XPO1 inhibitor) + FLAG (SELCLAX, St. Jude) | NCT04898894 | I | Yes | ||
NF-kB Inhibitor, CREB Inhibitor | Niclosamide | R/R | monotherapy | NCT05188170 | I | Yes |
E-selectin Antagonist | Uproleselan | ND or 1st R/R | + HSCT conditioning | NCT05569512 | I/II | Yes |
PARP Inhibitors | Talazoparib | R/R | POE22-01; + topotecan/gemcitabine | NCT05101551 | I | Yes |
IDH2 Inhibitor | Enasidenib | R/R | COG ADVL18P1; monotherapy | NCT04203316 | II | Yes |
NEDD8 Inhibitor | Pevonedistat | R/R | COG/PEP-CTN (ADVL1712); + azacitidine + FLA | NCT03813147 | I | Active, not recruiting |
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Murphy, L.A.; Winters, A.C. Emerging and Future Targeted Therapies for Pediatric Acute Myeloid Leukemia: Targeting the Leukemia Stem Cells. Biomedicines 2023, 11, 3248. https://doi.org/10.3390/biomedicines11123248
Murphy LA, Winters AC. Emerging and Future Targeted Therapies for Pediatric Acute Myeloid Leukemia: Targeting the Leukemia Stem Cells. Biomedicines. 2023; 11(12):3248. https://doi.org/10.3390/biomedicines11123248
Chicago/Turabian StyleMurphy, Lindsey A., and Amanda C. Winters. 2023. "Emerging and Future Targeted Therapies for Pediatric Acute Myeloid Leukemia: Targeting the Leukemia Stem Cells" Biomedicines 11, no. 12: 3248. https://doi.org/10.3390/biomedicines11123248