Research

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15 pages, 2582 KiB

Open AccessArticle

Irinotecan Induces Disease Remission in Xenograft Mouse Models of Pediatric MLL-Rearranged Acute Lymphoblastic Leukemia

by Mark Kerstjens, Patricia Garrido Castro, Sandra S. Pinhanços, Pauline Schneider, Priscilla Wander, Rob Pieters and Ronald W. Stam

Biomedicines 2021, 9(7), 711; https://doi.org/10.3390/biomedicines9070711 - 23 Jun 2021

Cited by 3 | Viewed by 2151

Abstract

Acute lymphoblastic leukemia (ALL) in infants (<1 year of age) remains one of the most aggressive types of childhood hematologic malignancy. The majority (~80%) of infant ALL cases are characterized by chromosomal translocations involving the MLL (or KMT2A) gene, which confer highly [...] Read more.

Acute lymphoblastic leukemia (ALL) in infants (<1 year of age) remains one of the most aggressive types of childhood hematologic malignancy. The majority (~80%) of infant ALL cases are characterized by chromosomal translocations involving the MLL (or KMT2A) gene, which confer highly dismal prognoses on current combination chemotherapeutic regimens. Hence, more adequate therapeutic strategies are urgently needed. To expedite clinical transition of potentially effective therapeutics, we here applied a drug repurposing approach by performing in vitro drug screens of (mostly) clinically approved drugs on a variety of human ALL cell line models. Out of 3685 compounds tested, the alkaloid drug Camptothecin (CPT) and its derivatives 10-Hydroxycamtothecin (10-HCPT) and 7-Ethyl-10-hydroxycamtothecin (SN-38: the active metabolite of the drug Irinotecan) appeared most effective at very low nanomolar concentrations in all ALL cell lines, including models of MLL-rearranged ALL (n = 3). Although the observed in vitro anti-leukemic effects of Camptothecin and its derivatives certainly were not specific to MLL-rearranged ALL, we decided to further focus on this highly aggressive type of leukemia. Given that Irinotecan (the pro-drug of SN-38) has been increasingly used for the treatment of various pediatric solid tumors, we specifically chose this agent for further pre-clinical evaluation in pediatric MLL-rearranged ALL. Interestingly, shortly after engraftment, Irinotecan completely blocked leukemia expansion in mouse xenografts of a pediatric MLL-rearranged ALL cell line, as well as in two patient-derived xenograft (PDX) models of MLL-rearranged infant ALL. Also, from a more clinically relevant perspective, Irinotecan monotherapy was able to induce sustainable disease remissions in MLL-rearranged ALL xenotransplanted mice burdened with advanced leukemia. Taken together, our data demonstrate that Irinotecan exerts highly potent anti-leukemia effects against pediatric MLL-rearranged ALL, and likely against other, more favorable subtypes of childhood ALL as well. Full article

(This article belongs to the Special Issue Cellular and Immunotherapy for Acute Lymphoblastic Leukemia)

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Review

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21 pages, 879 KiB

Open AccessReview

The Evolution of Chimeric Antigen Receptor T-Cell Therapy in Children, Adolescents and Young Adults with Acute Lymphoblastic Leukemia

by Dristhi Ragoonanan, Irtiza N. Sheikh, Sumit Gupta, Sajad J. Khazal, Priti Tewari, Demetrios Petropoulos, Shulin Li and Kris M. Mahadeo

Biomedicines 2022, 10(9), 2286; https://doi.org/10.3390/biomedicines10092286 - 14 Sep 2022

Cited by 3 | Viewed by 2101

Abstract

Chimeric antigen receptor T-cell (CAR T) therapy is a revolutionary treatment for pediatric, adolescent and young adult patients (AYA) with relapsed/refractory B-cell acute lymphoblastic leukemia. While the landscape of immunotherapy continues to rapidly evolve, widespread use of CAR T therapy is limited and [...] Read more.

Chimeric antigen receptor T-cell (CAR T) therapy is a revolutionary treatment for pediatric, adolescent and young adult patients (AYA) with relapsed/refractory B-cell acute lymphoblastic leukemia. While the landscape of immunotherapy continues to rapidly evolve, widespread use of CAR T therapy is limited and many questions remain regarding the durability of CAR T therapy, methods to avoid CAR T therapy resistance and the role of consolidative stem cell transplant. Modified strategies to develop effective and persistent CAR T cells at lower costs and decreased toxicities are warranted. In this review we present current indications, limitations and future directions of CAR T therapy for ALL in the pediatric and AYA population. Full article

(This article belongs to the Special Issue Cellular and Immunotherapy for Acute Lymphoblastic Leukemia)

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19 pages, 1083 KiB

Open AccessReview

T-Cell Acute Lymphoblastic Leukemia—Current Concepts in Molecular Biology and Management

by Parveen Shiraz, Waqas Jehangir and Vaibhav Agrawal

Biomedicines 2021, 9(11), 1621; https://doi.org/10.3390/biomedicines9111621 - 04 Nov 2021

Cited by 13 | Viewed by 3803

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an uncommon, yet aggressive leukemia that accounts for approximately one-fourth of acute lymphoblastic leukemia (ALL) cases. CDKN2A/CDKN2B and NOTCH1 are the most common mutated genes in T-ALL. Children and young adults are treated with pediatric [...] Read more.

T-cell acute lymphoblastic leukemia (T-ALL) is an uncommon, yet aggressive leukemia that accounts for approximately one-fourth of acute lymphoblastic leukemia (ALL) cases. CDKN2A/CDKN2B and NOTCH1 are the most common mutated genes in T-ALL. Children and young adults are treated with pediatric intensive regimens and have superior outcomes compared to older adults. In children and young adults, Nelarabine added to frontline chemotherapy improves outcomes and end of consolidation measurable residual disease has emerged as the most valuable prognostic marker. While outcomes for de-novo disease are steadily improving, patients with relapsed and refractory T-ALL fare poorly. Newer targeted therapies are being studied in large clinical trials and have the potential to further improve outcomes. The role of allogeneic stem cell transplant (HSCT) is evolving due to the increased use of pediatric-inspired regimens and MRD monitoring. In this review we will discuss the biology, treatment, and outcomes in pediatric and adult T-ALL. Full article

(This article belongs to the Special Issue Cellular and Immunotherapy for Acute Lymphoblastic Leukemia)

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