Targeted therapy and immunotherapy for T cell acute lymphoblastic leukemia/lymphoma

Huang, Yuan-hong; Wan, Chao‐Ling; Dai, Haiping; Xue, Sheng‐Li

doi:10.1007/s00277-023-05286-3

Cited by 9 publications

(3 citation statements)

References 96 publications

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“…AML is characterized by the abnormal proliferation of immature myeloid cells, disrupting the normal production of blood cells. These are the most common forms of childhood cancer, and ALL survival rates have improved from 10% to 90% with newly identified therapies through clinical trials with a focus on biomarkers and therapeutic strategies (7,(48)(49)(50). 2.…”

Section: Cancer Types In Pediatric Populationmentioning

confidence: 99%

Pediatric oncology drug development and dosage optimization

Cheung,

Hay,

Lin

et al. 2024

Front. Oncol.

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Oncology drug discovery and development has always been an area facing many challenges. Phase 1 oncology studies are typically small, open-label, sequential studies enrolling a small sample of adult patients (i.e., 3-6 patients/cohort) in dose escalation. Pediatric evaluations typically lag behind the adult development program. The pediatric starting dose is traditionally referenced on the recommended phase 2 dose in adults with the incorporation of body size scaling. The size of the study is also small and dependent upon the prevalence of the disease in the pediatric population. Similar to adult development, the dose is escalated or de-escalated until reaching the maximum tolerated dose (MTD) that also provides desired biological activities or efficacy. The escalation steps and identification of MTD are often rule-based and do not incorporate all the available information, such as pharmacokinetic (PK), pharmacodynamic (PD), tolerability and efficacy data. Therefore, it is doubtful if the MTD approach is optimal to determine the dosage. Hence, it is important to evaluate whether there is an optimal dosage below the MTD, especially considering the emerging complexity of combination therapies and the long-term tolerability and safety of the treatments. Identification of an optimal dosage is also vital not only for adult patients but for pediatric populations as well. Dosage-finding is much more challenging for pediatric populations due to the limited patient population and differences among the pediatric age range in terms of maturation and ontogeny that could impact PK. Many sponsors defer the pediatric strategy as they are often perplexed by the challenges presented by pediatric oncology drug development (model of action relevancy to pediatric population, budget, timeline and regulatory requirements). This leads to a limited number of approved drugs for pediatric oncology patients. This review article provides the current regulatory landscape, incentives and how they impact pediatric drug discovery and development. We also consider different pediatric cancers and potential clinical trial challenges/opportunities when designing pediatric clinical trials. An outline of how quantitative methods such as pharmacometrics/modelling & simulation can support the dosage-finding and justification is also included. Finally, we provide some reflections that we consider helpful to accelerate pediatric drug discovery and development.

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Section: Cancer Types In Pediatric Populationmentioning

confidence: 99%

Pediatric oncology drug development and dosage optimization

Cheung,

Hay,

Lin

et al. 2024

Front. Oncol.

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“…20−23 However, the development of CD7 CAR-T cells is complicated, costly, and associated with major challenges, such as cytokine release syndrome and fratricide. 24,25 Herein, a CD7-specific immuno-nanotoxin was engineered by clicking anti-CD7 nanobody onto the surface of polymerome-mertansine nanoconjugates (aCD7-Ps-DM1) for targeted chemotherapy of T-ALL in vivo (Scheme 1). DM1, a common warhead for ADCs, has been reported to inhibit microtubule depolymerization and has high potency against both solid and hematological tumors.…”

Section: Introductionmentioning

confidence: 99%

“…Unlike B-cell ALL, which has well-validated targets (CD19, CD20, and CD22) and a variety of FDA-approved immunotherapies, including monoclonal antibodies, bispecific antibodies, antibody-drug conjugates (ADCs), and chimeric antigen receptor (CAR)-T cells, the lack of mature and specific targets of T-ALL is a major reason underlying its dismal clinical prognosis. − CD7, a T-lineage-specific antigen, is overexpressed in T-ALL and known to mediate endocytosis, making it an attractive target for treating T-ALL recently. − Several CD7 CAR-T cell therapies are under early clinical evaluation and have shown some response. − However, the development of CD7 CAR-T cells is complicated, costly, and associated with major challenges, such as cytokine release syndrome and fratricide. , …”

Section: Introductionmentioning

confidence: 99%

CD7 Nanobody-Based Immuno-Nanotoxin for Targeted Treatment of T-Cell Acute Lymphoblastic Leukemia

Dong,

You,

Zhang

et al. 2024

ACS Appl. Nano Mater.

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T-cell acute lymphoblastic leukemia (T-ALL) has been plagued by high relapse and mortality rates due to the lack of available targeted treatment options in the clinic. Herein, a CD7specific immuno-nanotoxin based on anti-CD7 nanobody-modified polymersome-mertansine nanoconjugates (aCD7-Ps-DM1) was engineered to enable effective and targeted chemotherapy of orthotopic T-ALL in vivo. aCD7-Ps-DM1 with regulable aCD7 density showed no DM1 leakage while rapid DM1 release under reducing conditions. The aCD7-Ps-DM1 immuno-nanotoxin efficiently targeted CD7-positive CCRF-CEM T-ALL cells, leading to 5-fold and >13-fold greater anti-ALL activity than that of nontargeted Ps-DM1 and CD7-negative B-ALL cell lines, respectively. In orthotopic CCRF-CEM T-ALL-bearing mice, repetitive (multiple) dosing of aCD7-Ps-DM1 persistently inhibited leukemia progression and infiltration in the bone marrow, blood, and organs, leading to significantly improved survival. This CD7-specific immuno-nanotoxin may offer a potential targeted treatment strategy for T-ALL.

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