T Acute Lymphoblastic Leukemia

P2, N=30, Not yet recruiting, University of Washington

Different reports evidenced the interplay between Notch and the anti-apoptotic Bcl-2 family proteins in T-ALL. Although based on early research data, this review discusses recent advances in directly targeting Notch receptors and the use of validated BH3 mimetics for the treatment of T-ALL and their combined action in light of current evidence of their use.

Furthermore, αCD7/EVs/CytC/siBcl2 exhibited high safety, low immunogenicity and minimal impact on human T cells. Therefore, αCD7/EVs/CytC/siBcl2 are promising therapeutic approaches for treating CD7+ T-cell malignancies.

In conclusion, while ALL that does have CDKN2A/2B gene deletions is associated with certain clinical characteristics and genetic aberrations, they did not significantly impact OS or EFS. Furthermore, subgroup analysis revealed a potential prognostic role of ALL that does have CDKN2A/2B deletions presenting with hepatosplenomegaly on palpation, emphasizing the importance of comprehensive risk stratification in treatment decision-making for this subgroup.

Remarkably, T-ALL cells with an orphan TCRβ chain displayed the strongest stemness and resistance to chemotherapy. Our study provided transcriptome and epigenome characterisation of T-ALL cells categorised by TCR clonotypes, which may be helpful for the development of novel predictive markers to evaluate treatment effectiveness for T-ALL.

These results suggested that Stattic holds promise as a therapeutic agent in T‑ALL by modulating key pathways involved in cell survival and proliferation. In conclusion, Stattic exhibited a significant therapeutic potential for T‑ALL via a dose‑dependent reduction of cell viability, inhibiting STAT3 phosphorylation, and promoting both apoptotic and autophagic cell death; however, further studies are required before clinical application.

P2, N=20, Recruiting, Eastern Cooperative Oncology Group | Trial completion date: Oct 2024 --> Jun 2027 | Trial primary completion date: Oct 2024 --> Jun 2027

P1, N=19, Terminated, M.D. Anderson Cancer Center | Active, not recruiting --> Terminated; Administratively Complete

All patients had persistent NGS MRD post-induction, which is markedly lower than the reported 20-25% NGS undetectable MRD rate in B-ALL post-induction. Persistent NGS MRD has low PPV for relapse in T-ALL, which limits its utility in clinical decision making for this population.

In addition, all T-LBLs demonstrate constitutive expression of pAKT, indicating the presence of activated AKT signaling, and are sensitive to treatment with the pan-AKT inhibitor MK-2206, suggesting that these lymphomas are dependent on pAKT signaling for their survival. Lastly, ATM-deficiency itself does not cause loss of PTEN or dysregulated AKT signaling, as ATM-deficient non-malignant thymocytes express wild-type levels of PTEN and lack detectable pAKT. This study demonstrates for the first time that the majority of ATM-deficient thymic T-LBLs lose PTEN expression and all depend on AKT signaling for survival, suggesting their potential use as an animal model for PI3K/AKT/MTOR pathway dysfunction in human T-ALL.

P2, N=40, Recruiting, Goethe University | Not yet recruiting --> Recruiting

P1, N=71, Active, not recruiting, City of Hope Medical Center | Trial completion date: Sep 2024 --> Sep 2025 | Trial primary completion date: Sep 2024 --> Sep 2025

P2, N=53, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2024 --> Oct 2025

P2, N=108, Active, not recruiting, City of Hope Medical Center | Recruiting --> Active, not recruiting

The current follow-up data has shown that the patient is negative for MRD and has been disease-free for more than 42 months. The results of this case study provide evidence for the long-term efficacy of CD7-targeted autologous CAR-T-cell therapy without requiring secondary allo-HSCT in patients with r/r T-ALL that have relapsed after previous allogeneic PBSCT.

P1, N=32, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | N=54 --> 32

P2, N=28, Not yet recruiting, Seoul National University Hospital

Our study examined the somatic and germline gene mutations in R/R T-ALL/LBL and evaluated the prognosis after transplantation. Based our limited study, we found that using CD7 CAR T cells followed by allo-HSCT greatly enhanced the long-term DFS of chemo resistant T-ALL/LBL patients.

The fully humanized version of antibody HuMT99/3 was further engineered, exhibiting similar binding affinity at the 10-10 M level and specificity to the CD99 epitope without antigenic shift. HuMT99/3 demonstrates remarkable selectivity, recognizing both malignant and normal T cells but inducing apoptosis only in T-ALL/T-LBL cells, highlighting its potential for safe and targeted therapy.

Through in silico and in vitro drug screenings, we identified a therapeutic vulnerability of BMP-like blasts to apoptosis-inducing agents including venetoclax. Collectively, our study establishes multiomic signatures for rapid risk stratification and targeted treatment of high-risk T-ALL.

Although there was no significant difference in survival between the G5-sgc8-siBCL11B and G5-siBCL11B groups, a trend towards improved survival was observed (p = 0.0993). The G5-sgc8-siBCL11B nanoparticle system demonstrated efficient delivery and significant therapeutic efficacy, highlighting its potential as a promising novel approach for the treatment of T-ALL.

Analysis of 39 human T-ALL samples revealed significantly enhanced E-selectin binding activity in relapse/refractory samples compared with drug-sensitive samples. These characteristics of chemoresistant T-ALL CLCs provide key insights for prognostic stratification and novel therapeutic options.

Remarkably, exposure of Marilyn female T-ALL cells to endogenous agonist antigen in male recipient mice or exogenous peptide in female recipient mice resulted in T-ALL apoptosis and prolonged mouse survival. These findings underscore the dual role of the same αβ TCR complex in T-ALL, where tonic stimulation is leukemogenic, while strong stimulation suppresses leukemia.

Her favorable response to conventional therapy underscores the importance of molecular phenotyping in the treatment of this disease. The continued use of NGS to gather relevant molecular data is crucial for further understanding the molecular phenotype and prognosis of such atypical ALL cases.

P1, N=4, Completed, Xiaoyu Zhu | Recruiting --> Completed | N=12 --> 4 | Trial completion date: Apr 2025 --> Aug 2024 | Trial primary completion date: Apr 2024 --> Aug 2024

P1, N=8, Completed, Kai Lin Xu，MD | Recruiting --> Completed | N=18 --> 8 | Trial completion date: Mar 2025 --> Aug 2024 | Trial primary completion date: Mar 2024 --> Aug 2024

P1, N=20, Completed, He Huang | Recruiting --> Completed | Trial completion date: May 2025 --> Aug 2024 | Trial primary completion date: Mar 2024 --> Aug 2024

P3, N=440, Active, not recruiting, Children's Oncology Group | Recruiting --> Active, not recruiting

Demethylation treatment with 5-Aza-dC can inhibit T-ALL cell malignant biological behaviors and enhance the sensitivity to chemotherapy agents possibly, which may be related to the inhibited expressions of DNMT1, DNMT3a, MBD2, and MeCP2, and restored expression activity of PTEN to negatively regulate the PI3K/AKT signal transduction. Our silencing and restoration of PTEN expressions further support our findings, highlighting that demethylation with 5-Aza-dC to restore the anti-tumor activity of the tumor suppressor gene PTEN may be a promising therapeutic option for treating T-ALL.

We also evaluated the therapeutic potential of targeting these proteins with AZD0466, a novel drug-dendrimer conjugate of the BCL2/-XL inhibitor AZD4320, and with BCL2 inhibitor venetoclax (ABT-199). Our findings therefore suggest that the novel dual BCL2/-XL inhibitor AZD0466 outperforms single BCL2 inhibition by venetoclax in T-ALL. These findings facilitate the translation of dual BCL2/-XL inhibitors into ALL clinical trials, either alone or in combination with standard- of- care chemotherapy and immune therapies.

As a result, bi-CD47-IT appears to possess the "optimal" binding avidity, with effective binding to human CD47+ T-ALL tumor cells, no binding to human red blood cells and weak binding to human lymphocytes. We believe that bi-CD47-IT is a promising and safe therapeutic drug candidate for the targeted therapy of CD47+ cancers.

The subgroup analysis based on the CDKN2A, CDKN2A/b and different ALL subtypes further strengthen the validity of the findings. Our meta-analysis revealed that CDKN gene deletions (including CDKN 2A/B, CDKN 2A) serve as adverse prognostic indicators for T-ALL/B-ALL patients.

Transcriptomic and metabolic analysis of primary T-ALL cells next translated our findings to the human pathology, showing that PTEN-altered T-ALL cells activate ACLY and are sensitive to its genetic targeting. ACLY activation thus represents a metabolic vulnerability with therapeutic potential for high-risk T-ALL patients.

Dexamethasone (DXM) was used in average-risk 2 (AR2) T-ALL and B-ALL during induction, 10 and 6 mg/m2/day, respectively. Leucovorin rescue was delayed to 42 h instead of 36 h after initiation of high-dose methotrexate, and a postconsolidation MRD time point was added to stratify patients...The HR was 2.15 (99% CI: 0.67-6.85) for very low-risk but 0.34 (99% CI: 0.13-0.89) for AR2. The particularly favorable results observed in the T-ALLs and AR2 subgroups suggest the benefit of using DXM in specific patient groups and highlight the importance of risk stratification.

Treatment with a PU.1 inhibitor enhances glucocorticoid sensitivity, demonstrating the clinical potential of targeting this pathway. This study uncovers a mechanism involving PU.1 and the glucocorticoid receptor, linking transcription factor activity with drug response, and suggesting potential therapeutic strategies for overcoming resistance.

Importantly, various lines of experimentation reveal that BCL11B FR could fold into parallel G-quadruplex, triplex, and hairpin structures, which could act as a replication/transcription block, causing mutagenesis. Thus, our results suggest that AID binds to BCL11B exon 4 due to non-B DNA formation, causing U:G mismatches or replication blocks, which, when repaired erroneously, generates deleterious mutations, resulting in loss of functionality of BCL11B, and thus becomes the cause of T-ALL.

Our findings suggest that the NRAS p.Arg97Thr variant may disrupt the splicing machinery and functions of the protein, thus playing a vital role in leukemogenesis. In addition, the highly druggable pocket may possibly be studied for its therapeutic implications.

In this review, we emphasize the importance of distinct tissue-specific expression patterns, functional divergence, disease-specific considerations, and the necessity to minimize off-target effects that collectively underscore the significance of "individualized" targeting for Notch1 and Notch2. This comprehensive review sheds light on the receptor-specific characteristics of Notch1 and Notch2, providing insights into their roles in cellular processes and offering opportunities for developing tailored therapeutic interventions in the fields of biomedical research and clinical practice.

P1, N=19, Terminated, Beijing Boren Hospital | Recruiting --> Terminated; ethic commitee decision

P1, N=0, Withdrawn, Beijing Boren Hospital | N=18 --> 0 | Trial completion date: Jul 2024 --> Dec 2023 | Recruiting --> Withdrawn | Trial primary completion date: Jul 2024 --> Dec 2023

P1, N=16, Completed, Beijing Boren Hospital | Recruiting --> Completed

P3, N=847, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Sep 2025