Patient-Specific Circulating Tumor DNA for Monitoring Response to Menin Inhibitor Treatment in Preclinical Models of Infant Leukemia.Cancers • October 11, 2024
Louise Doculara, Kathryn Evans, J Gooding, Narges Bayat, Richard Lock
Background: In infant KMT2A (MLL1)-rearranged (MLL-r) acute lymphoblastic leukemia (ALL), early relapse and treatment response are currently monitored through invasive repeated bone marrow (BM) biopsies. Circulating tumor DNA (ctDNA) in peripheral blood (PB) provides a minimally invasive alternative, allowing for more frequent disease monitoring. However, a poor understanding of ctDNA dynamics has hampered its clinical translation. We explored the predictive value of ctDNA for detecting minimal/measurable residual disease (MRD) and drug response in a patient-derived xenograft (PDX) model of infant MLL-r ALL.
Methods: Immune-deficient mice engrafted with three MLL-r ALL PDXs were monitored for ctDNA levels before and after treatment with the menin inhibitor SNDX-50469.
Results: The amount of ctDNA detected strongly correlated with leukemia burden during initial engraftment prior to drug treatment. However, following SNDX-50469 treatment, the leukemic burden assessed by either PB leukemia cells through flow cytometry or ctDNA levels through droplet digital polymerase chain reaction (ddPCR) was discrepant. This divergence could be attributed to the persistence of leukemia cells in the spleen and BM, highlighting the ability of ctDNA to reflect disease dynamics in key leukemia infiltration sites.
Conclusions: Notably, ctDNA analysis proved to be a superior predictor of MRD compared to PB assessment alone, especially in instances of low disease burden. These findings highlight the potential of ctDNA as a sensitive biomarker for monitoring treatment response and detecting MRD in infant MLL-r ALL.
The CD123 antibody-drug conjugate pivekimab sunirine exerts profound activity in preclinical models of pediatric acute lymphoblastic leukemia.HemaSphere • October 02, 2024
Ben Watts, Christopher Smith, Kathryn Evans, Andrew Gifford, Sara M Mohamed, Stephen Erickson, Eric Earley, Steven Neuhauser, Timothy Stearns, Vivek Philip, Jeffrey Chuang, Patrick Zweidler Mckay, Sribalaji Lakshmikanthan, Emily Jocoy, Carol Bult, Beverly Teicher, Malcolm Smith, Richard Lock
Antibody-drug conjugates (ADCs) combining monoclonal antibodies with cytotoxic payloads are a rapidly emerging class of immune-based therapeutics with the potential to improve the treatment of cancer, including children with relapse/refractory acute lymphoblastic leukemia (ALL). CD123, the α subunit of the interleukin-3 receptor, is overexpressed in ALL and is a potential therapeutic target. Here, we show that pivekimab sunirine (PVEK), a recently developed ADC comprising the CD123-targeting antibody, G4723A, and the cytotoxic payload, DGN549, was highly effective in vivo against a large panel of pediatric ALL patient-derived xenograft (PDX) models (n = 39). PVEK administered once weekly for 3 weeks resulted in a median event-free survival (EFS) of 57.2 days across all PDXs. CD123 mRNA and protein expression was significantly higher in B-lineage (n = 65) compared with T-lineage (n = 25) ALL PDXs (p < 0.0001), and mice engrafted with B-lineage PDXs achieved significantly longer EFS than those engrafted with T-lineage PDXs (p < 0.0001). PVEK treatment also resulted in significant clearance of human leukemia cells in hematolymphoid organs in mice engrafted with B-ALL PDXs. Notably, our results showed no direct correlation between CD123 expression and mouse EFS, indicating that CD123 is necessary but not sufficient for in vivo PVEK activity. Importantly, a PDX with very high CD123 cell surface expression but resistant to in vivo PVEK treatment, failed to internalize the G4723A antibody while remaining sensitive to the PVEK payload, DGN549, suggesting a novel mechanism of resistance. In conclusion, PVEK was highly effective against a large panel of B-ALL PDXs supporting its clinical translation for B-lineage pediatric ALL.
Immune-deficient MISTRG mice support expansion of leukaemia-initiating cells in xenograft models of paediatric acute myeloid leukaemia.British Journal Of Haematology • September 26, 2024
Patrick Connerty, Jinhan Xie, Fatima El Najjar, Toby Trahair, Nisitha Jayatilleke, Chelsea Mayoh, Richard Lock
Acute myeloid leukaemia (AML) remains a deadly disease, largely due to the persistence of drug-resistant leukaemia-initiating cells (LICs) which promote relapse. Therefore, effective therapies must target LICs. Patient-derived xenografts (PDXs) are valuable for testing new therapies, though establishing AML PDX models is challenging. Two humanized mouse strains, MISTRG and NRGS, have been developed for this purpose. In this study, we show both are suitable strains for the development of AML PDXs; however, MISTRG-derived PDXs contain 10 times higher LIC frequencies than NRGS-derived PDXs. These differences have crucial implications for preclinical AML therapy testing and modelling relapse models of the disease.
The third generation AKR1C3-activated prodrug, ACHM-025, eradicates disease in preclinical models of aggressive T-cell acute lymphoblastic leukemia.Blood Cancer Journal • September 08, 2024
Cara Toscan, Hannah Mccalmont, Amir Ashoorzadeh, Xiaojing Lin, Zhe Fu, Louise Doculara, Hansen Kosasih, Roxanne Cadiz, Anthony Zhou, Sarah Williams, Kathryn Evans, Faezeh Khalili, Ruilin Cai, Kristy Yeats, Andrew Gifford, Russell Pickford, Chelsea Mayoh, Jinhan Xie, Michelle Henderson, Toby Trahair, Adam Patterson, Jeff Smaill, Charles De Bock, Richard Lock
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that expresses high levels of the enzyme aldo-keto reductase family 1 member C3 (AKR1C3). To exploit this finding, we developed a novel prodrug, ACHM-025, which is selectively activated by AKR1C3 to a nitrogen mustard DNA alkylating agent. We show that ACHM-025 has potent in vivo efficacy against T-ALL patient-derived xenografts (PDXs) and eradicated the disease in 7 PDXs. ACHM-025 was significantly more effective than cyclophosphamide both as a single agent and when used in combination with cytarabine/6-mercaptopurine. Notably, ACHM-025 in combination with nelarabine was curative when used to treat a chemoresistant T-ALL PDX in vivo. The in vivo efficacy of ACHM-025 directly correlated with AKR1C3 expression levels, providing a predictive biomarker for response. Together, our work provides strong preclinical evidence highlighting the potential of ACHM-025 as a targeted and effective therapy for aggressive forms of T-ALL.
Inhibition of the NLRP3 inflammasome using MCC950 reduces vincristine-induced adverse effects in an acute lymphoblastic leukemia patient-derived xenograft model.HemaSphere • August 08, 2024
Hana Starobova, Hannah Mccalmont, Svetlana Shatunova, Nicolette Tay, Christopher Smith, Avril Robertson, Ingrid Winkler, Richard Lock, Irina Vetter
Vincristine is one of the most important chemotherapeutic drugs used to treat acute lymphoblastic leukemia (ALL). Unfortunately, vincristine often causes severe adverse effects, including sensory-motor neuropathies, weight loss, and overall decreased well-being, that are difficult to control and that decrease the quality of life and survival of patients. Recent studies demonstrate that sensory-motor adverse effects of vincristine are driven by neuroinflammatory processes, including the activation of the Nod-like receptor 3 (NLRP3) inflammasome. In this study, we aimed to test the effects of MCC950, a specific NLRP3 inhibitor, on the prevention of vincristine-induced adverse effects as well as tumor progression and vincristine efficacy in NOD/SCID/interleukin-2 receptor Îł-negative mice patient-derived xenografts of ALL. We demonstrate that co-administration of MCC950 effectively prevented the development of mechanical allodynia, motor impairment, and weight loss and significantly improved the overall well-being of the animals without negatively impacting the in vivo efficacy of vincristine as a single agent or in combination with standard-of-care drugs. These results provide proof of principle that the adverse effects of vincristine chemotherapy can be prevented using NLRP3 inflammasome inhibitors and provide new options for the development of effective treatment strategies.
