Molecular TherapyPub Date : 2025-09-03Epub Date: 2025-05-28DOI: 10.1016/j.ymthe.2025.05.022
Jerusha Naidoo, Yin Ren, Matthew Rocco, Eric Bielefeld, Allison O'Brien, Hsuan-Chih Kuo, Nathan McFarland, Matthew Avenarius, Manpreet Takhar, Geneva Frank, Victor Van Laar, Krystof Bankiewicz
{"title":"Delivery of AAV vectors to the superior olivary complex enables efficient adult cochlear transduction via axonal transport.","authors":"Jerusha Naidoo, Yin Ren, Matthew Rocco, Eric Bielefeld, Allison O'Brien, Hsuan-Chih Kuo, Nathan McFarland, Matthew Avenarius, Manpreet Takhar, Geneva Frank, Victor Van Laar, Krystof Bankiewicz","doi":"10.1016/j.ymthe.2025.05.022","DOIUrl":"10.1016/j.ymthe.2025.05.022","url":null,"abstract":"<p><p>Significant breakthroughs have been made in translation of adeno-associated virus (AAV) vectors for hearing disorders targeting auditory hair cells (HCs). In addition to HCs, spiral ganglion neurons (SGNs) are also impacted in a large number of sensorineural hearing loss cases in adults. However when administered directly into the cochlea in rodents aged older than P1-P3, AAV-mediated SGN transduction efficiency decreases dramatically. An efficient gene-delivery method to transduce adult SGNs is needed. Our group has a track record of utilizing axonal transport to transduce brain structures distal from the site of AAV injection. We investigated whether SGNs could be transduced in adult rats following intraparenchymal AAV administration to the olivary complex. Cochlear transduction was observed with the following common AAV serotypes expressing green fluorescent protein: AAV6, AAV9, AAV-Anc80, and AAV-PhP.B. Cochlear transduction was observed with all serotypes, but the cellular tropism and efficiency of gene transfer varied across the cochlear spiral (apex, middle, base) with different AAV serotypes, with some transducing both SGNs and HCs, while others transduced SGNs or HCs exclusively. This study provides proof of concept that AAV delivery to the olivary complex can efficiently deliver transgenes to SGNs in the adult mammalian cochlea.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4290-4302"},"PeriodicalIF":12.0,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432906/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144181496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Inhibition of NAD-GPx4 axis and MEK triggers ferroptosis to suppress pancreatic ductal adenocarcinoma.","authors":"Hui Jiang, Yusuke Satoh, Ryodai Yamamura, Takako Ooshio, Yang Luo, Han Hai, Takuya Otsuka, Soichiro Hata, Reo Sato, Taiga Hirata, Tsuyoshi Osawa, Keisuke Goda, Masahiro Sonoshita","doi":"10.1016/j.ymthe.2025.05.037","DOIUrl":"10.1016/j.ymthe.2025.05.037","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) ranks among the most lethal malignancies, highlighting the critical need for innovative therapeutic strategies. In this study, we examined the roles of nicotinamide adenine dinucleotide (NAD) synthesis pathway in PDAC. Targeting the NAD synthesis pathway significantly mitigated lethality in a Drosophila model that recapitulated the PDAC genotype. Within this pathway, we identified Glutathione peroxidase 4 (GPx4) as a critical effector responsible for scavenging reactive oxygen species (ROS). The combined application of GPx4 and Mitogen-activated protein kinase kinase (MEK) inhibitors, namely ML210 and trametinib, respectively, reduced lethality and tumor-like phenotypes in these flies. Notably, this combination treatment synergistically suppressed the proliferation of human PDAC cells and their corresponding xenografts in mice by inducing ROS accumulation, which triggered ferroptosis. These results suggest that inducing ferroptosis could represent a promising therapeutic strategy for PDAC.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4618-4635"},"PeriodicalIF":12.0,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432899/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144226037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Molecular TherapyPub Date : 2025-09-03Epub Date: 2025-06-14DOI: 10.1016/j.ymthe.2025.06.022
David D Fuller, Sabhya Rana, Prajwal P Thakre, Ethan S Benevides, Megan K Pope, Adrian G Todd, Victoria N Jensen, Lauren Vaught, Denise A Cloutier, Roberto A Ribas, Reece C Larson, Matthew S Gentry, Ramon C Sun, Vijay Chandran, Manuela Corti, Darin J Falk, Barry J Byrne
{"title":"Neonatal systemic gene therapy restores cardiorespiratory function in a rat model of Pompe disease.","authors":"David D Fuller, Sabhya Rana, Prajwal P Thakre, Ethan S Benevides, Megan K Pope, Adrian G Todd, Victoria N Jensen, Lauren Vaught, Denise A Cloutier, Roberto A Ribas, Reece C Larson, Matthew S Gentry, Ramon C Sun, Vijay Chandran, Manuela Corti, Darin J Falk, Barry J Byrne","doi":"10.1016/j.ymthe.2025.06.022","DOIUrl":"10.1016/j.ymthe.2025.06.022","url":null,"abstract":"<p><p>Absence of functional acid-α-glucosidase (GAA) leads to early onset Pompe disease with cardiorespiratory and neuromuscular failure. A novel Pompe rat model (Gaa<sup>-/-</sup>) was used to test the hypothesis that neonatal gene therapy with adeno-associated virus serotype 9 (AAV9) restores cardiorespiratory neuromuscular function across the lifespan. Temporal vein administration of AAV9-DES-GAA or sham (saline) injection was done on postnatal day 1; rats were studied at 6-12 months old. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI) revealed that AAV-GAA treatment normalized diaphragm muscle glycogen as well as glycans. In vivo magnetic resonance imaging demonstrated that impaired cardiac volumes in Gaa<sup>-/-</sup> rats were corrected by AAV-GAA treatment. Biochemical assays showed that AAV treatment increased GAA activity in the heart, diaphragm, quadriceps, and spinal cord. Inspiratory tidal volume and minute ventilation were increased in AAV-GAA-treated vs. saline-treated Pompe rats. Neurophysiological phrenic nerve recordings and spinal histological evaluation indicated that AAV-GAA treatment drove functional neuronal GAA expression. We conclude that neonatal AAV9-DES-GAA therapy drives sustained, functional GAA expression and improved cardiorespiratory function in the Gaa<sup>-/-</sup> rat model of Pompe disease.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4276-4289"},"PeriodicalIF":12.0,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432874/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Molecular TherapyPub Date : 2025-09-03Epub Date: 2024-11-19DOI: 10.1016/j.ymthe.2024.11.021
Charalambos Kaittanis, Tyler Teceno, Ashley Knight, Yoann Petibon, Phil Sandoval, Lawrence Cohen, Shin Hye Ahn, Anthony P Belanger, Louise M Clark, Quang-De Nguyen, Wanida Ruangsiriluk, Shreya Mukherji, Cristian C Constantinescu, Amy Llopis Amenta, Sarav Narayanan, Mugdha Deshpande, Rizwana Islam, Shipeng Yuan, Paul McQuade, Christopher T Winkelmann, Talakad G Lohith
{"title":"Longitudinal imaging of therapeutic enzyme expression after gene therapy for Fabry disease using positron emission tomography and the radiotracer [<sup>18</sup>F]AGAL.","authors":"Charalambos Kaittanis, Tyler Teceno, Ashley Knight, Yoann Petibon, Phil Sandoval, Lawrence Cohen, Shin Hye Ahn, Anthony P Belanger, Louise M Clark, Quang-De Nguyen, Wanida Ruangsiriluk, Shreya Mukherji, Cristian C Constantinescu, Amy Llopis Amenta, Sarav Narayanan, Mugdha Deshpande, Rizwana Islam, Shipeng Yuan, Paul McQuade, Christopher T Winkelmann, Talakad G Lohith","doi":"10.1016/j.ymthe.2024.11.021","DOIUrl":"10.1016/j.ymthe.2024.11.021","url":null,"abstract":"<p><p>Longitudinal, non-invasive, in vivo monitoring of therapeutic gene expression is an unmet need for gene therapy (GT). Positron emission tomography (PET) radiotracers designed to bind to therapeutic proteins may provide a sensitive imaging platform to guide treatment response and dose optimization in GT. Herein, we evaluate a novel PET tracer ([<sup>18</sup>F]AGAL) for targeting α-galactosidase A (GLA), an enzyme deficient in Fabry disease. Gla knockout mice were subjected to either GT with an adeno-associated virus encoding the human GLA (AAV<sub>GLA</sub>) or recombinant GLA for enzyme replacement studies. PET imaging, ex vivo autoradiography, biochemical analyses and radiation dosimetry were performed. [<sup>18</sup>F]AGAL exhibited pH-dependent binding to GLA, suggesting recognition of the active enzyme residing within the acidified lysosomes. Imaging studies in the Fabry mouse model showed quick renal clearance with high radioactive uptake in the heart at 6 weeks that was sustained for 26 weeks after a single administration of AAV<sub>GLA</sub>, indicating effective and durable transgene expression from GT. Good concordance was achieved between in vivo PET imaging and ex vivo quantification of GLA levels in biofluids and tissues. Biodistribution and dosimetry in non-human primate showed acceptable radiation exposure for multiple injections, demonstrating its potential for translation to clinical trial use.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4381-4393"},"PeriodicalIF":12.0,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Molecular TherapyPub Date : 2025-09-03Epub Date: 2025-05-27DOI: 10.1016/j.ymthe.2025.05.025
Anna Maria Giudice, Sydney L Roth, Stephanie Matlaga, Evan Cresswell-Clay, Pamela Mishra, Patrick M Schürch, Kwame Attah M Boateng-Antwi, Minu Samanta, Guillem Pascual-Pasto, Vincent Zecchino, Timothy T Spear, Brendan McIntyre, Neil C Chada, Tingting Wang, Lingling Liu, Ruoning Wang, John T Wilson, Adam J Wolpaw, Kristopher R Bosse
{"title":"Reprogramming the neuroblastoma tumor immune microenvironment to enhance GPC2 CAR T cells.","authors":"Anna Maria Giudice, Sydney L Roth, Stephanie Matlaga, Evan Cresswell-Clay, Pamela Mishra, Patrick M Schürch, Kwame Attah M Boateng-Antwi, Minu Samanta, Guillem Pascual-Pasto, Vincent Zecchino, Timothy T Spear, Brendan McIntyre, Neil C Chada, Tingting Wang, Lingling Liu, Ruoning Wang, John T Wilson, Adam J Wolpaw, Kristopher R Bosse","doi":"10.1016/j.ymthe.2025.05.025","DOIUrl":"10.1016/j.ymthe.2025.05.025","url":null,"abstract":"<p><p>Poor tumor trafficking and the immunosuppressive tumor microenvironment (TME) limit chimeric antigen receptor (CAR) T cell efficacy in solid tumors, such as neuroblastoma. We previously optimized GPC2 CARs in human neuroblastoma xenografts leading to clinical translation; however, there have not been preclinical studies using immunocompetent models. Thus, here we generated murine GPC2 CAR T cells using the D3-GPC2-targeting single-chain variable fragment being utilized clinically (NCT05650749) and tested them in neuroblastoma syngeneic allografts. Immune-profiling of GPC2 CAR T cell-treated tumors revealed significant reprogramming of the TME, most notably poor intra-tumor CAR T cell persistence being associated with increased recruitment of myeloid-derived suppressor cells (MDSCs), along with MDSC-recruiting CXCL1/2 chemokines. These tumor-infiltrating MDSCs directly inhibited GPC2 CAR T cell activation, proliferation, and cytotoxicity ex vivo. To both capitalize on this chemokine gradient and mitigate MDSC-tumor trafficking, we engineered GPC2 CAR T cells to express the CXCL1/2 receptor, CXCR2. CXCR2-armored GPC2 CAR T cells migrated toward CXCL1/2 gradients, enhanced anti-neuroblastoma efficacy, and reduced the level of MDSCs in the TME. Together, these findings suggest CAR T cell studies in immunocompetent models are imperative to define mechanisms of solid tumor immune escape and rationally design armoring strategies that will lead to durable clinical efficacy.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4552-4569"},"PeriodicalIF":12.0,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432918/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144174195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Airway-applied mRNA vaccine needs tailored sequence design and high standard purification that removes devastating dsRNA contaminant.","authors":"Jingjing Zhang, Chao Li, Yuheng Liu, Rui Liao, Dian He, Lifeng Xu, Tingting Chen, Qin Xiao, Mingxing Luo, Yang Chen, Yali Li, Huaxing Zhu, Joseph Rosenecker, Xiaoyan Ding, Shuchen Pei, Shan Guan","doi":"10.1016/j.ymthe.2025.05.024","DOIUrl":"10.1016/j.ymthe.2025.05.024","url":null,"abstract":"<p><p>The development of mucosal mRNA vaccines is promising but extremely challenging. Major efforts have been focused on optimizing delivery systems, but it is still unknown whether the intrinsic quality of mRNA components significantly impacts the potency of airway-inoculated mRNA vaccines. Here, we systematically demonstrate that mucosal mRNA vaccine requires higher standards of purification and a tailor-designed sequence to fulfill its potency compared to its parenteral-route-inoculated counterpart. Double-stranded RNA (dsRNA) contaminants are prone to trigger the innate immune response in the airway that activates the mRNA degradation mechanism, thereby diminishing mRNA expression and subsequent antigen-specific immune responses. To address these challenges, we developed a strategy that combines optimized untranslated regions (UTRs) screened from endogenous genes of pulmonary cells with affinity chromatography-based purification, which effectively removed dsRNA contaminants. The optimized mRNA administered via the airway route not only demonstrated superior protein expression (30-fold increase) and reduced inflammation in the lung but also promoted robust adaptive immunity comprising significantly elevated systemic, cellular, and mucosal immune responses. This was in stark contrast to the intramuscular-injected counterpart that displayed less-pronounced benefits. Our findings offer new insights into the development of mucosal mRNA therapeutics from an overlooked but crucial perspective of optimizing mRNA components.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4193-4215"},"PeriodicalIF":12.0,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432847/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144183291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Molecular TherapyPub Date : 2025-09-03Epub Date: 2025-05-28DOI: 10.1016/j.ymthe.2025.05.030
Dan Lu, Hui-Yi Chu, Soo Park, Mark Landon, Masanao Tsuda, Earl Avramis, Carissa Dege, Thomas Dailey, Yijia Pan, Sandeep Kothapally Hanok, Matthew Denholtz, Ramzey Abujarour, Tom Lee, John Goulding, Martin Hosking, Jodie Goodridge, Eigen Peralta, Bahram Valamehr
{"title":"A novel CD3ε fusion receptor allows T cell engager use in TCR-less allogeneic CAR T cells to improve activity and prevent antigen escape.","authors":"Dan Lu, Hui-Yi Chu, Soo Park, Mark Landon, Masanao Tsuda, Earl Avramis, Carissa Dege, Thomas Dailey, Yijia Pan, Sandeep Kothapally Hanok, Matthew Denholtz, Ramzey Abujarour, Tom Lee, John Goulding, Martin Hosking, Jodie Goodridge, Eigen Peralta, Bahram Valamehr","doi":"10.1016/j.ymthe.2025.05.030","DOIUrl":"10.1016/j.ymthe.2025.05.030","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) T cell therapies have shown clinical success in treating hematologic malignancies. However, heterogeneous target antigen expression can impair the durability of response. Combining CAR and T cell engagers (TCEs) targeting additional tumor antigens can address tumor heterogeneity and antigen escape. In allogeneic settings, eliminating the T cell receptor (TCR) of the adoptive T cell therapy prevents graft-versus-host disease. However, the absence of TCR leads to loss of surface CD3 expression, preventing cooperative activity with CD3-directed TCEs. We utilized induced pluripotent stem cells (iPSCs) to support the required multiplexed editing, establish a renewable starting material for off-the-shelf manufacture, and create the desired TCR-less CAR<sup>+</sup> CD3<sup>+</sup> T cells. Here, we illustrate surface expression of a CD3ε fusion receptor (CD3FR) in iPSC-derived CAR T (CAR iT) cells, enabling TCE-mediated targeting of diverse antigens. In vitro and in vivo, CD3FR<sup>+</sup> CAR iT cells demonstrated potent cytotoxic response and cooperative activity against mixed tumor lines and multiple antigens. CD3FR<sup>+</sup> iT cells were further engineered to secrete TCEs, eliminating the need for extra supplementation with TCEs. Collectively, the data highlight the ability to integrate TCEs with allogeneic CAR iT cells for multi-antigen targeting, overcoming tumor relapse, and supporting off-the-shelf therapy for patient access.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4570-4583"},"PeriodicalIF":12.0,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432869/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144181458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Molecular TherapyPub Date : 2025-09-03Epub Date: 2025-05-31DOI: 10.1016/j.ymthe.2025.05.038
Elaina Coleborn, Raluca Ghebosu, Joy Wolfram, Fernando Souza-Fonseca-Guimaraes
{"title":"Cancer-derived extracellular vesicles in natural killer cell immune evasion: Molecular mechanisms and therapeutic insights.","authors":"Elaina Coleborn, Raluca Ghebosu, Joy Wolfram, Fernando Souza-Fonseca-Guimaraes","doi":"10.1016/j.ymthe.2025.05.038","DOIUrl":"10.1016/j.ymthe.2025.05.038","url":null,"abstract":"<p><p>Natural killer cells are innate lymphocytes equipped with the ability to rapidly identify and eliminate cancer cells. However, cancer cells release nanosized extracellular vesicles that can induce an immunosuppressive tumor microenvironment, subsequently hindering natural killer cell immunosurveillance. Studies have reported that extracellular vesicles derived from different cancers, such as acute myeloid leukemia, melanoma, mesothelioma, head and neck squamous carcinoma, lung carcinoma, breast cancer, hepatocellular carcinoma, and pancreatic ductal adenocarcinoma, can induce natural killer cell dysfunction by suppressing cytolytic proteins and downregulating expression of receptors involved in the recognition of oncogenic cells. Additionally, cancer-derived extracellular vesicles can interfere with natural killer cell survival, proliferation, cell migration, and metabolic functions. Therefore, extracellular vesicle-induced natural killer cell suppression has emerged as a key target for research and new therapeutic approaches to recover and enhance the tumoricidal potential of these immune cells. Here, we summarize the current knowledge regarding cancer-derived extracellular vesicles and natural killer cell interactions, their role in immunosuppression, implications for developing efficient cellular immunotherapies and outstanding questions in this field.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4113-4129"},"PeriodicalIF":12.0,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144199577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Molecular TherapyPub Date : 2025-09-03Epub Date: 2025-05-30DOI: 10.1016/j.ymthe.2025.05.033
Rubina Thomas, Julie K Ritchey, John F DiPersio, Miriam Y Kim
{"title":"Targeting CD117 on hematopoietic stem and progenitor cells impairs CAR T cell activity.","authors":"Rubina Thomas, Julie K Ritchey, John F DiPersio, Miriam Y Kim","doi":"10.1016/j.ymthe.2025.05.033","DOIUrl":"10.1016/j.ymthe.2025.05.033","url":null,"abstract":"<p><p>CD117 is a cell-surface receptor expressed on hematopoietic stem and progenitor cells and acute myeloid leukemia (AML), and thus CD117-targeting chimeric antigen receptor T cells (CART117) can function as both conditioning for hematopoietic stem cell transplantation and a therapy for AML. We developed human and mouse CART117 to evaluate the safety and feasibility of targeting CD117 in preclinical mouse models. Human CART117 had potent anti-tumor activity while also mediating significant hematopoietic toxicity in a humanized mouse model. Murine CART117 (mCART117) led to systemic and hematopoietic toxicity without anti-leukemic benefit in immunocompetent C57BL/6 mice. Intriguingly, mCART117 was able to eliminate CD117<sup>+</sup> cells in the spleen but not in the bone marrow (BM). Of note, proliferation of BM CD117<sup>+</sup> cells in response to lymphodepleting chemotherapy amplified mCART117-mediated systemic toxicity. Alternative lymphodepletion with radiation ameliorated the systemic toxicity of mCART117 but did not improve anti-leukemic efficacy. Immunodeficient mice given mCART117 in the absence of lymphodepletion died from severe pancytopenia, and this effect was recapitulated by regulatory T cell depletion in immunocompetent mice. Increasing CD117 expression on AML improved the anti-leukemic efficacy and toxicity profile of mCART117. In conclusion, mCART117 anti-leukemic activity is impaired in immunocompetent mice when CD117 is expressed at physiological levels on AML.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4584-4599"},"PeriodicalIF":12.0,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432900/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144226041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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