Molecular Cancer Therapeutics最新文献

{"title":"M4205 (IDRX-42) Is a Highly Selective and Potent Inhibitor of Relevant Oncogenic Driver and Resistance Variants of KIT in Cancer.","authors":"Christina Esdar, Nina Linde, Andreas Blum, Hanno Schieferstein, Christine Drechsler, Eva Sherbetjian, Carl Petersson, Edith Ross, Birgitta Leuthner, Ulrich Grädler, Dieter Dorsch, Andree Blaukat","doi":"10.1158/1535-7163.MCT-24-0699","DOIUrl":"10.1158/1535-7163.MCT-24-0699","url":null,"abstract":"<p><p>Primary activating mutations in KIT (exon 9/11) are key driver alterations in about 80% of gastrointestinal stromal tumors (GIST). Imatinib, a small-molecule tyrosine kinase inhibitor, is used successfully as first-line therapy for patients with unresectable metastatic or recurrent GIST, but secondary resistance mutations in the KIT kinase domains frequently occur. Currently approved later-line therapies target these mutations incompletely with limited clinical benefit. M4205, a kinome-selective KIT inhibitor, was designed to address this high unmet medical need by inhibiting all relevant KIT driver and resistance mutations. Compared with imatinib, M4205 shows stronger antitumor activity in preclinical GIST models driven by oncogenic KIT driver mutations. M4205 demonstrates clinically relevant efficacy in a range of preclinical GIST models expressing different secondary KIT resistance mutations. The kinase selectivity profile of M4205 is superior to the registered standard of care and investigational agents. M4205, now IDRX-42, is currently being investigated in a phase I first-in-human study in participants with GIST.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1040-1053"},"PeriodicalIF":5.3,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12214875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143523869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Coinhibition of Aurora Kinase B and SUV4-20H Induces Synthetic Lethality in Wild-type p53-Deficient Cancer Cells.","authors":"Lei Duan, Kelsey M O'Hara, Andrew Caldemeyer, Carl G Maki","doi":"10.1158/1535-7163.MCT-24-0928","DOIUrl":"10.1158/1535-7163.MCT-24-0928","url":null,"abstract":"<p><p>The tumor suppressor p53 is inactivated by mutation or deletion in more than half of all human cancers. Wild-type p53 induces a G1-phase arrest when activated to halt cell proliferation and division. Accordingly, p53-mutated or -deficient cancers may be especially sensitive to agents that target proliferating and/or dividing cells. Barasertib (AZD2811) targets the mitotic Aurora kinase B and is in current clinical trials for various cancers. SUV4-20H1 and H2 are histone methyltransferases that can affect mitosis by regulating chromatin compaction in and around centromeres. The drug A196 inhibits SUV4-20H1 and H2. In the current study, we found combined treatment with barasertib plus A196 induces a pronounced synthetic lethality effect in p53-deficient cancer cells. Mechanistically, we found barasertib plus A196 kills p53-deficient cells by inhibiting the spindle assembly checkpoint and inducing massive chromosome missegregations and toxic aneuploidy. Among breast cancer subtypes, triple-negative breast cancer cells were the most sensitive to this drug combination. Lastly, we found in two different p53-mutated cell line tumor models that barasertib plus A196 has greater antitumor activity than either single agent. Our results suggest cotargeting of Aurora kinase B and SUV4-20H1/2 could be effective against p53-mutated or -deficient cancers, including triple-negative breast cancers in which approximately 80% of cases are p53-mutated.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1020-1029"},"PeriodicalIF":5.3,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PF-08046032: A Novel, Investigational CD25-Directed Antibody-Drug Conjugate Optimized for Selective Depletion of Regulatory T Cells in Advanced Malignant Tumors.","authors":"Sherif Abdelhamed, Xinqun Zhang, Weiping Zeng, Bryan Grogan, Luke Schilperoort, Reice James, Kelli C Burley, Samantha M Sarrett, Lauren Bou, Paromita Raha, Devra J Olson, Heather L Sigurjonsson, Melissa M C Dominguez, Tyler Nicholas, Haley D Neff-LaFord, James Fishburn, Andrea R Lim, Daniel Diolaiti, Priyanka Gupta, Cristina L Abrahams, Christopher M Carosino, Ryan A Heiser, Shyra J Gardai, Matthew R Levengood","doi":"10.1158/1535-7163.MCT-25-0101","DOIUrl":"10.1158/1535-7163.MCT-25-0101","url":null,"abstract":"<p><p>Regulatory T cells (Treg) are known to suppress antitumor immune responses, and their presence in the tumor microenvironment is associated with cancer progression; therefore, Treg depletion is a promising strategy to enhance cancer immunotherapy. PF-08046032 is a novel antibody-drug conjugate (ADC) designed to target Tregs in the tumor microenvironment via CD25, the α-chain of the IL-2 receptor frequently upregulated by intratumoral Tregs. PF-08046032 is composed of an affinity-detuned anti-CD25 antibody linked to monomethyl auristatin E, a potent cytotoxic agent. Affinity detuning increases PF-08046032 selectivity for CD25high intratumoral Tregs while minimizing peripheral blood Treg depletion, thus reducing the risk of autoimmune toxicities. In preclinical experiments, PF-08046032 selectively depleted Tregs compared with CD8+ T cells and preferentially depleted Tregs with high CD25 expression. PF-08046032 showed dose-dependent antitumor activity in CD25-expressing human lymphoma xenograft models, whereas a similarly detuned anti-mouse CD25 surrogate ADC depleted intratumoral Tregs and drove CD8+ T-cell activation in murine tumor models. This effect resulted in robust antitumor activity as a single agent and in combination with anti-PD1 checkpoint inhibitor blockade. Lastly, PF-08046032 was well-tolerated in nonhuman primates and mitigated the persistent depletion of peripheral blood Treg that was observed with a high-affinity anti-CD25 ADC comparator, demonstrating the safety benefit of a detuned-affinity ADC format. PF-08046032 represents an innovative therapeutic approach for depletion of intratumoral Tregs that may offer an improved safety profile and efficacy over traditional Treg-depleting agents.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"963-975"},"PeriodicalIF":5.3,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144013332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"5'-S-(3-Aminophenyl)-5'-thioadenosine, a Novel Chemoprotective Agent for Reducing Toxic Side Effects of Fluorouracil in Treatment of MTAP-Deficient Cancers.","authors":"Si Zhang, Hui Xue, Nelson K Y Wong, Thomas Doerksen, Fuqiang Ban, Shawn Aderson, Stanislav Volik, Yen-Yi Lin, Zhongye Dai, Ivica Bratanovic, Hongwei Cheng, Colin Collins, Artem Cherkasov, Jeremy E Wulff, Yuzhuo Wang","doi":"10.1158/1535-7163.MCT-24-0656","DOIUrl":"10.1158/1535-7163.MCT-24-0656","url":null,"abstract":"<p><p>Nucleobase analogue (NBA) drugs, such as 5-fluorouracil (5-FU), are effective chemotherapeutics, but their clinical use is limited by severe side effects. Compelling evidence suggests that the use of S-methyl-5'-thioadenosine (MTA) can selectively reduce NBA toxicity on normal tissues while maintaining the efficacy of NBAs on methylthioadenosine phosphorylase (MTAP)-deficient cancers. However, we found that MTA induced hypothermia at its effective dose, limiting its translational potential. We hypothesized that an MTA analogue can retain the protective function of MTA without undesired side effects. We screened a library of MTA analogues and identified 5'-S-(3-aminophenyl)-5'-thioadenosine (m-APTA) as a substrate of MTAP that could be converted to adenine, a necessary step for protection of normal cells from NBA toxicity. It selectively protected MTAP-expressing cells from 5-FU toxicity while it did not interfere with the cytotoxicity of 5-FU on isogenic MTAP-deficient cell lines. At effective dose, m-APTA protected the mouse hosts from 5-FU-induced toxicity (i.e., anemia) without the induction of hypothermia. Importantly, m-APTA provided host protection without compromising the efficacy of 5-FU on MTAP-deficient bladder cancer xenografts. In silico docking studies revealed that, unlike MTA, m-APTA interacts inefficiently with adenosine A1 receptor, providing a plausible explanation of the superior safety profile of m-APTA. Therefore, m-APTA can significantly improve the translational potential of the combination treatment strategy that selectively reduces NBA toxicity in normal cells while targeting MTAP-deficient cancers.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1030-1039"},"PeriodicalIF":5.3,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12221788/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Histotripsy-Focused Ultrasound Treatment Abrogates Tumor Hypoxia Responses and Stimulates Antitumor Immune Responses in Melanoma.","authors":"Brian Song, Heineken Queen, Sarah F Ferris, Reliza McGinnis, Chaitanya Karanam, Natalie Gatteno, Katherine Buglak, Hanna Kim, Jintao Xu, Kristie D Goughenour, Zhen Xu, Michal A Olszewski, Clifford S Cho, Anutosh Ganguly","doi":"10.1158/1535-7163.MCT-24-0715","DOIUrl":"10.1158/1535-7163.MCT-24-0715","url":null,"abstract":"<p><p>Histotripsy-focused ultrasound treatment gives rise to systemic antitumor immune responses. We investigated whether histotripsy effects on immunosuppressive tumor hypoxia were a potential mechanism for these immunostimulatory effects. Immunocompetent or CD8-deficient C57BL/6 mice with flank B16F10 or YUMM1.7 melanoma tumors underwent sham or subtotal histotripsy. Tumor growth, immune cell infiltration, and intratumoral hypoxia responses were examined using flow cytometry and fluorescence microscopy. Chemokine receptor CXCR3 and hypoxia-inducible factor-1α (HIF1α) were intercepted with antibodies and inhibitors to assess their roles in immune responses after histotripsy. Histotripsy-treated tumors exhibited rapid loss of intratumoral hypoxia and suppression of HIF1α and downstream prosurvival proteins. Histotripsy was followed by intratumoral upregulation of the CXCR3 ligand CXCL10 and CXCR3+/CD8+ T-cell infiltration. Tumor growth inhibition by histotripsy was significantly diminished in CD8-deficient mice and mice receiving anti-CXCR3 mAb. Post-histotripsy inhibition of hypoxia and tumor growth eventually receded in parallel with cessation of CD8+ T-cell influx, and pharmacologic HIF1α suppression with the MEK inhibitor trametinib substantially augmented the therapeutic effects of histotripsy. Transient abrogation of intratumoral hypoxia and HIF1α-associated hypoxia responses is mechanistically linked with intratumoral infiltration of activated CXCR3+/CD8+ T cells via CXCL10-CXCR3 engagement. These findings suggest that the immune effects of histotripsy may be regulated by hypoxia abrogation and that pharmacologic hypoxia abrogation could potentiate the immunotherapeutic effects of histotripsy.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1088-1098"},"PeriodicalIF":5.3,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12221799/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Harnessing senolytics and PARP inhibition to expand the antitumor activity of CDK4/6 inhibitors in prostate cancer.","authors":"Julian Brandariz, Lara I de Llobet, Victor Esquefa, Daniel Aguilar, Andrei Salca, Sara Arce-Gallego, Pablo Cresta Morgado, Arnau Sole Casaramona, Laura Agundez Muriel, Gisela Mir Arnau, Natalia Castro, Teresa Casals Galobart, Anna Oliveira Tercero, Irene Casanova-Salas, Marcos Malumbres, Joan Carles, Ángela Morellá-Aucejo, Andrea Bernardos, Ramón Martínez-Mañez, Joaquin Mateo, Nicolas Herranz","doi":"10.1158/1535-7163.MCT-24-0903","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0903","url":null,"abstract":"<p><p>Metastatic prostate cancer (mPC) is a lethal disease; most therapeutic options focus on androgen receptor (AR) signalling inhibition, but resistance eventually arises. Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have shown antitumor efficacy in mPC preclinical models, but their efficacy in mPC clinical trials has been limited. We hypothesize that novel combination therapies designed leveraging mPC adaptation to CDK4/6i could lead to increased and sustained antitumor effect. Herein, we demonstrate in a range of in vitro and in vivo prostate cancer models, including patient-derived xenografts, that prostate cancer cells adopt a senescent phenotype upon CDK4/6 inhibition that can be selectively targeted using senolytic compounds. Notably, interrupting CDK4/6 inhibition in intermittent drug schedules prompts a rapid bypass of the senescent phenotype that associates with a temporal downregulation of replisome proteins in RB1 proficient, but not in RB1 KO models, leading to DNA damage accumulation and replication stress following treatment withdrawal. This effect opens a window of opportunity for treatment with PARP inhibitors (PARPi): while upfront combined inhibition of CDK4/6 and PARP1 has no antitumor effect, their sequential use adding PARPi upon CDK4/6i withdrawal and cell cycle re-entry results in major antitumor activity. Our findings underscore the potential of CDK4/6i in prostate cancer therapy, particularly when administered under biology-driven sequential use of senolytic therapy or PARPi. Such strategic interventions hold promise in overcoming resistance and enhancing treatment outcomes for advanced prostate cancer patients and open avenues for repurposing CDK4/6i therapy in mPC.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel B7-H4xCD3 Bispecific T-cell Engager (PF-07260437) Synergizes with Breast Cancer Standard of Care and Immune Checkpoint Therapies.","authors":"Keith Abayasiriwardana, Lei Wu, Hanane Laklai, Malgorzata Nocula-Lugowska, Lioudmila Tchistiakova, Jatin Narula, Amy Jackson-Fisher, Jonathon Golas, My-Hanh Lam, Veronika Grinstein, Jung Wook Kang, Jessica C Kearney, Christine Hosselet, Erik Upeslacis, LuAnna Lemon, Yun Zhang, Changhua Ji, Bernard S Buetow, Martin B Finkelstein, Netonia Marshall, Stephanie Bisulco, Edward Rosfjord, Divya Mathur, Jennifer Athanacio, Ashley Thomas, Alexander Trageser, Diane Fernandez, Ziyue Karen Jiang, Sripad Ram, Edward Cabral, Lisa Manzuk, Kevin Maresca, Anand Giddabasappa, Clare Lees, Andrea T Hooper, Puja Sapra, Sudhakar Chintharlapalli","doi":"10.1158/1535-7163.MCT-24-0379","DOIUrl":"10.1158/1535-7163.MCT-24-0379","url":null,"abstract":"<p><p>Immune checkpoint inhibitors have shown limited success in breast cancer, the most common and deadly cancer in women worldwide. Novel immune therapies, such as CD3-engaging bispecific antibodies, have shown clinical promise in hematologic malignancies. However, developing CD3 bispecifics for solid tumors has been challenging due to the difficulty in identifying tumor-specific antigens. B7-H4 is proposed as an attractive tumor-associated antigen for breast cancer therapeutics with comprehensive coverage regardless of breast cancer molecular subtype. We designed a B7-H4-targeting CD3 bispecific molecule, PF-07260437, and demonstrated B7-H4-dependent pharmacology in vitro by directing cytotoxic T-cell killing to breast cancer cell lines. Treatment of cell line- and patient-derived xenograft in vivo models of human breast cancer with PF-07260437 induced substantial tumoricidal activity, often resulting in complete responses. Mechanistically, PF-07260437 increased T-cell number and activation, leading to efficient tumor killing. Additionally, combining PF-07260437 with standard of care (palbociclib plus fulvestrant) and a checkpoint inhibitor (anti-PD-1) showed combinatorial benefits in an immune-competent in vivo model. Clinically relevant noninvasive PET/CT imaging with a CD8-targeting tracer demonstrated PF-07260437-mediated increases in intratumoral CD8 T cells, highlighting the utility of CD8-PET technology to potentially assess biomarker changes in the clinic. Finally, the manageable toxicity profile of PF-07260437 was highlighted in an exploratory toxicology study in cynomolgus monkeys. These data support the clinical testing of PF-07260437 for treating B7-H4-expressing solid tumors, including breast cancer.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"976-992"},"PeriodicalIF":5.3,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12214883/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144003210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential Efficacy of Bevacizumab and Erlotinib in Preclinical Models of Renal Medullary Carcinoma and Fumarate Hydratase-Deficient Renal Cell Carcinoma.","authors":"Niki M Zacharias, Manuel Ozambela, Menuka Karki, Rong He, Pankaj K Chauhan, Pedro I Pesquera, Andres E Hernandez Gonzalez, Oscar Ochoa, Alberto Pieretti, Huiqin Chen, Carolyn De La Cerda, Zhiyuan Yu, Abha Grover, Samantha Hicks-Peña, Natalie W Fowlkes, Lei Wang, Tapati Maity, Priya Rao, Giannicola Genovese, Nizar M Tannir, Jose A Karam, Pavlos Msaouel","doi":"10.1158/1535-7163.MCT-24-0703","DOIUrl":"10.1158/1535-7163.MCT-24-0703","url":null,"abstract":"<p><p>Renal medullary carcinoma (RMC) and fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) are rare and highly aggressive cancers. Although the combination of vascular endothelial growth factor (VEGF) inhibition by bevacizumab and epidermal growth factor receptor (EGFR) inhibition by erlotinib is clinically used for both diseases, the differential effect of each component has not been investigated. Transcriptomic profiling revealed that RMC and FH-deficient tumor tissues demonstrate increased EGFR but not VEGF expression compared with adjacent normal kidney. Subsequent in vitro studies revealed that RMC and FH-deficient cell lines are sensitive to erlotinib treatment, whereas clear cell RCC cell lines are resistant. We developed patient-derived xenograft (PDX) models of tumors exposed to first-line therapies to represent treatment-experienced RMC and FH-deficient RCC models. These models were then used to determine tumor growth response to angiogenesis inhibition by bevacizumab alone or in combination with erlotinib. The FH-deficient RCC PDX model responded to either bevacizumab or erlotinib alone or in combination while the RMC PDX responded only to erlotinib consistent with clinical and preclinical data suggesting that RMC is refractory to angiogenesis inhibition. Statistically higher expression of EGFR was observed in the RMC PDX model compared to the FH-deficient model; while higher phosphorylated tyrosine-416 SRC expression was observed in FH-deficient PDX model compared to the RMC model. Our preclinical data suggest that EGFR signaling differentially modulates tumor growth in RMC and FH-deficient RCC and that angiogenesis inhibition is a valid target in FH-deficient RCC but not RMC.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12323885/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of a Tumor-Specific Multivalent CD40 Agonist Antibody FAPxCD40 for Cancer Therapy: Balancing Efficacy and Toxicity.","authors":"Simeng Chen, Yuan Lin, Dan Li, Xiaoru Zhou, Xing Sun, Changyong Yang, Cheng Liao","doi":"10.1158/1535-7163.MCT-24-0717","DOIUrl":"10.1158/1535-7163.MCT-24-0717","url":null,"abstract":"<p><p>CD40 agonist antibodies are reported to augment tumor antigen presentation and have shown potential antitumor efficacy in clinical trials. Nevertheless, the limited efficacy and on-target, off-tumor toxicity restrict the further development of these antibodies. We hypothesize that the toxicity could be overcome by activating CD40 specifically through tumor-specific antigens. Additionally, limited efficacy can be improved through the strategic construction of CD40 bispecific antibodies (bsAb) to refine the degree of CD40 clustering. Therefore, we developed anti-FAPxCD40 bsAbs with varying valences of anti-CD40 moieties, including bivalent FAPxCD40-2, tetravalent FAPxCD40-4, and hexavalent FAPxCD40-6. The tetravalent design of FAPxCD40-4 led to efficient activation of antigen-presenting cells and T-cell priming in the presence of FAP. The antitumor activity and toxicity of FAPxCD40-4 were tested in the CD40-humanized mFAP-MC38 xenograft model. Compared with non-tumor-targeting CD40 agonist or bivalent bsAbs, FAPxCD40-4 displayed potent antitumor activity and negligible toxicity at low doses, indicating an ideal therapeutic window. Our results demonstrated that the valences of the anti-CD40 moieties in bsAbs can be modulated to optimize CD40 activation and enlarge the therapeutic window of this type of molecules.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1063-1074"},"PeriodicalIF":5.3,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD24-Targeted CAR-T Cells Mediated Long-term Antitumor Efficacy through Activation of Endogenous Tumor Immune Responses.","authors":"Yong Huang, Xiao Yang, Jing Li, Weilin Zhou, Fengling Wang, Jiaqian Li, Yalan Zhang, Feiyang Yan, Haozhan Gao, Xinyu Gu, Sha Luo, Yuening Yang, Mei Liu, Xiao Liang, Lin Jiang, Maorong Fu, Jinhua Su, Yuquan Wei, Wei Wang","doi":"10.1158/1535-7163.MCT-24-0597","DOIUrl":"10.1158/1535-7163.MCT-24-0597","url":null,"abstract":"<p><p>Chimeric antigen receptor-modified T (CAR-T) cell therapy has achieved remarkable progress in the treatment of B-cell malignancies, whereas suboptimal therapeutic outcomes have been observed in solid tumors. Immunosuppression from microenvironment of tumors causing decreased killing ability, poor expansion, and persistence of CAR-T cells results in reduced efficacy. Endeavors aimed at eliciting endogenous immune responses have been found to enhance and sustain the antitumor effects of CAR-T cell therapy. In this study, we reported that CAR-T cells targeting cluster of differentiation 24 (CD24), a potential tumor biomarker and an innate immune checkpoint molecule, evoked robust antitumor efficacy and elicited long-term tumor regression. CD24-targeted CAR-T (CD24 CAR-T) cells showed strong cytotoxicity to CD24-positive cancer cells in vitro and mediated inhibition of tumor growth in immunodeficient mice. Moreover, in immunocompetent mice, CD24 CAR-T cells exhibited robust antitumor ability without side effects. Of note, mice that received CD24 CAR-T cells withstood both CD24-positive and CD24-negative tumors rechallenge. We detected a high level of IFN-γ release in splenic lymphocytes of the rechallenged mice, as well as tumor-reactive antibody in serum, indicating the endogenous tumor immune responses was activated. In summary, our findings showed that CD24 CAR-T cells targeting immune checkpoint have superior antitumor efficacy in preclinical models and may provide a strategy for the treatment of solid tumors.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1075-1087"},"PeriodicalIF":5.3,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}