{"title":"Q&A: Owen Witte on Translational Research in Cancer.","authors":"","doi":"10.1158/2643-3230.BCD-24-0069","DOIUrl":"https://doi.org/10.1158/2643-3230.BCD-24-0069","url":null,"abstract":"","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"OF1-OF3"},"PeriodicalIF":11.2,"publicationDate":"2024-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140855845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rawan G Faramand, Sae Bom Lee, Michael D Jain, Biwei Cao, Xuefeng Wang, Kai Rejeski, Marion Subklewe, Johannes F Fahrmann, Neeraj Y Saini, Samir M Hanash, Yun Pyo Kang, Darwin Chang, Paolo C Rodriguez, Erin A Dean, Taiga Nishihori, Bijal D Shah, Aleksandr Lazaryan, Julio Chavez, Farhad Khimani, Javier A Pinilla-Ibarz, Marian Dam, Kayla M Reid, Salvatore A Corallo, Meghan Menges, Melanie Hidalgo Vargas, Jay K Mandula, Brian A Holliday, Christina A Bachmeier, Kelly Speth, Qinghua Song, Mike Mattie, Frederick L Locke, Marco L Davila
{"title":"Baseline Serum Inflammatory Proteins Predict Poor CAR T Outcomes in Diffuse Large B-cell Lymphoma.","authors":"Rawan G Faramand, Sae Bom Lee, Michael D Jain, Biwei Cao, Xuefeng Wang, Kai Rejeski, Marion Subklewe, Johannes F Fahrmann, Neeraj Y Saini, Samir M Hanash, Yun Pyo Kang, Darwin Chang, Paolo C Rodriguez, Erin A Dean, Taiga Nishihori, Bijal D Shah, Aleksandr Lazaryan, Julio Chavez, Farhad Khimani, Javier A Pinilla-Ibarz, Marian Dam, Kayla M Reid, Salvatore A Corallo, Meghan Menges, Melanie Hidalgo Vargas, Jay K Mandula, Brian A Holliday, Christina A Bachmeier, Kelly Speth, Qinghua Song, Mike Mattie, Frederick L Locke, Marco L Davila","doi":"10.1158/2643-3230.BCD-23-0056","DOIUrl":"10.1158/2643-3230.BCD-23-0056","url":null,"abstract":"<p><p>A subset of patients with diffuse large B-cell lymphoma (DLBCL) treated with CD19 chimeric antigen receptor (CAR) T-cell therapy have poor clinical outcomes. We report serum proteins associated with severe immune-mediated toxicities and inferior clinical responses in 146 patients with DLBCL treated with axicabtagene ciloleucel. We develop a simple stratification based on pre-lymphodepletion C reactive protein (CRP) and ferritin to classify patients into low-, intermediate-, and high-risk groups. We observe that patients in the high-risk category were more likely to develop grade ≥3 toxicities and had inferior overall and progression-free survival. We sought to validate our findings with two independent international cohorts demonstrating that patients classified as low-risk have excellent efficacy and safety outcomes. Based on routine and readily available laboratory tests that can be obtained prior to lymphodepleting chemotherapy, this simple risk stratification can inform patient selection for CAR T-cell therapy.</p><p><strong>Significance: </strong>CAR T-cell therapy has changed the treatment paradigm for patients with relapsed/refractory hematologic malignancies. Despite encouraging efficacy, a subset of patients have poor clinical outcomes. We show that a simple clinically applicable model using pre-lymphodepletion CRP and ferritin can identify patients at high risk of poor outcomes. This article is featured in Selected Articles from This Issue, p. 80.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"106-113"},"PeriodicalIF":11.5,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10905320/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139404649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The Siren Song of Synergy.","authors":"Patrick D Bhola, Anthony Letai","doi":"10.1158/2643-3230.BCD-24-0004","DOIUrl":"10.1158/2643-3230.BCD-24-0004","url":null,"abstract":"<p><strong>Summary: </strong>In ancient Greek mythology, sirens were creatures of stunning beauty whose mystical songs led sailors to sail their boats onto hidden rocks and into total destruction. In this issue, Mason-Osann and colleagues present data in the context of acute myelogenous leukemia to suggest that while synergy may show initial attractions in drug combinations, it may carry with it hazards previously unforeseen. See related article by Mason-Osann et al., p. 95 (1).</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"81-82"},"PeriodicalIF":11.5,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10905523/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139708086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Understanding Mechanisms of Response to CAR T-cell Therapy through Single-Cell Sequencing: Insights and Challenges.","authors":"Nicholas J Haradhvala, Marcela V Maus","doi":"10.1158/2643-3230.BCD-23-0212","DOIUrl":"10.1158/2643-3230.BCD-23-0212","url":null,"abstract":"<p><strong>Summary: </strong>Single-cell RNA sequencing has emerged as a powerful technique to understand the molecular features of chimeric antigen receptor (CAR) T cells that associate with clinical outcomes. Here we discuss the common themes that have emerged from across single-cell studies of CAR T-cell therapy, and summarize the challenges in interpreting this complex data type.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"86-89"},"PeriodicalIF":11.5,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10905509/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139703552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Correction: Defining an Optimal Dual-Targeted CAR T-cell Therapy Approach Simultaneously Targeting BCMA and GPRC5D to Prevent BCMA Escape-Driven Relapse in Multiple Myeloma.","authors":"","doi":"10.1158/2643-3230.BCD-24-0017","DOIUrl":"10.1158/2643-3230.BCD-24-0017","url":null,"abstract":"","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":"5 2","pages":"132"},"PeriodicalIF":11.2,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10905514/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139997703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Altered Oxidative Phosphorylation Confers Vulnerability on IDH1-Mutant Leukemia Cells: Is This Therapeutically Tractable?","authors":"David P Steensma","doi":"10.1158/2643-3230.BCD-23-0255","DOIUrl":"10.1158/2643-3230.BCD-23-0255","url":null,"abstract":"<p><strong>Summary: </strong>Isocitrate dehydrogenase (IDH)-mutant acute myeloid leukemia (AML) is treatable with inhibitors of mutant IDH and also responds well to combination therapies including venetoclax, but most patients with IDH-mutant AML either never achieve complete remission or relapse because mutant hematopoietic stem cells persist despite treatment. An interesting new study in Blood Cancer Discovery characterizes a specific vulnerability in the mitochondrial oxidative phosphorylation system in preleukemic hematopoietic stem cells from patients with IDH1 mutations that is not present in those with IDH2 mutations; will this susceptibility prove amenable to therapy? See related article by Landberg et al., p. 114 (10).</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"83-85"},"PeriodicalIF":11.5,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10905515/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139708085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Andrew Kowalski, Jill Lykon, Benjamin Diamond, David G Coffey, Marcella Kaddoura, Francesco Maura, James E Hoffman, Dickran Kazandjian, Ola Landgren
{"title":"Emerging Strategies for the Prevention of Immune Toxicities Associated with T cell-Engaging Cancer Therapies.","authors":"Andrew Kowalski, Jill Lykon, Benjamin Diamond, David G Coffey, Marcella Kaddoura, Francesco Maura, James E Hoffman, Dickran Kazandjian, Ola Landgren","doi":"10.1158/2643-3230.BCD-23-0228","DOIUrl":"10.1158/2643-3230.BCD-23-0228","url":null,"abstract":"<p><strong>Summary: </strong>Immune-related toxicities including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are common side effects of bispecific antibody and chimeric antigen receptor (CAR) T-cell therapies of hematologic malignancies. As anti-inflammatory therapy (the standard of care) is variably effective in mitigating these toxicities after onset, here we discuss emerging evidence for shifting the strategy from mitigation to prevention.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"90-94"},"PeriodicalIF":11.5,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10905506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139088850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Emily Mason-Osann, Amy E Pomeroy, Adam C Palmer, Jerome T Mettetal
{"title":"Synergistic Drug Combinations Promote the Development of Resistance in Acute Myeloid Leukemia.","authors":"Emily Mason-Osann, Amy E Pomeroy, Adam C Palmer, Jerome T Mettetal","doi":"10.1158/2643-3230.BCD-23-0067","DOIUrl":"10.1158/2643-3230.BCD-23-0067","url":null,"abstract":"<p><p>Combination therapy is an important part of cancer treatment and is often employed to overcome or prevent drug resistance. Preclinical screening strategies often prioritize synergistic drug combinations; however, studies of antibiotic combinations show that synergistic drug interactions can accelerate the emergence of resistance because resistance to one drug depletes the effect of both. In this study, we aimed to determine whether synergy drives the development of resistance in cancer cell lines using live-cell imaging. Consistent with prior models of tumor evolution, we found that when controlling for activity, drug synergy is associated with increased probability of developing drug resistance. We demonstrate that these observations are an expected consequence of synergy: the fitness benefit of resisting a drug in a combination is greater in synergistic combinations than in nonsynergistic combinations. These data have important implications for preclinical strategies aiming to develop novel combinations of cancer therapies with robust and durable efficacy.</p><p><strong>Significance: </strong>Preclinical strategies to identify combinations for cancer treatment often focus on identifying synergistic combinations. This study shows that in AML cells combinations that rely on synergy can increase the likelihood of developing resistance, suggesting that combination screening strategies may benefit from a more holistic approach rather than focusing on drug synergy. See related commentary by Bhola and Letai, p. 81. This article is featured in Selected Articles from This Issue, p. 80.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"95-105"},"PeriodicalIF":11.5,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10905516/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139486512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Niklas Landberg, Thomas Köhnke, Yang Feng, Yusuke Nakauchi, Amy C Fan, Miles H Linde, Daiki Karigane, Kelly Lim, Rahul Sinha, Luca Malcovati, Daniel Thomas, Ravindra Majeti
{"title":"IDH1-Mutant Preleukemic Hematopoietic Stem Cells Can Be Eliminated by Inhibition of Oxidative Phosphorylation.","authors":"Niklas Landberg, Thomas Köhnke, Yang Feng, Yusuke Nakauchi, Amy C Fan, Miles H Linde, Daiki Karigane, Kelly Lim, Rahul Sinha, Luca Malcovati, Daniel Thomas, Ravindra Majeti","doi":"10.1158/2643-3230.BCD-23-0195","DOIUrl":"https://doi.org/10.1158/2643-3230.BCD-23-0195","url":null,"abstract":"<p><p>Rare preleukemic hematopoietic stem cells (pHSC) harboring only the initiating mutations can be detected at the time of acute myeloid leukemia (AML) diagnosis. pHSCs are the origin of leukemia and a potential reservoir for relapse. Using primary human samples and gene editing to model isocitrate dehydrogenase 1 (IDH1) mutant pHSCs, we show epigenetic, transcriptional, and metabolic differences between pHSCs and healthy hematopoietic stem cells (HSC). We confirm that IDH1-driven clonal hematopoiesis is associated with cytopenia, suggesting an inherent defect to fully reconstitute hematopoiesis. Despite giving rise to multilineage engraftment, IDH1-mutant pHSCs exhibited reduced proliferation, blocked differentiation, downregulation of MHC class II genes, and reprogramming of oxidative phosphorylation metabolism. Critically, inhibition of oxidative phosphorylation resulted in the complete eradication of IDH1-mutant pHSCs but not IDH2-mutant pHSCs or wild-type HSCs. Our results indicate that IDH1-mutant preleukemic clones can be targeted with complex I inhibitors, offering a potential strategy to prevent the development and relapse of leukemia.</p><p><strong>Significance: </strong>A high burden of pHSCs is associated with worse overall survival in AML. Using single-cell sequencing, metabolic assessment, and gene-edited human models, we find human pHSCs with IDH1 mutations to be metabolically vulnerable and sensitive to eradication by complex I inhibition. See related commentary by Steensma.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"OF1-OF18"},"PeriodicalIF":11.2,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139543189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Paola Neri, Benjamin G Barwick, David Jung, Jonathan C Patton, Ranjan Maity, Ines Tagoug, Caleb K Stein, Remi Tilmont, Noemie Leblay, Sungwoo Ahn, Holly Lee, Seth J Welsh, Daniel L Riggs, Nicholas Stong, Erin Flynt, Anjan Thakurta, Jonathan J Keats, Sagar Lonial, P Leif Bergsagel, Lawrence H Boise, Nizar J Bahlis
{"title":"ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma.","authors":"Paola Neri, Benjamin G Barwick, David Jung, Jonathan C Patton, Ranjan Maity, Ines Tagoug, Caleb K Stein, Remi Tilmont, Noemie Leblay, Sungwoo Ahn, Holly Lee, Seth J Welsh, Daniel L Riggs, Nicholas Stong, Erin Flynt, Anjan Thakurta, Jonathan J Keats, Sagar Lonial, P Leif Bergsagel, Lawrence H Boise, Nizar J Bahlis","doi":"10.1158/2643-3230.BCD-23-0061","DOIUrl":"10.1158/2643-3230.BCD-23-0061","url":null,"abstract":"<p><p>Immunomodulatory drugs (IMiD) are a backbone therapy for multiple myeloma (MM). Despite their efficacy, most patients develop resistance, and the mechanisms are not fully defined. Here, we show that IMiD responses are directed by IMiD-dependent degradation of IKZF1 and IKZF3 that bind to enhancers necessary to sustain the expression of MYC and other myeloma oncogenes. IMiD treatment universally depleted chromatin-bound IKZF1, but eviction of P300 and BRD4 coactivators only occurred in IMiD-sensitive cells. IKZF1-bound enhancers overlapped other transcription factor binding motifs, including ETV4. Chromatin immunoprecipitation sequencing showed that ETV4 bound to the same enhancers as IKZF1, and ETV4 CRISPR/Cas9-mediated ablation resulted in sensitization of IMiD-resistant MM. ETV4 expression is associated with IMiD resistance in cell lines, poor prognosis in patients, and is upregulated at relapse. These data indicate that ETV4 alleviates IKZF1 and IKZF3 dependency in MM by maintaining oncogenic enhancer activity and identify transcriptional plasticity as a previously unrecognized mechanism of IMiD resistance.</p><p><strong>Significance: </strong>We show that IKZF1-bound enhancers are critical for IMiD efficacy and that the factor ETV4 can bind the same enhancers and substitute for IKZF1 and mediate IMiD resistance by maintaining MYC and other oncogenes. These data implicate transcription factor redundancy as a previously unrecognized mode of IMiD resistance in MM. See related article by Welsh, Barwick, et al., p. 34. See related commentary by Yun and Cleveland, p. 5. This article is featured in Selected Articles from This Issue, p. 4.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"56-73"},"PeriodicalIF":11.2,"publicationDate":"2024-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10772538/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71486777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}