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2. Characteristics of anti-CD19 CAR T cell infusion products associated with efficacy and toxicity in patients with large B cell lymphomas

Author

Deng, Qing, Han, Guangchun, Puebla-Osorio, Nahum, Ma, Man Chun John, Strati, Paolo, Chasen, Beth, and Dai, Enyu

Subjects
T cells -- Receptors, Antigen receptors, T cell -- Usage -- Complications and side effects -- Physiological aspects, Non-Hodgkin's lymphomas -- Drug therapy, Immunotherapy -- Methods, Biological sciences, Health
Abstract

Autologous chimeric antigen receptor (CAR) T cell therapies targeting CD19 have high efficacy in large B cell lymphomas (LBCLs), but long-term remissions are observed in less than half of patients, and treatment-associated adverse events, such as immune effector cell-associated neurotoxicity syndrome (ICANS), are a clinical challenge. We performed single-cell RNA sequencing with capture-based cell identification on autologous axicabtagene ciloleucel (axi-cel) anti-CD19 CAR T cell infusion products to identify transcriptomic features associated with efficacy and toxicity in 24 patients with LBCL. Patients who achieved a complete response by positron emission tomography/computed tomography at their 3-month follow-up had three-fold higher frequencies of CD8 T cells expressing memory signatures than patients with partial response or progressive disease. Molecular response measured by cell-free DNA sequencing at day 7 after infusion was significantly associated with clinical response (P = 0.008), and a signature of CD8 T cell exhaustion was associated (q = 2.8 × 10.sup.-149) with a poor molecular response. Furthermore, a rare cell population with monocyte-like transcriptional features was associated (P = 0.0002) with high-grade ICANS. Our results suggest that heterogeneity in the cellular and molecular features of CAR T cell infusion products contributes to variation in efficacy and toxicity after axi-cel therapy in LBCL, and that day 7 molecular response might serve as an early predictor of CAR T cell efficacy. Single-cell transcriptomics reveals that the heterogeneity of anti-CD19 CAR T cell infusion products contributes to variability in clinical response, early molecular response and development of immune effector cell-associated neurotoxicity syndrome in patients with large B cell lymphomas., Author(s): Qing Deng [sup.1] , Guangchun Han [sup.2] , Nahum Puebla-Osorio [sup.1] , Man Chun John Ma [sup.1] , Paolo Strati [sup.1] , Beth Chasen [sup.3] , Enyu Dai [sup.2] [...]

Published
2020
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3. Genome Sequencing Reveals Loci under Artificial Selection that Underlie Disease Phenotypes in the Laboratory Rat

Author

Atanur, Santosh S., Diaz, Ana Garcia, Maratou, Klio, Sarkis, Allison, Rotival, Maxime, Game, Laurence, Tschannen, Michael R., Kaisaki, Pamela J., Otto, Georg W., Ma, Man Chun John, Keane, Thomas M., Hummel, Oliver, Saar, Kathrin, Chen, Wei, Guryev, Victor, Gopalakrishnan, Kathirvel, Garrett, Michael R., Joe, Bina, Citterio, Lorena, Bianchi, Giuseppe, McBride, Martin, Dominiczak, Anna, Adams, David J., Serikawa, Tadao, Flicek, Paul, Cuppen, Edwin, Hubner, Norbert, Petretto, Enrico, Gauguier, Dominique, Kwitek, Anne, Jacob, Howard, and Aitman, Timothy J.

Published
2013
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4. Follicular Lymphoma Microenvironment Characteristics Associated with Tumor Cell Mutations and MHC Class II Expression

Author

Han, Guangchun, primary, Deng, Qing, additional, Marques-Piubelli, Mario L., additional, Dai, Enyu, additional, Dang, Minghao, additional, Ma, Man Chun John, additional, Li, Xubin, additional, Yang, Haopeng, additional, Henderson, Jared, additional, Kudryashova, Olga, additional, Meerson, Mark, additional, Isaev, Sergey, additional, Kotlov, Nikita, additional, Nomie, Krystle J., additional, Bagaev, Alexander, additional, Parra, Edwin R., additional, Solis Soto, Luisa M., additional, Parmar, Simrit, additional, Hagemeister, Fredrick B., additional, Ahmed, Sairah, additional, Iyer, Swaminathan P., additional, Samaniego, Felipe, additional, Steiner, Raphael, additional, Fayad, Luis, additional, Lee, Hun, additional, Fowler, Nathan H., additional, Flowers, Christopher R., additional, Strati, Paolo, additional, Westin, Jason R., additional, Neelapu, Sattva S., additional, Nastoupil, Loretta J., additional, Vega, Francisco, additional, Wang, Linghua, additional, and Green, Michael R., additional

Published
2022
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5. Subtype-specific and co-occurring genetic alterations in B-cell non-Hodgkin lymphoma

Author

Ma, Man Chun John, primary, Tadros, Saber, additional, Bouska, Alyssa, additional, Heavican, Tayla, additional, Yang, Haopeng, additional, Deng, Qing, additional, Moore, Dalia, additional, Akhter, Ariz, additional, Hartert, Keenan, additional, Jain, Neeraj, additional, Showell, Jordan, additional, Ghosh, Sreejoyee, additional, Street, Lesley, additional, Davidson, Marta, additional, Carey, Christopher, additional, Tobin, Joshua, additional, Perumal, Deepak, additional, Vose, Julie M., additional, Lunning, Matthew A., additional, Sohani, Aliyah R., additional, Chen, Benjamin J., additional, Buckley, Shannon, additional, Nastoupil, Loretta J., additional, Davis, R. Eric, additional, Westin, Jason R., additional, Fowler, Nathan H., additional, Parekh, Samir, additional, Gandhi, Maher, additional, Neelapu, Sattva, additional, Stewart, Douglas, additional, Bhalla, Kapil, additional, Iqbal, Javeed, additional, Greiner, Timothy, additional, Rodig, Scott J., additional, Mansoor, Adnan, additional, and Green, Michael R., additional

Published
2021
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6. Mitochondrial ClpP-Mediated Proteolysis Induces Selective Cancer Cell Lethality

Author

Ishizawa, Jo, primary, Zarabi, Sarah F., additional, Davis, R. Eric, additional, Halgas, Ondrej, additional, Nii, Takenobu, additional, Jitkova, Yulia, additional, Zhao, Ran, additional, St-Germain, Jonathan, additional, Heese, Lauren E., additional, Egan, Grace, additional, Ruvolo, Vivian R., additional, Barghout, Samir H., additional, Nishida, Yuki, additional, Hurren, Rose, additional, Ma, Wencai, additional, Gronda, Marcela, additional, Link, Todd, additional, Wong, Keith, additional, Mabanglo, Mark, additional, Kojima, Kensuke, additional, Borthakur, Gautam, additional, MacLean, Neil, additional, Ma, Man Chun John, additional, Leber, Andrew B., additional, Minden, Mark D., additional, Houry, Walid, additional, Kantarjian, Hagop, additional, Stogniew, Martin, additional, Raught, Brian, additional, Pai, Emil F., additional, Schimmer, Aaron D., additional, and Andreeff, Michael, additional

Published
2019
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7. Adoptive T-Cell Therapy with TCL1-Specific TCR for B-Cell Lymphomas

Author

Weng, Jinsheng, primary, Moriarty, Kelsey, additional, Pan, Yong, additional, MA, Man Chun John, additional, Mathur, Rohit, additional, Zhang, Zheng, additional, Torikai, Hiroki, additional, Maiti, Sourindra N, additional, Chu, Fuliang, additional, Cheng, Xiaoyun, additional, Karri, Swathi, additional, Medapalli, Deepshika, additional, Cooper, Laurence J N, additional, Davis, R. Eric, additional, and Neelapu, Sattva S., additional

Published
2018
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8. Predictive Gene Signatures Determine Tumor Sensitivity to MDM2 Inhibition

Author

Ishizawa, Jo, primary, Nakamaru, Kenji, additional, Seki, Takahiko, additional, Tazaki, Koichi, additional, Kojima, Kensuke, additional, Chachad, Dhruv, additional, Zhao, Ran, additional, Heese, Lauren, additional, Ma, Wencai, additional, Ma, Man Chun John, additional, DiNardo, Courtney, additional, Pierce, Sherry, additional, Patel, Keyur P., additional, Tse, Archie, additional, Davis, R. Eric, additional, Rao, Arvind, additional, and Andreeff, Michael, additional

Published
2018
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11. Upregulation of MAPK/MCL-1 Maintaining Mitochondrial Oxidative Phosphorylation Confers Acquired Resistance to BCL-2 Inhibitor Venetoclax in AML

Author

Zhang, Qi, primary, Han, Lina, additional, Shi, Ce, additional, Pan, Rongqing, additional, MA, Man Chun John, additional, Ryan, Jeremy, additional, Kurtz, Stephen E, additional, Mu, Hong, additional, Ruvolo, Vivian, additional, Ma, Helen, additional, Andreeff, Michael, additional, Mi, Yingchang, additional, Tyner, Jeffrey W., additional, Leverson, Joel, additional, Letai, Anthony, additional, Davis, Richard Eric, additional, and Konopleva, Marina, additional

Published
2016
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16. Subtype-specific and co-occurring genetic alterations in B-cell non-Hodgkin lymphoma.

Author

Ma MCJ, Tadros S, Bouska A, Heavican T, Yang H, Deng Q, Moore D, Akhter A, Hartert K, Jain N, Showell J, Ghosh S, Street L, Davidson M, Carey C, Tobin J, Perumal D, Vose JM, Lunning MA, Sohani AR, Chen BJ, Buckley S, Nastoupil LJ, Davis RE, Westin JR, Fowler NH, Parekh S, Gandhi M, Neelapu S, Stewart D, Bhalla K, Iqbal J, Greiner T, Rodig SJ, Mansoor A, and Green MR

Subjects
Adult, Cross-Sectional Studies, Humans, Mutation, Burkitt Lymphoma, Lymphoma, Follicular genetics, Lymphoma, Large B-Cell, Diffuse
Abstract

B-cell non-Hodgkin lymphoma (B-NHL) encompasses multiple clinically and phenotypically distinct subtypes of malignancy with unique molecular etiologies. Common subtypes of B-NHL, such as diffuse large B-cell lymphoma, have been comprehensively interrogated at the genomic level, but rarer subtypes, such as mantle cell lymphoma, remain less extensively characterized. Furthermore, multiple B-NHL subtypes have thus far not been comprehensively compared using the same methodology to identify conserved or subtype-specific patterns of genomic alterations. Here, we employed a large targeted hybrid-capture sequencing approach encompassing 380 genes to interrogate the genomic landscapes of 685 B-NHL tumors at high depth, including diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, and Burkitt lymphoma. We identified conserved hallmarks of B-NHL that were deregulated in the majority of tumors from each subtype, including frequent genetic deregulation of the ubiquitin proteasome system. In addition, we identified subtype-specific patterns of genetic alterations, including clusters of co-occurring mutations and DNA copy number alterations. The cumulative burden of mutations within a single cluster were more discriminatory of B-NHL subtypes than individual mutations, implicating likely patterns of genetic cooperation that contribute to disease etiology. We therefore provide the first cross-sectional analysis of mutations and DNA copy number alterations across major B-NHL subtypes and a framework of co-occurring genetic alterations that deregulate genetic hallmarks and likely cooperate in lymphomagenesis.

Published
2022
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