Featured Publications

Monje, M., Mahdi, J., Majzner, R., Yeom, K. W., Schultz, L. M., Richards, R. M., ... & Mackall, C.L. (2024). Intravenous and intracranial GD2-CAR T cells for H3K27M+ diffuse midline gliomas. Nature, 1-8.

Guerrero, J. A., Klysz, D. D., Chen, Y., Malipatlolla, M., Lone, J., Fowler, C., ... & Mackall, C. L. (2024). GLUT1 overexpression in CAR-T cells induces metabolic reprogramming and enhances potency. Nature Communications, 15(1), 8658.

Frank, M. J.*, Baird, J. H.*, Kramer, A. M.*, Srinagesh, H. K., Patel, S., Brown, A. K., ... Mackall, C.L., ... & Tunuguntla, R. (2024). CD22-directed CAR T-cell therapy for large B-cell lymphomas progressing after CD19-directed CAR T-cell therapy: a dose-finding phase 1 study. The Lancet, 404(10450), 353-363.

Mackall, C. L., Bollard, C. M., Goodman, N., Carr, C., Gardner, R., Rouce, R., ... & Kohn, D. B. (2024). Enhancing pediatric access to cell and gene therapies. Nature Medicine, 1-11.

Yamada-Hunter, S. A.*, Theruvath, J.*, McIntosh, B. J., Freitas, K. A., Lin, F., Radosevich, M. T., Leruste, A., ... & Mackall, C. L. (2024). Engineered CD47 protects T cells for enhanced antitumor immunity. Nature, 1-9.

Doan, A. E.*, Mueller, K. P.*, Chen, A. Y.*, Rouin, G. T., Chen, Y., Daniel, B., ... & Mackall, C.L., Weber, E. W. (2024). FOXO1 is a master regulator of memory programming in CAR T cells. Nature, 1-8.

Tieu, V., Sotillo, E., Bjelajac, J.R., Chen, C., Malipatlolla, M., Guerrero, J.A., ... & Mackall, C.L., Qi, L.S. (2024). A versatile CRISPR-Cas13d platform for multiplexed transcriptomic regulation and metabolic engineering in primary human T cells. Cell.

Klysz, D.D., Fowler, C., Malipatlolla, M., Stuani, L., Freitas, K.A., Chen, Y., ... & Mackall, C.L. (2023). Inosine Induces Stemness Features in CAR T cells and Enhances Potency. Cancer Cell.

Kaczanowska, S.*, Murty, T.*, Alimadadi, A.*, Contreras, C. F., Duault, C., Subrahmanyam, P. B., ... & Mackall, C.L., Ramakrishna, S., Kaplan, R. N. (2023). Immune determinants of CAR-T cell expansion in solid tumor patients receiving GD2 CAR-T cell therapy. Cancer Cell, 42(1), P35-51.E8.

Balke-Want, H., Keerthi, V., Gkitsas, N., Mancini, A. G., Kurgan, G. L., Fowler, C., ... & Mackall, C.L., Feldman, S. A. (2023). Homology-independent targeted insertion (HITI) enables guided CAR knock-in and efficient clinical scale CAR-T cell manufacturing. Molecular Cancer, 22(1), 1-16.

Labanieh, L., Mackall, C.L. (2023) CAR immune cells: design principles, resistance and the next generation. Nature, 614, 635–648.

Freitas, K. A.*, Belk, J. A.*, Sotillo, E., Quinn, P. J., Ramello, M. C., Malipatlolla, M., ... & Mackall, C. L. (2022). Enhanced T cell effector activity by targeting the Mediator kinase module. Science, 378(6620).

Good, Z., Spiegel, J.Y., Sahaf, B., Malipatlolla, M., Ehlinger, Z., Kurra, S.... & Mackall, C. L. (2022). Post-infusion CAR TReg cells identify patients resistant to CD19-CAR therapy. Nature Medicine, 28(9), 1860-1871.

Labanieh, L., Majzner, R. G., Klysz, D., Sotillo, E., Fisher, C. J., Vilches-Moure, J. G., ... & Mackall, C. L. (2022). Enhanced safety and efficacy of protease-regulated CAR-T cell receptors. Cell, 185(10), 1745-1763.

Majzner, R. G., Ramakrishna, S., Yeom, K. W., Patel, S., Chinnasamy, H., Schultz, L. M., Richards, R. M., Jiang, L., Barsan, V., Mancusi, R., Geraghty, A. C., Good, Z., Mochizuki, A. Y., Gillespie, S. M., Toland, A., Mahdi, J., Reschke, A., Nie, E., Chau, I. J., Rotiroti, M. C., … & Monje, M. (2022). GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature, 603(7903), 934-941.

Theruvath, J., Menard, M., Smith, B., Linde, M. H., Coles, G. L., Dalton, G. N., Wu, W., Kiru, L., Delaidelli, A., Sotillo, E., Silberstein, J. L., Geraghty, A. C., Banuelos, A., Radosevich, M. T., Dhingra, S., Heitzeneder, S., Tousley, A., Lattin, J., Xu, P., Huang, J., … & Majzner, R. G. (2022). Anti-GD2 synergizes with CD47 blockade to mediate tumor eradication. Nature Medicine, 28(2), 333-344.

Heitzeneder, S., Bosse, K. R., Zhu, Z., Zhelev, D., Majzner, R. G., Radosevich, M. T., Dhingra, S., Sotillo, E., Buongervino, S., Pascual-Pasto, G., Garrigan, E., Xu, P., Huang, J., Salzer, B., Delaidelli, A., Raman, S., Cui, H., Martinez, B., Bornheimer, S. J., Sahaf, B., … & Mackall, C. L. (2021). GPC2-CAR T cells tuned for low antigen density mediate potent activity against neuroblastoma without toxicity. Cancer Cell, S1535-6108(21)00658-9.

Richards, R. M., Zhao, F., Freitas, K. A., Parker, K. R., Xu, P., Fan, A., Sotillo, E., Daugaard, M., Oo, H. Z., Liu, J., Hong, W.-J., Sorensen, P. H., Chang, H. Y., Satpathy, A. T., Majzner, R. G., Majeti, R., & Mackall, C. L. (2021). Not-gated CD93 CAR T cells effectively target AML with minimized endothelial cross-reactivity. Blood Cancer Discovery, 2(6), 648.

Gennert, D. G., Lynn, R. C., Granja, J. M., Weber, E. W., Mumbach, M. R., Zhao, Y., Duren, Z., Sotillo, E., Greenleaf, W. J., Wong, W. H., Satpathy, A. T., Mackall, C. L., & Chang, H. Y. (2021). Dynamic chromatin regulatory landscape of human CAR T cell exhaustion. Proceedings of the National Academy of Sciences of the United States of America, 118(30), e2104758118.

Weber, E. W., Parker, K. R., Sotillo, E., Lynn, R. C., Anbunathan, H., Lattin, J., Good, Z., Belk, J. A., Daniel, B., Klysz, D., Malipatlolla, M., Xu, P., Bashti, M., Heitzeneder, S., Labanieh, L., Vandris, P., Majzner, R. G., Qi, Y., Sandor, K., Chen, L. C., … & Mackall, C. L. (2021). Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling. Science, 372(6537), eaba1786.

Theruvath, J., Sotillo, E., Mount, C. W., Graef, C. M., Delaidelli, A., Heitzeneder, S., Labanieh, L., Dhingra, S., Leruste, A., Majzner, R. G., Xu, P., Mueller, S., Yecies, D. W., Finetti, M. A., Williamson, D., Johann, P. D., Kool, M., Pfister, S., Hasselblatt, M., Frühwald, M. C., … & Mackall, C. L. (2020). Locoregionally administered B7-H3-targeted CAR T cells for treatment of atypical teratoid/rhabdoid tumors. Nature Medicine, 26(5), 712–719.

Weber, E. W., Maus, M. V., & Mackall, C. L. (2020). The Emerging Landscape of Immune Cell Therapies. Cell, 181(1), 46–62. 

Majzner, R. G., Rietberg, S. P., Sotillo, E., Dong, R., Vachharajani, V. T., Labanieh, ... & Mackall, C. L. (2020). Tuning the Antigen Density Requirement for CAR T-cell Activity. Cancer Discovery, 10(5), 702–723.

Murty, S.*, Labanieh, L.*, Murty, T., Gowrishankar, G., Haywood, T., Alam, I. S., ... & Mackall, C. L., Gambhir, S. S. (2020). PET reporter gene imaging and ganciclovir-mediated ablation of chimeric antigen receptor T cells in solid tumors. Cancer Research, 80(21), 4731-4740.

Lynn, R. C., Weber, E. W., Sotillo, E., Gennert, D., Xu, P., Good, Z., Anbunathan, H., Lattin, J., Jones, R., Tieu, V., Nagaraja, S., Granja, J., de Bourcy, C., Majzner, R., Satpathy, A. T., Quake, S. R., Monje, M., Chang, H. Y., & Mackall, C. L. (2019). c-Jun overexpression in CAR T cells induces exhaustion resistance. Nature, 576(7786), 293–300.

Majzner, R. G., & Mackall, C. L. (2019). Clinical lessons learned from the first leg of the CAR T cell journey. Nature Medicine, 25(9), 1341–1355.

Majzner, R. G., Theruvath, J. L., Nellan, A., Heitzeneder, S., Cui, Y., Mount, C. W., Rietberg, S. P., Linde, M. H., Xu, P., Rota, C., Sotillo, E., Labanieh, L., Lee, D. W., Orentas, R. J., Dimitrov, D. S., Zhu, Z., Croix, B. S., Delaidelli, A., Sekunova, A., Bonvini, E., … & Mackall, C. L. (2019). CAR T Cells Targeting B7-H3, a Pan-Cancer Antigen, Demonstrate Potent Preclinical Activity Against Pediatric Solid Tumors and Brain Tumors. Clinical Cancer Research, 25(8), 2560–2574.

Labanieh, L., Majzner, R. G., & Mackall, C. L. (2018). Programming CAR-T cells to kill cancer. Nature Biomedical Engineering, 2(6), 377–391.

Long, A. H., Haso, W. M., Shern, J. F., Wanhainen, K. M., Murgai, M., Ingaramo, M., Smith, J. P., Walker, A. J., Kohler, M. E., Venkateshwara, V. R., Kaplan, R. N., Patterson, G. H., Fry, T. J., Orentas, R. J., & Mackall, C. L. (2015). 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nature Medicine, 21(6), 581–590.

All Publications

Crystal Mackall

Publications

  • Effects of an initial anti-CD19 CAR T-cell therapy on subsequent anti-CD22 CAR T-cell manufacturing and clinical outcomes in patients with r/r LBCL. Cancer discovery Su, Y. J., Kramer, A. M., Hamilton, M. P., Agarwal, N., Srinagesh, H. K., Baird, J. H., Sahaf, B., Kuo, A., Ehlinger, Z. J., Desai, M. H., Rietberg, S. P., Tunuguntla, R., Patel, S., Chinnasamy, H., Gkitsas-Long, N., Klysz, D. D., Brown, A. K., Bharadwaj, S., Dahiya, S., Smith, M., Muffly, L., Mackall, C. L., Good, Z., Feldman, S. A., Miklos, D. B., Frank, M. J. 2025

    Abstract

    Patients with large B-cell lymphoma (LBCL) progressing after anti-CD19 CAR T-cell (CAR19) therapy have poor outcomes. Subsequent CAR T-cell therapy shows promise, but the impact of residual CAR19 and early relapse remains unclear. We evaluated 37 CAR19-refractory LBCL patients who received anti-CD22 CAR T-cell (CAR22) in a phase 1b trial (NCT04088890). Residual CAR19 was unquantifiable in 17 of 33 evaluable patients post-CAR22 infusion. Single-cell RNA sequencing revealed minimal CAR19/CAR22 co-transduction. Peak CAR19 transgene levels did not affect CAR22 efficacy or toxicities. CAR22 products from patients undergoing leukapheresis > 6 months post-CAR19 had higher CD4+ naïve T and CD4+/CD8+ T- central memory (TCM) cells, with lower CD4+ T-effector memory cells. High and low percentages of CAR22 TCM and TEM, respectively, were correlated with CAR22 transduction efficiency and achieving complete response. Residual CAR19 and leukapheresis timing did not significantly affect outcomes, while CAR22 product composition was significantly correlated with treatment response.

    View details for DOI 10.1158/2159-8290.CD-24-1071

    View details for PubMedID 39775812

  • Tumor-Associated Microglia Secrete Extracellular ATP to Support Glioblastoma Progression. Cancer research Wu, C. Y., Chen, Y., Lin, Y. J., Wei, K. C., Chang, K. Y., Feng, L. Y., Chen, K. T., Li, G., Ren, A. L., Nitta, R. T., Wu, J. Y., Cho, K. B., Pant, A., Choi, J., Mackall, C. L., Kim, L. H., Wu, A. C., Chuang, J. Y., Huang, C. Y., Jackson, C. M., Chen, P. Y., Lim, M. 2024; 84 (23): 4017-4030

    Abstract

    Glioblastoma (GBM) is a highly aggressive brain tumor with poor prognosis and high recurrence rates. The complex immune microenvironment of GBM is highly infiltrated by tumor-associated microglia and macrophages (TAM). TAMs are known to be heterogeneous in their functional and metabolic states and can transmit either protumoral or antitumoral signals to glioma cells. Here, we performed bulk RNA sequencing and single-cell RNA sequencing on samples from patients with GBM, which revealed increased ATP synthase expression and oxidative phosphorylation activity in TAMs located in the tumor core relative to the tumor periphery. Both in vitro and in vivo models displayed similar trends of augmented TAM mitochondrial activity, along with elevated mitochondrial fission, glucose uptake, mitochondrial membrane potential, and extracellular ATP (eATP) production by TAMs in the presence of GBM cells. Tumor-secreted factors, including GM-CSF, induced the increase in TAM eATP production. Elevated eATP in the GBM microenvironment promoted glioma growth and invasion by activating the P2X purinoceptor 7 (P2X7R) on glioma cells. Inhibition of the eATP-P2X7R axis attenuated tumor cell viability in vitro and reduced tumor size and prolonged survival in glioma-bearing mouse models. Overall, this study revealed elevated TAM-derived eATP in GBM and provided the basis for targeting the eATP-P2X7R signaling axis as a therapeutic strategy in GBM. Significance: Glioblastoma-mediated metabolic reprogramming in tumor-associated microglia increases ATP secretion that supports cancer cell proliferation and invasion by activating P2X7R, which can be inhibited to attenuate tumor growth.

    View details for DOI 10.1158/0008-5472.CAN-24-0018

    View details for PubMedID 39618248

  • Author Correction: Intravenous and intracranial GD2-CAR T cells for H3K27M+ diffuse midline gliomas. Nature Monje, M., Mahdi, J., Majzner, R., Yeom, K. W., Schultz, L. M., Richards, R. M., Barsan, V., Song, K. W., Kamens, J., Baggott, C., Kunicki, M., Rietberg, S. P., Lim, A. S., Reschke, A., Mavroukakis, S., Egeler, E., Moon, J., Patel, S., Chinnasamy, H., Erickson, C., Jacobs, A., Duh, A. K., Tunuguntla, R., Klysz, D. D., Fowler, C., Green, S., Beebe, B., Carr, C., Fujimoto, M., Brown, A. K., Petersen, A. G., McIntyre, C., Siddiqui, A., Lepori-Bui, N., Villar, K., Pham, K., Bove, R., Musa, E., Reynolds, W. D., Kuo, A., Prabhu, S., Rasmussen, L., Cornell, T. T., Partap, S., Fisher, P. G., Campen, C. J., Grant, G., Prolo, L., Ye, X., Sahaf, B., Davis, K. L., Feldman, S. A., Ramakrishna, S., Mackall, C. 2024

    View details for DOI 10.1038/s41586-024-08452-3

    View details for PubMedID 39613972

  • Intravenous and intracranial GD2-CAR T cells for H3K27M+ diffuse midline gliomas. Nature Monje, M., Mahdi, J., Majzner, R., Yeom, K. W., Schultz, L. M., Richards, R. M., Barsan, V., Song, K. W., Kamens, J., Baggott, C., Kunicki, M., Rietberg, S. P., Lim, A. S., Reschke, A., Mavroukakis, S., Egeler, E., Moon, J., Patel, S., Chinnasamy, H., Erickson, C., Jacobs, A., Duh, A. K., Tunuguntla, R., Klysz, D. D., Fowler, C., Green, S., Beebe, B., Carr, C., Fujimoto, M., Brown, A. K., Petersen, A. G., McIntyre, C., Siddiqui, A., Lepori-Bui, N., Villar, K., Pham, K., Bove, R., Musa, E., Reynolds, W. D., Kuo, A., Prabhu, S., Rasmussen, L., Cornell, T. T., Partap, S., Fisher, P. G., Campen, C. J., Grant, G., Prolo, L., Ye, X., Sahaf, B., Davis, K. L., Feldman, S. A., Ramakrishna, S., Mackall, C. 2024

    Abstract

    H3K27M-mutant diffuse midline gliomas (DMGs) express high levels of the disialoganglioside GD2 (ref. 1). Chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) eradicated DMGs in preclinical models2. Arm A of Phase I trial no. NCT04196413 (ref. 3) administered one intravenous (IV) dose of autologous GD2-CART to patients with H3K27M-mutant pontine (DIPG) or spinal DMG (sDMG) at two dose levels (DL1, 1 × 106 kg-1; DL2, 3 × 106 kg-1) following lymphodepleting chemotherapy. Patients with clinical or imaging benefit were eligible for subsequent intracerebroventricular (ICV) intracranial infusions (10-30 × 106 GD2-CART). Primary objectives were manufacturing feasibility, tolerability and the identification of maximally tolerated IV dose. Secondary objectives included preliminary assessments of benefit. Thirteen patients enroled, with 11 receiving IV GD2-CART on study (n = 3 DL1 (3 DIPG); n = 8 DL2 (6 DIPG, 2 sDMG)). GD2-CART manufacture was successful for all patients. No dose-limiting toxicities occurred on DL1, but three patients experienced dose-limiting cytokine release syndrome on DL2, establishing DL1 as the maximally tolerated IV dose. Nine patients received ICV infusions, with no dose-limiting toxicities. All patients exhibited tumour inflammation-associated neurotoxicity, safely managed with intensive monitoring and care. Four patients demonstrated major volumetric tumour reductions (52, 54, 91 and 100%), with a further three patients exhibiting smaller reductions. One patient exhibited a complete response ongoing for over 30 months since enrolment. Nine patients demonstrated neurological benefit, as measured by a protocol-directed clinical improvement score. Sequential IV, followed by ICV GD2-CART, induced tumour regressions and neurological improvements in patients with DIPG and those with sDMG.

    View details for DOI 10.1038/s41586-024-08171-9

    View details for PubMedID 39537919

    View details for PubMedCentralID 5996391

  • SPATIAL TRANSCRIPTOMICS ANALYSIS OF GLIOBLASTOMA REVEALS THREE DISTINCT REGIONAL PROGRAMS OF T-CELL INFILTRATION Wang, W. L., Chen, Y., Mo, C., Good, Z., Sotillo, E., Mackall, C. L. OXFORD UNIV PRESS INC. 2024

    View details for DOI 10.1093/neuonc/noae165.0045

    View details for Web of Science ID 001362575400003