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

  • CSF1R+ myeloid-monocytic cells drive CAR-T cell resistance in aggressive B cell lymphoma. Cancer cell Stahl, D., Gödel, P., Balke-Want, H., Gholamipoorfard, R., Segbers, P., Tetenborg, L., Koker, M., Dörr, J., Gregor, L., Bachurski, D., Rose, F., Simon, A. G., Good, Z., Jakob, J., Häupl, B., Nill, M., Flümann, R., Riet, T., Lange, D., Blakemore, S. J., Baurmann, H., Voltin, C. A., Potter, N., Schlözer, L., Freihammer, M., Wagener-Ryczek, S., Iuga, A. I., Heger, J. M., Ludwig, H., Schleifenbaum, J. K., Propp, J., Bröckelmann, P. J., Jachimowicz, R. D., Knittel, G., Borchmann, S., Merkelbach-Bruse, S., Pallasch, C., Peifer, M., Rybniker, J., Quaas, A., Nitz, M., Brägelmann, J., Müller, W., Persigehl, T., Bozek, K., Theobald, S. J., Büttner, R., Oellerich, T., Hallek, M., Kobold, S., Chmielewski, M., Reinhardt, H. C., Mackall, C., Abedpour, N., Borchmann, P., Ullrich, R. T. 2025

    Abstract

    Despite the improvement, approximately 60% of patients with relapsed or refractory (r/r) aggressive B cell lymphoma (B-NHL) do not achieve durable benefit from CAR-T cell therapy. To elucidate factors associated with CAR-T therapy resistance, we conducted high-dimensional analyses of pre- and post-CAR-T cell specimens. In patients with non-durable response, we identified a prognostically relevant lymphoma-associated myeloid-monocytic (LAMM) gene signature. In-depth profiling revealed a distinct CSF1R+CD14+CD68+ LAMM cell population in both human and murine B-NHL that inhibits CAR-T cell function and correlates with poor outcome. Cell-cell inference analysis uncovered that LAMM cells impair CAR-T cell function through a direct LAMM-T cell interaction via the PGE2-EP2/EP4 axis. In an autochthonous lymphoma mouse model, combined anti-CD19 CAR-T cell therapy with CSF1R blockade exhibited synergistic effects and improved survival. These findings provide strong rationale for combining anti-CD19 CAR-T cells with CSF1R inhibitors in treating r/r aggressive B-NHL patients.

    View details for DOI 10.1016/j.ccell.2025.05.013

    View details for PubMedID 40513575

  • Intentional heterogeneity in autologous cell-based gene therapies: strategic considerations for first-in-human trials. Journal for immunotherapy of cancer Cabanski, C. R., Yang, E., Stewart, M. D., Allen, J. D., Connolly, J. E., Dugan, U., Greenberg, P. D., Mackall, C. L., June, C. H., Marson, A., Maus, M. V., Ribas, A. 2025; 13 (6)

    Abstract

    Cell-based gene therapies, including chimeric antigen receptor-T, T-cell receptor-T, and tumor-infiltrating lymphocyte therapies, have transformed the treatment landscape for certain cancers, yet their efficacy in solid tumors remains limited. Next-generation therapies aim to overcome biological barriers, enhance potency and safety, and streamline development timelines through innovative approaches. Recent advances in genome editing technologies have identified hundreds of gene edits that improve T-cell functionality in preclinical models. However, the limited direct translatability of these findings and the impracticality of testing each of the individual edits in a traditional clinical trial highlight the need for more efficient strategies.This article provides an overview of genome-wide screens that identify gene knockouts and knock-ins to enhance T-cell function and the limitations with translating these results to human trials. Next, we propose a novel clinical trial design for testing multiple gene modifications simultaneously within a single T-cell infusion product. This approach would enable head-to-head evaluation of edits in an internally controlled setting, accelerating the identification of promising candidate edits. Key considerations for Chemistry, Manufacturing, and Controls, non-clinical evaluation, and clinical protocols are discussed, with an emphasis on patient safety and ethical transparency.This framework is informed by insights shared at the "Unlocking Complex Cell-based Gene Therapies" workshop, held on May 6, 2024. Co-hosted by Friends of Cancer Research and the Parker Institute for Cancer Immunotherapy, the event brought together participants from academia, the US Food and Drug Administration, and patient advocacy groups. By fostering collaboration among these stakeholders, this innovative approach aims to accelerate the development of effective cell-based therapies for complex diseases.

    View details for DOI 10.1136/jitc-2024-011301

    View details for PubMedID 40480658

    View details for PubMedCentralID PMC12142127

  • Immunotherapy-related cognitive impairment after CAR T cell therapy in mice. Cell Geraghty, A. C., Acosta-Alvarez, L., Rotiroti, M. C., Dutton, S., O'Dea, M. R., Kim, W., Trivedi, V., Mancusi, R., Shamardani, K., Malacon, K., Woo, P. J., Martinez-Velez, N., Pham, T., Reche-Ley, N. N., Otubu, G., Castenada, E. H., Nwangwu, K., Xu, H., Mulinyawe, S. B., Zamler, D. B., Ni, L., Cross, K., Rustenhoven, J., Kipnis, J., Liddelow, S. A., Mackall, C. L., Majzner, R. G., Monje, M. 2025

    Abstract

    Immunotherapies have revolutionized cancer care for many tumor types, but their potential long-term cognitive impacts are incompletely understood. Here, we demonstrated in mouse models that chimeric antigen receptor (CAR) T cell therapy for both central nervous system (CNS) and non-CNS cancers impaired cognitive function and induced a persistent CNS immune response characterized by white matter microglial reactivity, microglial chemokine expression, and elevated cerebrospinal fluid (CSF) cytokines and chemokines. Consequently, oligodendroglial homeostasis and hippocampal neurogenesis were disrupted. Single-nucleus sequencing studies of human frontal lobe from patients with or without previous CAR T cell therapy for brainstem tumors confirmed reactive states of microglia and oligodendrocytes following treatment. In mice, transient microglial depletion or CCR3 chemokine receptor blockade rescued oligodendroglial deficits and cognitive performance in a behavioral test of attention and short-term memory function following CAR T cell therapy. Taken together, these findings illustrate targetable neural-immune mechanisms underlying immunotherapy-related cognitive impairment.

    View details for DOI 10.1016/j.cell.2025.03.041

    View details for PubMedID 40359942

  • IKAROS levels are associated with antigen escape in CD19- and CD22-targeted therapies for B-cell malignancies. Nature communications Domizi, P., Sarno, J., Jager, A., Merchant, M., Pacheco, K. Z., Yamada-Hunter, S. A., Rotiroti, M. C., Liu, Y., Baskar, R., Reynolds, W. D., Sworder, B. J., Sahaf, B., Bendall, S. C., Mullighan, C. G., Alizadeh, A. A., Leahy, A. B., Myers, R. M., Yates, B., Wang, H. W., Shah, N. N., Majzner, R. G., Mackall, C. L., Grupp, S. A., Barrett, D. M., Sotillo, E., Davis, K. L. 2025; 16 (1): 3800

    Abstract

    Antigen escape relapse is a major challenge in targeted immunotherapies, including CD19- and CD22-directed chimeric antigen receptor (CAR) T-cell for B-cell acute lymphoblastic leukemia (B-ALL). To identify tumor-intrinsic factors driving antigen loss, we perform single-cell analyses on 61 B-ALL patient samples treated with CAR T cells. Here we show that low levels of IKAROS in pro-B-like B-ALL cells before CAR T treatment correlate with antigen escape. IKAROSlow B-ALL cells undergo epigenetic and transcriptional changes that diminish B-cell identity, making them resemble progenitor cells. This shift leads to reduced CD19 and CD22 surface expression. We demonstrate that CD19 and CD22 expression is IKAROS dose-dependent and reversible. Furthermore, IKAROSlow cells exhibit higher resistance to CD19- and CD22-targeted therapies. These findings establish a role for IKAROS as a regulator of antigens targeted by widely used immunotherapies and in the risk of antigen escape relapse, identifying it as a potential prognostic target.

    View details for DOI 10.1038/s41467-025-58868-2

    View details for PubMedID 40268897

    View details for PubMedCentralID PMC12019336

  • New models for the development of and access to CAR T-cell therapies for children and adolescents with cancer: an ACCELERATE multistakeholder analysis. The Lancet. Oncology Pearson, A. D., Rossig, C., Mackall, C. L., Shah, N. N., Baruchel, A., Daems, S., Anderson, J., Biondi, A., Bird, N., Bodmer, N., Brivio, E., Buechner, J., Calkoen, F. G., Cooper, T., de Rojas, T., Fox, E., Gardner, R., Ghorashian, S., Heenen, D., Ifversen, M., Jacoby, E., Juan, M., Knox, L., Komanduri, K., Larghero, J., Locatelli, F., Ludwinski, D., Majzner, R. G., McDonough, J., Minard-Colin, V., Nysom, K., Pappo, A., Park, J. R., Qasim, W., Quintarelli, C., Rives, S., Rouce, R. H., Scobie, N., Seitz, C., Tasian, S. K., Weigel, B., Weiner, S., Zwaan, C. M., Vassal, G. 2025; 26 (4): e214-e224

    Abstract

    Realising the potentially substantial benefits of chimeric antigen receptor (CAR) T-cell therapy for children with cancer is hindered by non-scientific barriers that are also relevant for other rare diseases. A solely commercial development model will not deliver optimally due to insufficient return on investment for pharmaceutical companies. Access to therapies is restricted for patients who might benefit and advancing innovation in the academic research setting is difficult. Challenges relating to CAR T-cell therapies in paediatric malignancies and how they might be addressed were discussed in a meeting convened by ACCELERATE-an international multistakeholder organisation aiming to advance the timely investigation of new anticancer drugs. New academic and biopharma hybrid development models could benefit rare populations and coordination of early development can promote synergy and avoid duplicative efforts. Following promising first-in-child trials, new models are needed to support pivotal trials, decentralised manufacturing, registration, and reduced costs. The European Medicines Agency and the US Food and Drug Administration encourage academic development and early discussions. A biotech company funded via a pooled investment vehicle could provide access to safe and effective products for children and adolescents with cancer through registration and reimbursement.

    View details for DOI 10.1016/S1470-2045(24)00736-8

    View details for PubMedID 40179917