Featured Publications

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.

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. Science378(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 Medicine28(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. Cell185(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 Medicine28(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 Discovery2(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 Research80(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 Research25(8), 2560–2574.

Labanieh, L., Majzner, R. G., & Mackall, C. L. (2018). Programming CAR-T cells to kill cancer. Nature Biomedical Engineering2(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

Publications

  • A Phase 1 Clinical Trial of NKTR-255 with CD19-22 CAR-T Cell Therapy for Refractory B-cell Acute Lymphoblastic Leukemia. Blood Srinagesh, H. K., Jackson, C., Shiraz, P., Jeyakumar, N., Hamilton, M. P., Egeler, E., Mavroukakis, S., Kuo, A., Cancilla, J., Sahaf, B., Agarwal, N., Kanegai, A. M., Kramer, A. M., Arai, S., Bharadwaj, S., Dahiya, S., Hosoya, H., Johnston, L. J., Kennedy, V. E., Liedtke, M., Lowsky, R., Mikkilineni, L., Negrin, R. S., Rezvani, A. R., Sidana, S., Shizuru, J. A., Smith, M., Weng, W. K., Feldman, S. A., Frank, M. J., Lee, Z., Tagliaferri, M., Marcondes, A. M., Miklos, D. B., Mackall, C. L., Muffly, L. 2024

    Abstract

    While chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of B-cell malignancies, many patients relapse and therefore strategies to improve antitumor immunity are needed. We previously designed a novel autologous bispecific CAR targeting CD19 and CD22 (CAR19-22), which was well tolerated and associated with high response rates but relapse was common. Interleukin-15 (IL15) induces proliferation of diverse immune cells and can augment lymphocyte trafficking. Here, we report the results of a phase 1 clinical trial of the first combination of a novel recombinant polymer-conjugated IL15 receptor agonist (NKTR-255), with CAR19-22, in adults with relapsed / refractory B-cell acute lymphoblastic leukemia. Eleven patients were enrolled, nine of whom successfully received CAR19-22 followed by NKTR-255. There were no dose limiting toxicities, with transient fever and myelosuppression as the most common possibly related toxicities. We observed favorable efficacy with eight out of nine patients (89%) achieving measurable residual disease negative remission. At 12 months, progression-free survival for NKTR-255 was double that of historical controls (67% vs 38%). We performed correlative analyses to investigate the effects of IL15 receptor agonism. Cytokine profiling showed significant increases in IL15 and the chemokines CXCL9 and CXCL10. The increase in chemokines was associated with decreases in absolute lymphocyte counts and CD8+ CAR T-cells in blood and ten-fold increases in CSF CAR-T cells, suggesting lymphocyte trafficking to tissue. Combining NKTR-255 with CAR19-22 was safe, feasible and associated with high rates of durable responses (NCT03233854).

    View details for DOI 10.1182/blood.2024024952

    View details for PubMedID 38968138

  • Bendamustine is a safe and effective lymphodepletion agent for axicabtagene ciloleucel in patients with refractory or relapsed large B-cell lymphoma. Journal for immunotherapy of cancer Bharadwaj, S., Lau, E., Hamilton, M. P., Goyal, A., Srinagesh, H., Jensen, A., Lee, D., Mallampet, J., Elkordy, S., Syal, S., Patil, S., Latchford, T., Sahaf, B., Arai, S., Johnston, L. J., Lowsky, R., Negrin, R., Rezvani, A. R., Shizuru, J., Meyer, E. H., Shiraz, P., Mikkilineni, L., Weng, W. K., Smith, M., Sidana, S., Muffly, L., Maecker, H. T., Frank, M. J., Mackall, C., Miklos, D., Dahiya, S. 2024; 12 (7)

    Abstract

    Fludarabine in combination with cyclophosphamide (FC) is the standard lymphodepletion regimen for CAR T-cell therapy (CAR T). A national fludarabine shortage in 2022 necessitated the exploration of alternative regimens with many centers employing single-agent bendamustine as lymphodepletion despite a lack of clinical safety and efficacy data. To fill this gap in the literature, we evaluated the safety, efficacy, and expansion kinetics of bendamustine as lymphodepletion prior to axicabtagene ciloleucel (axi-cel) therapy.84 consecutive patients with relapsed or refractory large B-cell lymphoma treated with axi-cel and managed with a uniform toxicity management plan at Stanford University were studied. 27 patients received alternative lymphodepletion with bendamustine while 57 received FC.Best complete response rates were similar (73.7% for FC and 74% for bendamustine, p=0.28) and there was no significant difference in 12-month progression-free survival or overall survival estimates (p=0.17 and p=0.62, respectively). The frequency of high-grade cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome was similar in both the cohorts. Bendamustine cohort experienced lower proportions of hematological toxicities and antibiotic use for neutropenic fever. Immune reconstitution, as measured by quantitative assessment of cellular immunity, was better in bendamustine cohort as compared with FC cohort. CAR T expansion as measured by peak expansion and area under the curve for expansion was comparable between cohorts.Bendamustine is a safe and effective alternative lymphodepletion conditioning for axi-cel with lower early hematological toxicity and favorable immune reconstitution.

    View details for DOI 10.1136/jitc-2024-008975

    View details for PubMedID 38955420

  • Enhancing pediatric access to cell and gene therapies. Nature medicine Mackall, C. L., Bollard, C. M., Goodman, N., Carr, C., Gardner, R., Rouce, R., Sotillo, E., Stoner, R., Urnov, F. D., Wayne, A. S., Park, J., Kohn, D. B. 2024

    Abstract

    Increasing numbers of cell and gene therapies (CGTs) are emerging to treat and cure pediatric diseases. However, small market sizes limit the potential return on investment within the traditional biopharmaceutical drug development model, leading to a market failure. In this Perspective, we discuss major factors contributing to this failure, including high manufacturing costs, regulatory challenges, and licensing practices that do not incorporate pediatric development milestones, as well as potential solutions. We propose the creation of a new entity, the Pediatric Advanced Medicines Biotech, to lead late-stage development and commercialize pediatric CGTs outside the traditional biopharmaceutical model in the United States-where organized efforts to solve this problem have been lacking. The Pediatric Advanced Medicines Biotech would partner with the academic ecosystem, manufacture products in academic good manufacturing practice facilities and work closely with regulatory bodies, to ferry CGTs across the drug development 'valley of death' and, ultimately, increase access to lifesaving treatments for children in need.

    View details for DOI 10.1038/s41591-024-03035-1

    View details for PubMedID 38886624

    View details for PubMedCentralID 5996391

  • Risk of Second Tumors and T-Cell Lymphoma after CAR T-Cell Therapy. The New England journal of medicine Hamilton, M. P., Sugio, T., Noordenbos, T., Shi, S., Bulterys, P. L., Liu, C. L., Kang, X., Olsen, M. N., Good, Z., Dahiya, S., Frank, M. J., Sahaf, B., Mackall, C. L., Gratzinger, D., Diehn, M., Alizadeh, A. A., Miklos, D. B. 2024; 390 (22): 2047-2060

    Abstract

    The risk of second tumors after chimeric antigen receptor (CAR) T-cell therapy, especially the risk of T-cell neoplasms related to viral vector integration, is an emerging concern.We reviewed our clinical experience with adoptive cellular CAR T-cell therapy at our institution since 2016 and ascertained the occurrence of second tumors. In one case of secondary T-cell lymphoma, a broad array of molecular, genetic, and cellular techniques were used to interrogate the tumor, the CAR T cells, and the normal hematopoietic cells in the patient.A total of 724 patients who had received T-cell therapies at our center were included in the study. A lethal T-cell lymphoma was identified in a patient who had received axicabtagene ciloleucel therapy for diffuse large B-cell lymphoma, and both lymphomas were deeply profiled. Each lymphoma had molecularly distinct immunophenotypes and genomic profiles, but both were positive for Epstein-Barr virus and were associated with DNMT3A and TET2 mutant clonal hematopoiesis. No evidence of oncogenic retroviral integration was found with the use of multiple techniques.Our results highlight the rarity of second tumors and provide a framework for defining clonal relationships and viral vector monitoring. (Funded by the National Cancer Institute and others.).

    View details for DOI 10.1056/NEJMoa2401361

    View details for PubMedID 38865660

  • Advancing childhood cancer research through young investigator and advocate collaboration. Pediatric blood & cancer Weiner, A. K., Palmer, A., Moll, M. F., Lindberg, G., Reidy, K., Diskin, S. J., Mackall, C. L., Maris, J. M., Sullivan, P. J. 2024: e31127

    View details for DOI 10.1002/pbc.31127

    View details for PubMedID 38867370