Featured Publications

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, L., Myklebust, J. H., Kadapakkam, M., Weber, E. W., Tousley, A. M., Richards, R. M., Heitzeneder, S., Nguyen, S. M., Wiebking, V., Theruvath, J., Lynn, R. C., Xu, P., Dunn, A. R., Vale, R. D., & Mackall, C. L. (2020). Tuning the Antigen Density Requirement for CAR T-cell Activity. Cancer Discovery, 10(5), 702–723.

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

  • The Impact of Race, Ethnicity, and Obesity on CAR T-cell Therapy Outcomes in Children and Young Adults with B-cell Acute Lymphoblastic Leukemia (B-ALL) Faruqi, A. J., Ligon, J., Borgman, P., Steinberg, S. M., Foley, T., Little, L., Mackall, C., Lee, D. W., Fry, T. J., Shalabi, H., Yates, B., Shah, N. N. WILEY. 2022

    View details for Web of Science ID 000788322300444

  • Real-World Use of Tisagenlecleucel in Infant Acute Lymphoblastic Leukemia. Blood advances Moskop, A., Pommert, L., Baggott, C., Prabhu, S., Pacenta, H. L., Phillips, C. L., Rossoff, J., Stefanski, H., Talano, J., Margossian, S. P., Verneris, M. R., Myers, G. D., Karras, N. A., Brown, P. A., Qayed, M., Hermiston, M. L., Satwani, P., Krupski, C., Keating, A. K., Wilcox, R., Rabik, C. A., Fabrizio, V. A., Chinnabhandar, V., Goksenin, A. Y., Curran, K. J., Mackall, C. L., Laetsch, T. W., Guest, E. M., Breese, E. H., Schultz, L. M. 2022

    Abstract

    Infants with B-cell acute lymphoblastic leukemia (B-ALL) have poor outcomes due to chemotherapy resistance leading to high relapse rates. Tisagenlecleucel, a CD19-directed chimeric antigen receptor T-cell (CART) therapy, is FDA approved for relapsed or refractory (R/R) B-ALL in patients ≤25 years; however, the safety and efficacy of this therapy in young patients is largely unknown since children <3 years of age were excluded from licensing studies. We retrospectively evaluated data from the Pediatric Real-World CAR Consortium to examine outcomes of patients with infant B-ALL who received tisagenlecleucel between 2017 and 2020 (n=14). Sixty-four percent of patients (n=9) achieved minimal residual disease (MRD)-negative remission post-CART and 50% of patients remain in remission at last follow-up. All patients with high disease burden at time of CART infusion (>M1 marrow) were refractory to this therapy (n=5). Overall, tisagenlecleucel was tolerable in this population, with only 3 patients experiencing > grade 3 cytokine release syndrome. No neurotoxicity was reported. This is the largest report of tisagenlecleucel use in infant B-ALL and shows that this therapy is safe and can be effective in this population. Incorporating this novel immunotherapy into the treatment of infant B-ALL offers a promising therapy for a highly aggressive leukemia.

    View details for DOI 10.1182/bloodadvances.2021006393

    View details for PubMedID 35580324

  • Efficacy of second CAR-T (CART2) infusion limited by poor CART expansion and antigen modulation. Journal for immunotherapy of cancer Holland, E. M., Molina, J. C., Dede, K., Moyer, D., Zhou, T., Yuan, C. M., Wang, H., Stetler-Stevenson, M., Mackall, C., Fry, T. J., Panch, S., Highfill, S., Stroncek, D., Little, L., Lee, D. W., Shalabi, H., Yates, B., Shah, N. 2022; 10 (5)

    Abstract

    Chimeric antigen receptor T-cells (CART) are active in relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL), but relapse remains a substantial challenge. Reinfusion with the same CART product (CART2) in patients with suboptimal response or antigen positive relapse following first infusion (CART1) represents a potential treatment strategy, though early experiences suggest limited efficacy of CART2 with CD19 targeting. We report on our experience with CART2 across a host of novel CAR T-cell trials. This was a retrospective review of children and young adults with B-ALL who received reinfusion with an anti-CD19, anti-CD22, or anti-CD19/22 CART construct on one of 3 CAR T-cells trials at the National Cancer Institute (NCT01593696, NCT02315612, NCT0344839) between July 2012 and January 2021. All patients received lymphodepletion (LD) pre-CART (standard LD: 75mg/m2 fludarabine, 900mg/m2 cyclophosphamide; or intensified LD: 120mg/m2 fludarabine, 1200mg/m2 cyclophosphamide). Primary objectives were to describe response to and toxicity of CART2. Indication for CART2, impact of LD intensity, and CAR T-cell expansion and leukemia antigen expression between CART infusions was additionally evaluated. Eighteen patients proceeded to CART2 due to persistent (n=7) or relapsed antigen positive disease (n=11) following CART1. Seven of 18 (38.9%) demonstrated objective response (responders) to CART2: 5 achieved a minimal residual disease (MRD) negative CR, 1 had persistent MRD level disease, and 1 showed a partial remission, the latter with eradication of antigen positive disease and emergence of antigen negative B-ALL. Responders included four patients who had not achieved a CR with CART1. Limited cytokine release syndrome was seen following CART2. Peripheral blood CART1 expansion was higher than CART2 expansion (p=0.03). Emergence of antigen negative/dim B-ALL in 6 (33.3%) patients following CART2 contributed to lack of CR. Five of seven (71.4%) responders received intensified LD pre-CART2, which corresponded with higher CART2 expansion than in those receiving standard LD (p=0.029). Diminished CAR T-cell expansion and antigen downregulation/loss impeded robust responses to CART2. A subset of patients, however, may derive benefit from CART2 despite suboptimal response to CART1. Intensified LD may be one strategy to augment CART2 responses, though further study of factors associated with CART2 response, including serial monitoring of antigen expression, is warranted.

    View details for DOI 10.1136/jitc-2021-004483

    View details for PubMedID 35534047

  • Enhanced safety and efficacy of protease-regulated CAR-T cell receptors. Cell Labanieh, L., Majzner, R. G., Klysz, D., Sotillo, E., Fisher, C. J., Vilches-Moure, J. G., Pacheco, K. Z., Malipatlolla, M., Xu, P., Hui, J. H., Murty, T., Theruvath, J., Mehta, N., Yamada-Hunter, S. A., Weber, E. W., Heitzeneder, S., Parker, K. R., Satpathy, A. T., Chang, H. Y., Lin, M. Z., Cochran, J. R., Mackall, C. L. 2022

    Abstract

    Regulatable CAR platforms could circumvent toxicities associated with CAR-T therapy, but existing systems have shortcomings including leakiness and attenuated activity. Here, we present SNIP CARs, a protease-based platform for regulating CAR activity using an FDA-approved small molecule. Design iterations yielded CAR-T cells that manifest full functional capacity with drug and no leaky activity in the absence of drug. In numerous models, SNIP CAR-T cells were more potent than constitutive CAR-T cells and showed diminished T cell exhaustion and greater stemness. In a ROR1-based CAR lethality model, drug cessation following toxicity onset reversed toxicity, thereby credentialing the platform as a safety switch. In the same model, reduced drug dosing opened a therapeutic window that resulted in tumor eradication in the absence of toxicity. SNIP CARs enable remote tuning of CAR activity, which provides solutions to safety and efficacy barriers that are currently limiting progress in using CAR-T cells to treat solid tumors.

    View details for DOI 10.1016/j.cell.2022.03.041

    View details for PubMedID 35483375

  • Delivery of CAR-T cells in a transient injectable stimulatory hydrogel niche improves treatment of solid tumors. Science advances Grosskopf, A. K., Labanieh, L., Klysz, D. D., Roth, G. A., Xu, P., Adebowale, O., Gale, E. C., Jons, C. K., Klich, J. H., Yan, J., Maikawa, C. L., Correa, S., Ou, B. S., d'Aquino, A. I., Cochran, J. R., Chaudhuri, O., Mackall, C. L., Appel, E. A. 2022; 8 (14): eabn8264

    Abstract

    Adoptive cell therapy (ACT) has proven to be highly effective in treating blood cancers, but traditional approaches to ACT are poorly effective in treating solid tumors observed clinically. Novel delivery methods for therapeutic cells have shown promise for treatment of solid tumors when compared with standard intravenous administration methods, but the few reported approaches leverage biomaterials that are complex to manufacture and have primarily demonstrated applicability following tumor resection or in immune-privileged tissues. Here, we engineer simple-to-implement injectable hydrogels for the controlled co-delivery of CAR-T cells and stimulatory cytokines that improve treatment of solid tumors. The unique architecture of this material simultaneously inhibits passive diffusion of entrapped cytokines and permits active motility of entrapped cells to enable long-term retention, viability, and activation of CAR-T cells. The generation of a transient inflammatory niche following administration affords sustained exposure of CAR-T cells, induces a tumor-reactive CAR-T phenotype, and improves efficacy of treatment.

    View details for DOI 10.1126/sciadv.abn8264

    View details for PubMedID 35394838