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    cacarr@stanford.edu
    University - Staff Department: SCI Cancer Cell Therapy - Administration Position: Executive Director, Center for Cancer Cell Therapy
    • 265 CAMPUS DR
    • G2103d
    • STANFORD,  California  94305 

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  • Mail Code: 5456

All Publications

  • 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

  • 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