All Publications

  • Engineered CD47 protects T cells for enhanced antitumour immunity. Nature Yamada-Hunter, S. A., Theruvath, J., McIntosh, B. J., Freitas, K. A., Lin, F., Radosevich, M. T., Leruste, A., Dhingra, S., Martinez-Velez, N., Xu, P., Huang, J., Delaidelli, A., Desai, M. H., Good, Z., Polak, R., May, A., Labanieh, L., Bjelajac, J., Murty, T., Ehlinger, Z., Mount, C. W., Chen, Y., Heitzeneder, S., Marjon, K. D., Banuelos, A., Khan, O., Wasserman, S. L., Spiegel, J. Y., Fernandez-Pol, S., Kuo, C. J., Sorensen, P. H., Monje, M., Majzner, R. G., Weissman, I. L., Sahaf, B., Sotillo, E., Cochran, J. R., Mackall, C. L. 2024


    Adoptively transferred T cells and agents designed to block the CD47-SIRPα axis are promising cancer therapeutics that activate distinct arms of the immune system1,2. Here we administered anti-CD47 antibodies in combination with adoptively transferred T cells with the goal of enhancing antitumour efficacy but observed abrogated therapeutic benefit due to rapid macrophage-mediated clearance of T cells expressing chimeric antigen receptors (CARs) or engineered T cell receptors. Anti-CD47-antibody-mediated CAR T cell clearance was potent and rapid enough to serve as an effective safety switch. To overcome this challenge, we engineered the CD47 variant CD47(Q31P) (47E), which engages SIRPα and provides a 'don't eat me' signal that is not blocked by anti-CD47 antibodies. TCR or CAR T cells expressing 47E are resistant to clearance by macrophages after treatment with anti-CD47 antibodies, and mediate substantial, sustained macrophage recruitment to the tumour microenvironment. Although many of the recruited macrophages manifested an M2-like profile3, the combined therapy synergistically enhanced antitumour efficacy. Our study identifies macrophages as major regulators of T cell persistence and illustrates the fundamental challenge of combining T-cell-directed therapeutics with those designed to activate macrophages. It delivers a therapeutic approach that is capable of simultaneously harnessing the antitumour effects of T cells and macrophages, offering enhanced potency against solid tumours.

    View details for DOI 10.1038/s41586-024-07443-8

    View details for PubMedID 38750365

    View details for PubMedCentralID 4182950

  • Immune determinants of CAR-T cell expansion in solid tumor patients receiving GD2 CAR-T cell therapy. Cancer cell Kaczanowska, S., Murty, T., Alimadadi, A., Contreras, C. F., Duault, C., Subrahmanyam, P. B., Reynolds, W., Gutierrez, N. A., Baskar, R., Wu, C. J., Michor, F., Altreuter, J., Liu, Y., Jhaveri, A., Duong, V., Anbunathan, H., Ong, C., Zhang, H., Moravec, R., Yu, J., Biswas, R., Van Nostrand, S., Lindsay, J., Pichavant, M., Sotillo, E., Bernstein, D., Carbonell, A., Derdak, J., Klicka-Skeels, J., Segal, J. E., Dombi, E., Harmon, S. A., Turkbey, B., Sahaf, B., Bendall, S., Maecker, H., Highfill, S. L., Stroncek, D., Glod, J., Merchant, M., Hedrick, C. C., Mackall, C. L., Ramakrishna, S., Kaplan, R. N. 2023


    Chimeric antigen receptor T cells (CAR-Ts) have remarkable efficacy in liquid tumors, but limited responses in solid tumors. We conducted a Phase I trial (NCT02107963) of GD2 CAR-Ts (GD2-CAR.OX40.28.z.iC9), demonstrating feasibility and safety of administration in children and young adults with osteosarcoma and neuroblastoma. Since CAR-T efficacy requires adequate CAR-T expansion, patients were grouped into good or poor expanders across dose levels. Patient samples were evaluated by multi-dimensional proteomic, transcriptomic, and epigenetic analyses. T cell assessments identified naive T cells in pre-treatment apheresis associated with good expansion, and exhausted T cells in CAR-T products with poor expansion. Myeloid cell assessment identified CXCR3+ monocytes in pre-treatment apheresis associated with good expansion. Longitudinal analysis of post-treatment samples identified increased CXCR3- classical monocytes in all groups as CAR-T numbers waned. Together, our data uncover mediators of CAR-T biology and correlates of expansion that could be utilized to advance immunotherapies for solid tumor patients.

    View details for DOI 10.1016/j.ccell.2023.11.011

    View details for PubMedID 38134936

  • Deep myeloid cell profiling provides new insights into modulators of CAR T cell expansion in patients with pediatric solid tumors Kaczanowska, S., Murty, T., Alimadadi, A., Contreras, C. F., Hedrick, C. C., Ramakrishna, S., Kaplan, R. AMER ASSOC IMMUNOLOGISTS. 2023
  • Caudolenticular Gray Bridges of the Brain: A Magnetic Resonance Imaging Study. Clinical anatomy (New York, N.Y.) Dang, B., Necker, F. N., Dhawan, S. S., Murty, T., Massoud, T. F. 2023


    The caudolenticular (or transcapsular) gray bridges (CLGBs) connect the caudate nucleus (CN) and putamen across the internal capsule. The CLGBs function as the main efferent terminus from premotor and supplementary motor area cortex to the basal ganglia (BG). We conjectured if inherent variations in numbers and sizes of CLGBs could contribute to abnormal cortical-subcortical connectivity in Parkinson's disease (PD), a neurodegenerative disorder featuring a hindrance of BG processing. However, there are no literature accounts of normative anatomy and morphometry of CLGBs. We therefore retrospectively analyzed axial and coronal 3T FSPGR MRIs of 34 healthy individuals for bilateral CLGBs symmetry, their numbers, dimensions of thickest and longest bridge, and axial surface areas of CN head and putamen. We calculated Evans' index (EI) to account for any brain atrophy. We statistically tested associations between sex or age and measured dependent variables, and linear correlations between all measured variables (significance at p<.05). Study subjects were F:M=23:11 with mean age 49.9 years. All EI's were normal (<.3). All but three CLGBs were bilaterally symmetrical with a mean 7.4 CLGBs per side. Mean CLGBs thickness and lengths were 1.0mm and 4.6mm, respectively; CN head and putamen areas were 205mm2 and 382.0mm2 , respectively. Females had thicker CLGBs (p=.02) but we found no significant interactions between sex or age and measured dependent variables, and no correlations between CN head or putamen areas and CLGBs dimensions. These normative MRI dimensions of the CLGBs will help guide future studies on the possible role of CLGBs morphometry in PD predisposition.

    View details for DOI 10.1002/ca.24026

    View details for PubMedID 36795325

  • Portal Venous Aneurysm. Radiology Murty, T., Negrete, L. 2023: 221311


    Supplemental material is available for this article.

    View details for DOI 10.1148/radiol.221311

    View details for PubMedID 36749214

  • DEFINING T CELL EXHAUSTION AND MEMORY CORRELATES OF GD2 CAR T CELL EXPANSION IN PEDIATRIC PATIENTS WITH SOLID TUMOR MALIGNANCIES Murty, T., Ramakrishna, S., Kaczanowska, S., Contreras, C., Duault, C., Balasubrahmanyam, P., Reynolds, W., Baskar, R., Jhaveri, A., Liu, Y., Altreuter, J., Michor, F., Pichavant, M., Sahaf, B., Bendall, S., Maecker, H., Merchant, M., Mackall, C., Kaplan, R. BMJ PUBLISHING GROUP. 2022: A381
  • DEEP MYELOID CELL PROFILING PROVIDES NEW INSIGHTS INTO MODULATORS OF CAR T CELL EXPANSION IN PATIENTS WITH SOLID TUMOR MALIGNANCIES Kaczanowska, S., Ramakrishna, S., Murty, T., Contreras, C., Alimadadi, A., Gutierrez, N., Jhaveri, A., Liu, Y., Altreuter, J., Michor, F., Duault, C., Balasubrahmanyam, P., Reynolds, W., Baskar, R., Pichavant, M., Sahaf, B., Bendall, S., Maecker, H., Merchant, M., Mackall, C., Hedrick, C., Kaplan, R. BMJ PUBLISHING GROUP. 2022: A418
  • Exploring the role of telomerase in senescence and exhaustion in CAR T cell immunotherapy Murty, T., Ramello, M. C., Sotillo, E., Chen, L., Artandi, S. A., Mackall, C. L. AMER ASSOC CANCER RESEARCH. 2022
  • 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


    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

  • Gene Editing to Enhance the Efficacy of Cancer Cell Therapies. Molecular therapy : the journal of the American Society of Gene Therapy Murty, T., Mackall, C. L. 2021


    Adoptive T cell therapies have shown impressive signals of activity, but their clinical impact could be enhanced by technologies to increase T cell potency and diminish the cost and labor involved in manufacturing these products. Gene editing platforms are under study in this arena to 1) enhance immune cell potency by knocking out molecules that inhibit immune responses; 2) deliver genetic payloads into precise genomic locations and thereby enhance safety and/or improve the gene expression profile by leveraging physiologic promoters, enhancers, and repressors; and 3) enable off-the-shelf therapies by preventing alloreactivity and immune rejection (Figure 1). This review will discuss gene editing approaches that have been most well studied in the context of human T cells and adoptive T cell therapies, summarizing their current status and near-term potential for translation.

    View details for DOI 10.1016/j.ymthe.2021.10.001

    View details for PubMedID 34673274

  • PET reporter gene imaging and ganciclovir-mediated ablation of chimeric antigen receptor T-cells in solid tumors. Cancer research Murty, S., Labanieh, L., Murty, T., Gowrishankar, G., Haywood, T., Alam, I. S., Beinat, C., Robinson, E., Aalipour, A., Klysz, D. D., Cochran, J. R., Majzner, R. G., Mackall, C. L., Gambhir, S. S. 2020


    Imaging strategies to monitor chimeric antigen receptor (CAR) T-cell biodistribution and proliferation harbor the potential to facilitate clinical translation for the treatment of both liquid and solid tumors. Additionally, the potential adverse effects of CAR T-cells highlight the need for mechanisms to modulate CAR T-cell activity. The herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene has previously been translated as a positron emission tomography (PET) reporter gene for imaging of T-cell trafficking in brain tumor patients. The HSV1-TK enzyme can act as a suicide gene of transduced cells through treatment with the prodrug ganciclovir (GCV). Here we report the molecular engineering, imaging, and GCV-mediated destruction of B7H3 CAR T-cells incorporating a mutated version of the HSV1-tk gene (sr39tk) with improved enzymatic activity for GCV. The sr39tk gene did not affect B7H3 CAR T-cell functionality and in vitro and in vivo studies in osteosarcoma models showed no significant effect on B7H3 CAR T-cell antitumor activity. PET/CT imaging with 9-(4-[18F]-fluoro-3-[hydroxymethyl]butyl)guanine [18F]FHBG of B7H3-sr39tk CAR T-cells in an orthotopic model of osteosarcoma revealed tumor homing and systemic immune expansion. Bioluminescence and PET imaging of B7H3-sr39tk CAR T-cells confirmed complete tumor ablation with intraperitoneal GCV administration. This imaging and suicide ablation system can provide insight into CAR T-cell migration and proliferation during clinical trials while serving as a suicide switch to limit potential toxicities.

    View details for DOI 10.1158/0008-5472.CAN-19-3579

    View details for PubMedID 32958548

  • Intravital imaging reveals synergistic effect of CAR T-cells and radiation therapy in a preclinical immunocompetent glioblastoma model Oncoimmunology Murty, S., Haile, S. T., Beinat, C., Aalipour, A., Alam, I. S., Murty, T., Shaffer, T. M., Patel, C. B., Graves, E. E., Mackall, C. L., Gambhir, S. S. 2020; 9 (1)