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Phase I study to evaluate toxicity and feasibility of intratumoral injection of α-gal glycolipids in patients with advanced melanoma

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Abstract

Effective uptake of tumor cell-derived antigens by antigen-presenting cells is achieved pre-clinically by in situ labeling of tumor with α-gal glycolipids that bind the naturally occurring anti-Gal antibody. We evaluated toxicity and feasibility of intratumoral injections of α-gal glycolipids as an autologous tumor antigen-targeted immunotherapy in melanoma patients (pts). Pts with unresectable metastatic melanoma, at least one cutaneous, subcutaneous, or palpable lymph node metastasis, and serum anti-Gal titer ≥1:50 were eligible for two intratumoral α-gal glycolipid injections given 4 weeks apart (cohort I: 0.1 mg/injection; cohort II: 1.0 mg/injection; cohort III: 10 mg/injection). Monitoring included blood for clinical, autoimmune, and immunological analyses and core tumor biopsies. Treatment outcome was determined 8 weeks after the first α-gal glycolipid injection. Nine pts received two intratumoral injections of α-gal glycolipids (3 pts/cohort). Injection-site toxicity was mild, and no systemic toxicity or autoimmunity could be attributed to the therapy. Two pts had stable disease by RECIST lasting 8 and 7 months. Tumor nodule biopsies revealed minimal to no change in inflammatory infiltrate between pre- and post-treatment biopsies except for 1 pt (cohort III) with a post-treatment inflammatory infiltrate. Two and four weeks post-injection, treated nodules in 5 of 9 pts exhibited tumor cell necrosis without neutrophilic or lymphocytic inflammatory response. Non-treated tumor nodules in 2 of 4 evaluable pts also showed necrosis. Repeated intratumoral injections of α-gal glycolipids are well tolerated, and tumor necrosis was seen in some tumor nodule biopsies after tumor injection with α-gal glycolipids.

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Abbreviations

ADCC:

Antibody-dependent cell-mediated cytotoxicity

ANA:

Antinuclear antibodies

DLT:

Dose-limiting toxicity

ECOG:

Eastern Cooperative Oncology Group

ESR:

Erythrocyte sedimentation rate

MFI:

Median fluorescence intensity

MTD:

Maximum tolerated dose

PD:

Progressive disease

pt:

Patient

SD:

Stable disease

ULN:

Upper limit of normal

UW:

University of Wisconsin

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Acknowledgments

We thank Michael D. Macklin for technical assistance and Laddie Johnson for assistance with manuscript preparation. The authors thank the UW Translational Research Initiatives in Pathology laboratory, in part supported by the UW Department of Pathology and Laboratory Medicine and the UW Carbone Cancer Center, for use of its facilities and services. We also thank the nurses on the UW Clinical Research Unit for outstanding nursing care and for clinical trial support.

Financial support

Support was provided by NIH Grants CA130295, P30 CA014520 from the National Cancer Institute, by resources at the William S. Middleton Memorial Veterans Hospital, Madison, WI, and by the Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000427. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the views of the Department of Veterans Affairs or the US Government. Additional support was provided by Ann’s Hope Foundation, the Tim Eagle Memorial, the Jay Van Sloan Memorial from the Steve Leuthold Family, the Gretchen and Andrew Dawes Melanoma Research Fund, and Agalimmune.

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Authors and Affiliations

  1. University of Wisconsin Carbone Cancer Center, Madison, WI, USA

    Mark R. Albertini, Erik A. Ranheim, Cindy L. Zuleger, Paul M. Sondel, Jacquelyn A. Hank, Michael A. Newton, Thomas McFarland, Jennifer Collins, Erin Clements, Heather B. Neuman & Sharon Weber

  2. Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    Mark R. Albertini, Cindy L. Zuleger, Alan Bridges & Thomas McFarland

  3. Medical Service, William S. Middleton Memorial Veterans Hospital, Madison, WI, USA

    Mark R. Albertini & Alan Bridges

  4. Department of Pathology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    Erik A. Ranheim

  5. Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    Paul M. Sondel & Jacquelyn A. Hank

  6. Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    Paul M. Sondel

  7. Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    Michael A. Newton

  8. Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    Mary Beth Henry, Heather B. Neuman & Sharon Weber

  9. Department of Surgery, University of Massachusetts Medical School, Worcester, MA, USA

    Giles Whalen & Uri Galili

  10. University of Wisconsin Clinical Sciences Center, Room K6/530, 600 Highland Avenue, Madison, WI, 53792, USA

    Mark R. Albertini

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  1. Mark R. Albertini
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Correspondence to Mark R. Albertini.

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Conflict of interest

The authors have the following financial or other conflicts of interests to disclose related to this publication: Uri Galili is the inventor of this immunotherapy and is a consultant to Agalimmune Inc. which further develops cancer immunotherapy with α-gal glycolipids. All other authors declare no financial or other conflicts of interests related to this publication.

Statement of human rights

The UW Human Subjects Committee and the FDA approved this study (IND 12946). Informed consent was obtained from all individual participants included in the study and all individual participants registered with the Biostatistics Registration Desk prior to treatment. The clinical trial registration number for this study is: NCT00668512. All procedures performed in studies involving human participants were in accordance with ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Albertini, M.R., Ranheim, E.A., Zuleger, C.L. et al. Phase I study to evaluate toxicity and feasibility of intratumoral injection of α-gal glycolipids in patients with advanced melanoma. Cancer Immunol Immunother 65, 897–907 (2016). https://doi.org/10.1007/s00262-016-1846-1

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