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

ABSTRACT: Effective uptake of tumor cell-derived antigens by antigen-presenting cells is achieved pre-clinically by in situ labeling of tumor with ?-gal glycolipids that bind the naturally occurring anti-Gal antibody. We evaluated toxicity and feasibility of intratumoral injections of ?-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 ?-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 ?-gal glycolipid injection. Nine pts received two intratumoral injections of ?-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 ?-gal glycolipids are well tolerated, and tumor necrosis was seen in some tumor nodule biopsies after tumor injection with ?-gal glycolipids.

SUBMITTER: Albertini MR

PROVIDER: S-EPMC4958541 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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

Albertini Mark R MR Ranheim Erik A EA Zuleger Cindy L CL Sondel Paul M PM Hank Jacquelyn A JA Bridges Alan A Newton Michael A MA McFarland Thomas T Collins Jennifer J Clements Erin E Henry Mary Beth MB Neuman Heather B HB Weber Sharon S Whalen Giles G Galili Uri U

Cancer immunology, immunotherapy : CII 20160520 8

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 seru ...[more]

PMID: 27207605

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Project description:IntroductionAlpha-gal syndrome (AGS) is characterized by delayed hypersensitivity to non-primate mammalian meat in people having specific immunoglobulin E (sIgE) to the oligosaccharide galactose-alpha-1,3-galactose. AGS has been linked to tick bites from Amblyomma americanum (Aa) in the U.S. A small animal model of meat allergy is needed to study the mechanism of alpha-gal sensitization, the effector phase leading to delayed allergic responses and potential therapeutics to treat AGS.MethodsEight- to ten-weeks old mice with a targeted inactivation of alpha-1,3-galactosyltransferase (AGKO) were injected intradermally with 50 μg of Aa tick salivary gland extract (TSGE) on days 0, 7, 21, 28, 42, and 49. Total IgE and alpha-gal sIgE were quantitated on Day 56 by enzyme-linked immunosorbent assay. Mice were challenged orally with 400 mg of cooked pork kidney homogenate or pork fat. Reaction severity was assessed by measuring a drop in core body temperature and scoring allergic signs.ResultsCompared to control animals, mice treated with TSGE had 190-fold higher total IgE on Day 56 (0.60 ± 0.12 ng/ml vs. 113.2 ± 24.77 ng/ml; p < 0.001). Alpha-gal sIgE was also produced in AGKO mice following TSGE sensitization (undetected vs. 158.4 ± 72.43 pg/ml). Further, sensitized mice displayed moderate clinical allergic signs along with a drop in core body temperature of ≥2°C as an objective measure of a systemic allergic reaction. Interestingly, female mice had higher total IgE responses to TSGE treatment but male mice had larger declines in mean body temperature.ConclusionTSGE-sensitized AGKO mice generate sIgE to alpha-gal and demonstrate characteristic allergic responses to pork fat and pork kidney. In keeping with the AGS responses documented in humans, mice reacted more rapidly to organ meat than to high fat pork challenge. This mouse model establishes the central role of tick bites in the development of AGS and provides a small animal model to mechanistically study mammalian meat allergy.

Dataset Information

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

Publications

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

Similar Datasets

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