Treatment Efficacy and Immune Stimulation by AdCD40L Gene Therapy of Spontaneous Canine Malignant Melanoma

Westberg, Sara; Sadeghi, Arian; Svensson, Emma; Segall, Thomas; Dimopoulou, Maria; Korsgren, Olle; Hemminki, Akseli; Loskog, Angelica; Tötterman, Thomas H.; Euler, Henrik von

doi:10.1097/cji.0b013e31829d8a1b

Cited by 60 publications

(58 citation statements)

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“…Recently, it was demonstrated that local administration of agonistic CD40 antibodies into tumorbearing mice resulted in improved antitumor effect, and caused less adverse immune-related events than systemic treatment (4,14,15). The concept of intratumoral CD40 stimulation has also been validated using local injection of adenoviral vectors expressing CD40L, demonstrating antitumor effects in human and murine bladder cancer as well as in dog melanoma, with minimal side effects (16,17).…”

Section: Introductionmentioning

confidence: 99%

The Human Agonistic CD40 Antibody ADC-1013 Eradicates Bladder Tumors and Generates T-cell–Dependent Tumor Immunity

Mangsbo

Broos

Fletcher

et al. 2015

Clinical Cancer Research

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Purpose: Local administration of immune-activating antibodies may increase the efficacy and reduce the immune-related adverse events associated with systemic immunotherapy of cancer. Here, we report the development and affinity maturation of a fully human agonistic CD40 antibody (IgG1), ADC-1013.Experimental Design: We have used molecular engineering to generate an agonistic antibody with high affinity for CD40. The functional activity of ADC-1013 was investigated in human and murine in vitro models. The in vivo effect was investigated in two separate bladder cancer models, both using human xenograft tumors in immune deficient NSG mice and using a syngeneic bladder cancer model in a novel human CD40 transgenic mouse.Results: Activation of dendritic cells (DC) by ADC-1013 results in upregulation of the costimulatory molecules CD80 and CD86, and secretion of IL12. ADC-1013 also activates DCs from human CD40 transgenic mice, and peptide-pulsed and ADC-1013-stimulated DCs induce antigen-specific T-cell proliferation in vitro. In vivo, treatment with ADC-1013 in a syngeneic bladder cancer model, negative for hCD40, induces significant antitumor effects and long-term tumor-specific immunity. Furthermore, ADC-1013 demonstrates significant antitumor effects in a human bladder cancer transplanted into immunodeficient NSG mice.Conclusions: Our data demonstrate that ADC-1013 induces long-lasting antitumor responses and immunologic memory mediated by CD40 stimulation. To the best of our knowledge, ADC-1013 represents the first immunomodulatory antibody developed for local immunotherapy of cancer.

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Section: Introductionmentioning

confidence: 99%

The Human Agonistic CD40 Antibody ADC-1013 Eradicates Bladder Tumors and Generates T-cell–Dependent Tumor Immunity

Mangsbo

Broos

Fletcher

et al. 2015

Clinical Cancer Research

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“…When one such molecule CD40, a receptor found on the surface of B cells and APCs binds to CD40L expressed on T-cells it activates the CD40 bearing cells and thus enhances humoural as well as cell mediated immunity (Elgueta et al, 2009). Treatment of CMM with a replicate deficient adenovirus expressing CD40L administered intra-tumourally has been piloted (dVon Euler et al, 2008von Euler et al, 2008 and succeded by a larger clinical trial of CMM patients (Westberg et al, 2013). The use of viral agents as cancer immunotherapeutics is a rapidly growing field and results from on-going human and veterinary trials are eagerly awaited.…”

Section: Adaptive Iimmunitymentioning

confidence: 99%

Cancer immunology and canine malignant melanoma: A comparative review

Atherton

Morris

McDermott

et al. 2016

Veterinary Immunology and Immunopathology

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Canine melanoma as a model of human melanomaFor at least two decades, veterinary oncologists have advocated using spontaneously occurring tumours in companion animals as models for human cancer (Knapp and Waters, 1997;MacEwen, 1990). Several recent reviews have readdressed this approach identifying osteosarcoma, mammary tumours, head and neck cancers, bladder carcinomas, non-Hodgkin lymphoma, prostatic carcinoma, lung cancer and pertinently oral canine malignant melanoma (CMM) as good models for human neoplasms (Hansen and Khanna, 2004;Khanna and Hunter, 2005;Paoloni and Khanna, 2008). The major benefits of dogs as tumour models include the ability to study genetically outbred and immunologically intact animals in which cancers develop spontaneously and thus, more likely reflect the process of tumourigenesis compared to experimentally-induced neoplasms. As pets and owners share the same environment, they may be exposed to the same carcinogens, which, in part, drive tumour development. Regarding disease modelling, animal tumours often have similar clinical presentation, tumour biology and histopathological appearance to their human counterparts and usually progress more rapidly, thereby shortening data maturation times. In addition, few "standard of care" therapies exist for dogs meaning that within reason, trial therapeutics can be instigated at any point. Given these benefits, companion animal tumour models more accurately reflect the features of human cancers compared to rodent models with CMM being a desirable example of one such neoplasm. Conversely, the opportunity to translate the potential value of state of the art human therapeutics to the veterinary clinic also exists. Oral canine malignant melanoma (CMM) is a spontaneously occurring aggressive tumour with relatively few medical treatment options, which provides a suitable model for the disease in humans. Historically, multiple immunotherapeutic strategies aimed at provoking both innate and adaptive anti-tumour immune responses have been published with varying levels of activity against CMM. Recently, a plasmid DNA vaccine expressing human tyrosinase has been licensed for the adjunct treatment of oral CMM. This article reviews the immunological similarities between CMM and the human counterpart; mechanisms by which tumours evade the immune system; reasons why melanoma is an attractive target for immunotherapy; the premise of whole cell, dendritic cell (DC), viral and DNA vaccination strategies alongside preliminary clinical results in dogs. Current "gold standard" treatments for advanced human malignant melanoma are evolving quickly with remarkable results being achieved following the introduction of immune checkpoint blockade and adoptively transferred cell therapies. The rapidly expanding field of cancer immunology and immunotherapeutics means that rational targeting of this disease in both species should enhance treatment outcomes in veterinary and human clinics.

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“…Several comparative studies of novel immunotherapy protocols have been performed in dogs affected by MM, and promising results have been achieved [87][88][89][90][91]. These efforts led to the development of the first USDA-approved antitumor vaccine; ONCEPT (Merial), a xenogeneic DNA vaccine targeting tyrosinase which can extend survival in dogs with locally controlled stage II-III oral MM.…”

Section: Melanomamentioning

confidence: 99%