The updated VCOG‐CTCAE v2 guidelines contain several important updates and additions since the last update (v1.1) was released in 2011 and published within Veterinary and Comparative Oncology in 2016. As the Veterinary Cooperative Oncology Group (VCOG) is no longer an active entity, the original authors and contributors to the VCOG‐CTCAE v1.0 and v1.1 were consulted for input, and additional co‐authors sought for expansion and refinement of the adverse event (AE) categories. VCOG‐CTCAE v2 includes expanded neurology, cardiac and immunologic AE sections, and the addition of procedural‐specific AEs. It is our intent that, through inclusion of additional authors from ACVIM subspecialties and the American College of Veterinary Surgery, that we can more comprehensively capture AEs that are observed during clinical studies conducted across a variety of disease states, clinical scenarios, and body systems. It is also our intent that these updated veterinary CTCAE guidelines will offer improved application and ease of use within veterinary practice in general, as well as within clinical trials that assess new therapeutic strategies for animals with a variety of diseases. Throughout the revision process, we strived to ensure the grading structure for each AE category was reflective of the decision‐making process applied to determination of dose‐limiting events. As phase I trial decisions are based on these criteria and ultimately determine the maximally tolerated dose, there is impact on standard dosing recommendations for any new drug registration or application. This document should be updated regularly to reflect ongoing application to clinical studies carried out in veterinary patients.
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.
Cytosolic DNA-mediated activation of the transcription factor IRF3 is a key event in host antiviral responses. Here, we show that infection of DNA viruses induced the interaction of the mTOR downstream effector S6K1 (S6 kinase 1) and the signaling adaptor STING in a cGAS (cGAMP synthase)-dependent manner. We further demonstrate that the kinase domain, but not the kinase function of S6K1, was required for the S6K1-STING interaction and that the TBK1 critically promotes this process. The formation of a tripartite S6K1-STING-TBK1 complex was necessary for IRF3 activation and disruption of this signaling axis impaired the early-phase expression of IRF3 target genes and the induction of T cell responses and mucosal antiviral immunity. Thus, our results have uncovered a fundamental regulatory mechanism for IRF3 activation in the cytosolic DNA pathway.
Mason (2020) Establishing a model system for evaluating CAR T cell therapy using dogs with spontaneous diffuse large B cell lymphoma, OncoImmunology, 9:1, 1676615,
Multiple immunotherapeutics have been approved for cancer patients, however advanced solid tumors are frequently refractory to treatment. We evaluated the safety and immunogenicity of a vaccination approach with multimodal oncolytic potential in non-human primates (NHP) (Macaca fascicularis). Primates received a replication-deficient adenoviral prime, boosted by the oncolytic Maraba MG1 rhabdovirus. Both vectors expressed the human MAGE-A3. No severe adverse events were observed. Boosting with MG1-MAGEA3 induced an expansion of hMAGE-A3-specific CD4+ and CD8+ T-cells with the latter peaking at remarkable levels and persisting for several months. T-cells reacting against epitopes fully conserved between simian and human MAGE-A3 were identified. Humoral immunity was demonstrated by the detection of circulating MAGE-A3 antibodies. These preclinical data establish the capacity for the Ad:MG1 vaccination to engage multiple effector immune cell populations without causing significant toxicity in outbred NHPs. Clinical investigations utilizing this program for the treatment of MAGE-A3-positive solid malignancies are underway (NCT02285816, NCT02879760).
The viral-transforming proteins E6 and E7 make human papillomavirus-positive (HPV) malignancies an attractive target for cancer immunotherapy. However, therapeutic vaccination exerts limited efficacy in the setting of advanced disease. We designed a strategy to induce substantial specific immune responses against multiple epitopes of E6 and E7 proteins based on an attenuated transgene from HPV serotypes 16 and 18 that is incorporated into MG1-Maraba virotherapy (MG1-E6E7). Mutations introduced to the transgene abrogate the ability of E6 and E7 to perturb p53 and retinoblastoma, respectively, while maintaining the ability to invoke tumor-specific, multifunctional CD8 T-cell responses. Boosting with MG1-E6E7 significantly increased the magnitude of T-cell responses compared with mice treated with a priming vaccine alone (greater than 50 × 10 E7-specific CD8 T cells per mouse was observed, representing a 39-fold mean increase in boosted animals). MG1-E6E7 vaccination in the HPV murine model TC1 clears large tumors in a CD8-dependent manner and results in durable immunologic memory. MG1-Maraba can acutely alter the tumor microenvironment and exploit molecular hallmarks of HPV cancer, as demonstrated by marked infection of HPV patient tumor biopsies and is, therefore, ideally suited as an oncolytic treatment against clinical HPV cancer. This approach has the potential to be directly translatable to human clinical oncology to tackle a variety of HPV-associated neoplasms that cause significant morbidity and mortality globally. .
Limited veterinary literature is available regarding prognostic markers for canine renal cell carcinoma (CRCC). We retrospectively evaluated COX-2 expression, histological and clinical features associated with prognosis of CRCC. Sixty-four cases post-nephrectomy were included, 54 had histopathological assessment and 30 had COX-2 immunostaining performed. Eight dogs (13%) had metastatic disease at initial diagnosis. Twenty-seven dogs (42%) received adjuvant therapy after nephrectomy. On univariate analysis, COX-2 expression, mitotic index (MI), histologic type, vascular invasion, neoplastic invasiveness and metastasis at diagnosis were significantly associated with overall median survival time (MST). COX-2 score (COX-2 score> 3 MST 420 days versus 1176 days if COX-2 score <3; P = 0.011) and MI (MI > 30 MST 120 days versus 540 days for MI < 30; P = 0.003) were the only variables associated with CRCC outcome on multivariate analysis. The addition of MI and COX-2 immunostaining to standard histopathological evaluation would help predicting outcome in CRCC patients.
Many viruses have documented oncolytic activity, with the first evidence observed clinically over a decade ago. In recent years, there has been a resurgence of interest in the field of oncolytic viruses. Viruses may be innately oncotropic, lacking the ability to cause disease in people or they may require engineering to allow selective tumor targeting and attenuation of pathogenicity. Following infection of a neoplastic cell, several events may occur, including direct viral oncolysis, apoptosis, necrotic cell death and autophagic cellular demise. Of late, a large body of work has recognized the ability of oncolytic viruses (OVs) to activate the innate and adaptive immune system, as well as directly killing tumors. The production of viruses expressing transgenes encoding for cytokines, colony-stimulating factors, costimulatory molecules and tumor-associated antigens has been able to further incite immune responses against target tumors. Multiple OVs are now in the advanced stages of clinical trials, with several individual viruses having completed their respective trials with positive results. This review introduces the multiple mechanisms by which OVs are able to act as an antineoplastic therapy, either on their own or in combination with other more traditional treatment modalities. The full benefit and the place where OVs will be integrated into standard-of-care therapies will be determined with ongoing studies ranging from the laboratory to the patient. With various different viruses now in the clinic this therapeutic option is beginning to prove its worth, and the versatility of these agents means further innovative and novel applications will continue to be developed.
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