Mechanisms of Drug Resistance in Veterinary Oncology— A Review with an Emphasis on Canine Lymphoma

Zandvliet, Maurice M.J.M.; Teske, Erik

doi:10.3390/vetsci2030150

Cited by 35 publications

(37 citation statements)

References 161 publications

(205 reference statements)

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“…While chemotherapy effects only last as long as the drugs remain in the body, immunotherapy can provide long-term protection against cancer due to the immune memory, overcoming the “honeymoon effect” provided in the short term by cytotoxic drugs, more over if negative prognostic factors are present. Chemotherapy fails when drug-resistant clones emerge, preventing tumor cell eradication [23]. It may be possible that dogs with negative prognostic factors, such as advanced disease stage and high LDH levels, are more susceptible of developing chemo-resistance [2, 24, 25].…”

Section: Discussionmentioning

confidence: 99%

Opportunities and challenges of active immunotherapy in dogs with B-cell lymphoma: a 5-year experience in two veterinary oncology centers

Marconato¹,

Aresu²,

Stefanello³

et al. 2019

j. immunotherapy cancer

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Background Pet dogs spontaneously develop lymphoma. An anthracycline-based multidrug chemotherapy regimen represents the treatment cornerstone; however, cure is rarely achieved. We have been treating dogs with B-cell lymphoma with an autologous vaccine (APAVAC®) and CHOP-based chemotherapy since 2011. Methods To better characterize the safety and efficacy of APAVAC®, and to find the best candidates for immunotherapy, we designed a retrospective study on all dogs treated with chemo-immunotherapy to date and compared them with those dogs treated with chemotherapy only. All dogs were completely staged and re-staged at the end of treatment. The primary endpoint was the effectiveness of chemo-immunotherapy, measured as time to progression (TTP), lymphoma-specific survival (LSS), and 1-, 2-, and 3-year survival rates. The secondary objective was safety. Results Three hundred dogs were included: 148 (49.3%) received chemotherapy and 152 (50.7%) chemo-immunotherapy. Overall, the latter survived significantly longer (median LSS, 401 vs 220; P < 0.001). Among dogs with diffuse large B-cell lymphoma, the 1-, 2- and 3-year survival rates were 20, 13 and 8% for chemotherapy, and 51, 19 and 10% for chemo-immunotherapy. The benefit of chemo-immunotherapy was particularly relevant in dogs with concurrent high serum LDH, stage V, substage a disease and not previously treated with steroids (median LSS, 480 vs 85 days; P < 0.001). Among dogs with nodal marginal zone lymphoma, those having at least 3 of the aforementioned characteristics significantly benefited from chemo-immunotherapy (median LSS, 680 vs 160 days, P < 0.001). The 1-, 2- and 3-year survival rates were 30, 16 and 10% for chemotherapy, and 55, 28 and 10% for chemo-immunotherapy. Among dogs with follicular lymphoma, lack of immunotherapy administration was the only variable significantly associated with increased risk of tumor-related death. Chemo-immunotherapy was remarkably well tolerated, with no local or systemic adverse events. Conclusions Overall, the addition of immunotherapy to a traditional CHOP protocol is associated with improved outcome in dogs with B-cell lymphoma, regardless of histotype and evaluated prognostic factors. Moreover, the identikit of the best candidate for immune-therapy was delineated for the most common histotypes. The study also confirms the excellent tolerability of the vaccine. Electronic supplementary material The online version of this article (10.1186/s40425-019-0624-y) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Opportunities and challenges of active immunotherapy in dogs with B-cell lymphoma: a 5-year experience in two veterinary oncology centers

Marconato¹,

Aresu²,

Stefanello³

et al. 2019

j. immunotherapy cancer

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“…In addition to its expression in somatic tissues, P‐GP can be expressed in a variety of tumor tissues in dogs and cats, and is considered one of the many mechanisms associated with chemotherapy resistance . High tumor cell P‐GP expression has been correlated with an inferior oncologic outcome in several studies of canine lymphoma, but other studies have not identified significant correlations …”

Section: P‐glycoprotein Mutation and Expression To Predict Chemotheramentioning

confidence: 99%

Drug dose and drug choice: Optimizing medical therapy for veterinary cancer

Thamm

Gustafson

2019

Vet Comparative Oncology

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Although novel agents hold great promise for the treatment of animal neoplasia, there may be room for significant improvement in the use of currently available agents. These improvements include altered dosing schemes, novel combinations, and patient-specific dosing or selection of agents. Previous studies have identified surrogates for "individualized dose intensity,", for example, patient size, development of adverse effects, and pharmacokinetic parameters, as potential indicators of treatment efficacy in canine lymphoma, and strategies for patient-specific dose escalation are discussed. Strategies for treatment selection in individual patients include conventional histopathology, protein-based target assessment (eg, flow cytometry, immunohistochemistry, and mass spectrometry), and gene-based target assessment (gene expression profiling and targeted or global sequencing strategies). Currently available data in animal cancer evaluating these strategies are reviewed, as well as ongoing studies and suggestions for future directions. K E Y W O R D S canine, chemotherapy, feline, oncology, personalized medicine 1 | INTRODUCTION Although novel agents hold great promise for the treatment of animal cancer, there may be room for significant optimization in the utilization of currently available agents. These improvements may include altered dosing schemes, novel combinations, and patient-specific selection or dosing. This review will discuss human and veterinary examples of alterations in dosing, outcome, or antineoplastic drug choice in specific patient populations, with ideas for future implementation of these observations. | DOSE INTENSITY AND OUTCOME-THE CANINE LYMPHOMA EXAMPLEThe concept of dose intensity can be interrogated in two ways. One is to evaluate the planned dose intensity for a given protocol, which can be quantified by measurement of "summation dose intensity" (SDI), the amount of chemotherapy on a mg/kg or mg/m 2 basis delivered per unit time. The SDI has been shown to modestly influence outcome in human tumors such as breast cancer, osteosarcoma (OSA), and others, although sometimes at the expense of increased adverse events. 1,2 In the studies evaluated to date, planned SDI has not correlated with patient outcome in canine lymphoma, 3,4 and studies in other canine tumor types have likewise failed to demonstrate an association between calculated SDI and outcome. 5,6 The second method is to use pharmacokinetic (PK) or pharmacodynamic (PD) measures to assess surrogates of "individual dose intensity." This approach has merit owing to the demonstrably wide interpatient variability in drug exposure to a given cytotoxic agent. In dogs, this has been best demonstrated in studies evaluating doxorubicin (DOX). 7,8 Wittenburg et al recently demonstrated that DOX exposure following a standard 30 mg/m 2 dose, as estimated from a "limited sampling" PK schema requiring only three time points within an hour of dosing, 9 was a significant predictor of neutrophil nadir, whereas mg/kg dose was not. 8

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“…To quote Seelig, “In both species diffuse large B-cell lymphoma (DLBCL) is the most common subtype (of lymphoma), but this is where the similarities end.” Their article, like all the others in this collection, is heavily cited to provide the reader abundant background material and context. Back-to-back articles by Tomiyasu and Tsujimoto [ 8 ] and by Zandvliet and Teske [ 9 ] offer a glimpse into mechanisms of drug resistance with emphasis on lymphoma.…”

Section: Editorialmentioning

confidence: 99%