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Emerging Translational Opportunities in Comparative Oncology With Companion Canine Cancers: Radiation Oncology.
It is estimated that more than 6 million pet dogs are diagnosed with cancer annually in the USA. Both primary care and specialist veterinarians are frequently called upon to provide clinical care that improves the quality and/or quantity of life for affected animals. Because these cancers develop spontaneously in animals that often share the same environment as their owners, have intact immune systems and are of similar size to humans, and because the diagnostic tests and treatments for these cancers are similar to those used for management of human cancers, canine cancer provides an opportunity for research that simultaneously helps improve both canine and human health care. This is especially true in the field of radiation oncology, for which there is a rich and continually evolving history of learning from the careful study of pet dogs undergoing various forms of radiotherapy. The purpose of this review article is to inform readers of the potential utility and limitations of using dogs in that manner; the peer-reviewed literature will be critically reviewed, and current research efforts will be discussed. The article concludes with a look toward promising future directions and applications of this pet dog "model.
Characterizing the immune microenvironment of malignant peripheral nerve sheath tumor by PD-L1 expression and presence of CD8+ tumor infiltrating lymphocytes.
BackgroundMalignant peripheral nerve sheath tumor (MPNST) is an aggressive sarcoma with few treatment options. Tumor immune state has not been characterized in MPNST, and is important in determining response to immune checkpoint blockade. Our aim was to evaluate the expression of programmed death-ligand 1 (PD-L1), programmed cell death protein 1 (PD-1), and presence of CD8+ tumor infiltrating lymphocytes (TILs) in MPNST, and correlate these findings with clinical behavior and outcome.ResultsPD-L1 staining of at least 1% was seen in 0/20 nerves, 2/68 benign lesions and 9/53 MPNST. Two of 68 benign lesions and 7/53 (13%) MPNST had at least 5% PD-L1 staining. CD8 staining of at least 5% was seen in 1/20 (5%) nerves, 45/68 (66%) benign lesions and 30/53 (57%) MPNST. PD-L1 was statistically more prevalent in MPNST than both nerves and benign lesions (p=0.049 and p=0.008, respectively). Expression of PD-1 was absent in all tissue specimens. There was no correlation of PD-L1 or CD8 expression with disease state (primary versus metastatic) or patient survival.MethodsA comprehensive PNST tissue microarray was created from 141 surgical specimens including primary, recurrent, and metastatic MPNST (n=53), neurofibromas (n=57), schwannoma (n=11), and normal nerve (n=20). Cores were stained in triplicate for PD-L1, PD-1, and CD8, and expression compared between tumor types. These data were then examined for survival correlates in 35 patients with primary MPNST.ConclusionsMPNST is characterized by low PD-L1 and absent PD-1 expression with significant CD8+ TIL presence. MPNST immune microenvironment does not correlate with patient outcome
Hyperthermia combined with chemotherapy - Biological rationale, clinical application, and treatment results
There is substantial evidence from preclinical data that the antitumor cytotoxicity of selected chemotherapeutic agents either alone or combined with radiation can be enhanced by appropriate heat exposure (40-44 degrees C) of cells or tumor tissues. Based upon these results the integration of hyperthermia as an additional treatment modality, given simultaneously with systemic chemotherapy or in combination with radiochemotherapy, is currently tested at the clinic. Regional hyperthermia combined with chemotherapy or radiochemotherapy showed impressive results (phase II studies) at clinical relevant temperatures in locally advanced tumors of different entities in terms of objective response rate, local tumor control and relapse-free survival. Clinical protocols of well-designed phase III trials on combined treatment modalities integrating hyperthermia are rather limited but for some tumors confirm its clinical benefit. In general, the clinical approach to use hyperthermia has gained much more interest within in the field of medical oncology. One of the major reason is the substantial technical improvements made with the available commercial equipment for local or regional heating, especially in case of deep-seated lesions or systemic heating. Further testing of the potential of hyperthermia combined with chemotherapy or radiochemotherapy in prospective randomized trials are warranted. At this time, hyperthermia as an adjunct to conventional treatment strategies is recommended in the setting of clinical protocols. The results of prospective trials should answer the question for which types of local advanced or metastatic tumors hyperthermia becomes standard as part of a multi-modal treatment strategy
Blood and tissue biomarker analysis in dogs with osteosarcoma treated with palliative radiation and intra-tumoral autologous natural killer cell transfer.
We have previously reported radiation-induced sensitization of canine osteosarcoma (OSA) to natural killer (NK) therapy, including results from a first-in-dog clinical trial. Here, we report correlative analyses of blood and tissue specimens for signals of immune activation in trial subjects. Among 10 dogs treated with palliative radiotherapy (RT) and intra-tumoral adoptive NK transfer, we performed ELISA on serum cytokines, flow cytometry for immune phenotype of PBMCs, and PCR on tumor tissue for immune-related gene expression. We then queried The Cancer Genome Atlas (TCGA) to evaluate the association of cytotoxic/immune-related gene expression with human sarcoma survival. Updated survival analysis revealed five 6-month survivors, including one dog who lived 17.9 months. Using feeder line co-culture for NK expansion, we observed maximal activation of dog NK cells on day 17-19 post isolation with near 100% expression of granzyme B and NKp46 and high cytotoxic function in the injected NK product. Among dogs on trial, we observed a trend for higher baseline serum IL-6 to predict worse lung metastasis-free and overall survival (P = 0.08). PCR analysis revealed low absolute gene expression of CD3, CD8, and NKG2D in untreated OSA. Among treated dogs, there was marked heterogeneity in the expression of immune-related genes pre- and post-treatment, but increases in CD3 and CD8 gene expression were higher among dogs that lived > 6 months compared to those who did not. Analysis of the TCGA confirmed significant differences in survival among human sarcoma patients with high and low expression of genes associated with greater immune activation and cytotoxicity (CD3e, CD8a, IFN-Îł, perforin, and CD122/IL-2 receptor beta). Updated results from a first-in-dog clinical trial of palliative RT and autologous NK cell immunotherapy for OSA illustrate the translational relevance of companion dogs for novel cancer therapies. Similar to human studies, analyses of immune markers from canine serum, PBMCs, and tumor tissue are feasible and provide insight into potential biomarkers of response and resistance
Clinical Trials of Immunogene Therapy for Spontaneous Tumors in Companion Animals
Despite the important progress obtained in the treatment of some petsâ malignancies, new treatments need to be developed. Being critical in cancer control and progression, the immune systemâs appropriate modulation may provide effective therapeutic options. In this review we summarize the outcomes of published immunogene therapy veterinary clinical trials reported by many research centers. A variety of tumors such as canine melanoma, soft tissue sarcomas, osteosarcoma and lymphoma, feline fibrosarcoma, and equine melanoma were subjected to different treatment approaches. Both viral and mainly nonviral vectors were used to deliver gene products as cytokines, xenogeneic tumor associated antigens, specific ligands, and proapoptotic regulatory factors. In some cases autologous, allogenic, or xenogeneic transgenic cytokine producing cells were assayed. In general terms, minor or no adverse collateral effects appeared during this kind of therapies and treated patients usually displayed a better course of the disease (longer survival, delayed or suppressed recurrence or metastatic spread, and improvement of the quality of life). This suggests the utility of these methodologies as standard adjuvant treatments. The encouraging outcomes obtained in companion animals support their ready application in veterinary clinical oncology and serve as preclinical proof of concept and safety assay for future human gene therapy trials.Fil: Glikin, Gerardo Claudio. Universidad de Buenos Aires. Facultad de Medicina. Instituto de OncologĂa "Dr. Ăngel Roffo". Unidad de Transferencia GenĂ©tica; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Oficina de CoordinaciĂłn Administrativa Houssay; ArgentinaFil: Finocchiaro, Liliana Maria Elena. Universidad de Buenos Aires. Facultad de Medicina. Instituto de OncologĂa "Dr. Ăngel Roffo". Unidad de Transferencia GenĂ©tica; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Oficina de CoordinaciĂłn Administrativa Houssay; Argentin
Targeting cyclin-dependent kinases in sarcoma treatment: Current perspectives and future directions
Effective treatment of advanced/metastatic bone and soft tissue sarcomas still represents an unmet medical need. Recent advances in targeted therapies have highlighted the potential of cyclin-dependent kinases (CDK) inhibitors in several cancer types, including sarcomas. CDKs are master regulators of the cell cycle; their dysregulation is listed among the âhallmarks of cancerâ and sarcomas are no exception to the rule. In this review, we report both the molecular basis, and the potential therapeutic implications for the use of CDK inhibitors in sarcoma treatment. What is more, we describe and discuss the possibility and biological rationale for combination therapies with conventional treatments, target therapy and immunotherapy, highlighting potential avenues for future research to integrate CDK inhibition in sarcoma treatment
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