Page 567 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 25 Tumors of the Skeletal System 545

one study, dogs were treated with limb amputation and cisplatin exerted by ADXS31-164. Overall, the adjuvant use of ADXS31-
every 4 weeks for four treatments. Upon completion of cisplatin 164 after standard-of-care therapy was well tolerated, and treated
dogs achieved prolonged disease control with a median DFI and
therapy, 25 dogs without overt evidence of pulmonary metastasis
VetBooks.ir were randomized to receive either L-MTP-PE or empty liposomes MST of 615 and 956 days, respectively. 287
twice a week for 8 weeks. Dogs treated with L-MTP-PE had a
significantly longer MST (14.4 months) than dogs treated with Molecular Targeted Therapies for Dogs with
empty liposomes (9.8 months). Osteosarcoma
Unlike the first study in which cisplatin and L-MTP-PE was
administered serially, the second study investigated the anticancer The GH and IGF-1 growth factor signaling cascade has been thor-
activities of concurrently administered cisplatin and L-MTP-PE oughly investigated in OSA. The putative roles of GH and IGF-1
in 64 dogs. All dogs were treated with limb amputation and cis- in OSA pathogenesis are supported by several clinical observations
platin every 3 weeks for four treatments. Within 24 hours after the in both humans and dogs. Given the central roles of GH and
first cisplatin treatment, dogs were randomized to concurrently IGF-1 in skeletal growth and homeostasis, as well as their role
receive either L-MTP-PE twice weekly, L-MTP-PE once weekly, in cell survival, it has been hypothesized that aberrant or exces-
or empty liposomes once weekly for 8 weeks. Dogs treated with sive GH and IGF-1 signaling is likely involved in OSA patho-
concurrent L-MTP-PE (once or twice weekly) and cisplatin did genesis. 288 To investigate the biologic consequences of attenuating
not have an improvement in median DFI or MST compared with GH and IGF-1 autocrine and/or paracrine signaling in OSA, a
dogs treated with concurrent empty liposomes and cisplatin. The randomized clinical trial of 44 dogs with OSA was conducted
MSTs for the twice weekly, once weekly L-MTP-PE, and empty in which circulating IGF-1 concentrations were suppressed with
liposome groups were 10.3, 10.5, and 7.6 months, respectively. the administration of a long-acting somatostatin analog (Onco-
These studies suggest that innate immune activation may be a LAR). 268 All dogs were treated with amputation and carbopla-
strategy for improving outcomes in dogs with OSA. This priming tin in combination with either OncoLAR or control vehicle. The
of the innate immune system has been leveraged through different administration of OncoLAR resulted in a 43% reduction in
strategies. The potential to create localized inflammation, apopto- circulating IGF-1 concentrations in comparison to baseline val-
sis, and necrosis within the immediate tumor microenvironment ues; however, incomplete suppression in IGF-1 did not result in
with subsequent adaptive immune cell priming was evaluated in improved DFIs or overall MSTs in comparison to dogs treated
dogs with OSA receiving an intratumoral adenoviral vector for with carboplatin and the vehicle.
FasL (Ad-FasL). Through an open-label clinical trial, 52 dogs with Molecular therapies with the capacity to delay or inhibit
OSA were treated with intratumoral Ad-FasL and subsequent limb the development of pulmonary metastases would dramatically
amputation 10 days post-Ad-FasL administration and carboplatin improve current treatment outcomes. As such, novel anticancer
chemotherapy. After amputation, histologic examination of the agents have been designed to selectively inhibit obligate steps nec-
primary tumor was performed to characterize degree of inflam- essary for successful tumor cell invasion and metastasis. One spe-
mation, apoptosis, necrosis, and lymphocyte infiltration. Dogs cific strategy has been the inhibition of matrix metalloproteinases
with greater inflammation and lymphocyte infiltration scores had (MMPs), which are proteolytic enzymes involved in local tissue
improved median DFIs and MSTs. When inflammation induced invasion and metastases. Based upon documented gelatinolytic
by Ad-FasL was categorized into low (score 1) versus high (score activities of MMP-2 and MMP-9 in canine cell lines and OSA
2 or 3), the MSTs were 198 versus 359 days, respectively. Col- samples, 91,93 it has been rationalized that specific inhibitors of
lectively, these studies support the notion that creating a robust MMP activity may have the potential to increase the metastasis-
innate immune response within the immediate primary tumor free period after amputation and systemic chemotherapy. A pro-
microenvironment has the capacity to induce sufficient immuno- spective, double-blind, randomized, placebo-controlled clinical
genic abscopal effects to delay the onset of metastatic disease. 286 trial evaluating the adjuvant activity of a MMP-2 and -9 inhibitor
In addition to innate immune activation strategies, a vaccine (BAY 12-9566) was conducted in 223 dogs with nonmetastatic
approach to specifically induce tumor-specific T-cell responses OSA. 180 After amputation and DOX therapy, dogs were random-
against the dominant immune epitopes of HER2/neu expressed ized and treated with either BAY 12-9566 (10 mg/kg) or placebo
by canine OSA cells has been reported. Through the generation control daily until clinical failure. The addition of BAY 12-9566
and IV administration of a highly attenuated, recombinant Liste- did not improve DFI or MST in comparison to placebo control.
+
ria monocytogenes expressing a chimeric human HER2/neu fusion Correlating with the absence of biologic effect, serum MMP-2
protein (ADXS31-164), the capacity to elicit a HER2-specific and -9 activities were not different between dogs receiving BAY
immune response was evaluated in 18 dogs with OSA treated with 12-9566 or placebo.
three consecutive dosages of ADXS31-164 every 3 weeks after the With the approval of toceranib phosphate (TOC) in veteri-
completion of conventional therapy (amputation or LSS and four nary medicine, this small molecule inhibitor of multiple kinase
doses of carboplatin chemotherapy). In 15 dogs, HER2-specific signaling pathways (KIT, VEGF receptor 2 [VEGFR2], platelet-
responses could be serially assessed through the quantification of derived growth factor receptor [PDGFR]) has generated scientific
antigen-induced T-cell interferon-gamma (IFNγ) secretion, and interest for its inclusion as an adjuvant treatment for dogs with
this served as an immune biomarker to measure the immune reac- appendicular OSA. In a randomized, prospective clinical trial,
tion elicited by vaccination with ADXS31-164. Although T-cell 126 dogs with OSA were treated with amputation and four doses
IFNγ secretion profiles did not correlate with long-term survival of carboplatin and, if there was no evidence of metastatic disease,
outcomes, the magnitude of white blood cell, neutrophil, and this was followed by either oral metronomic therapy (cyclophos-
monocyte elevations 24 hours after ADXS31-164 administration phamide and piroxicam) alone or oral metronomic therapy and
were significantly greater in dogs with STs exceeding 18 months. TOC. Although the inclusion of toceranib phosphate was toler-
These collective findings would suggest that innate immune able, there was no statistical difference in the median DFI for dogs
responses are contributing to the anticancer immune effects treated with the control protocol (215 days) or TOC (233 days).