Page 258 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 14 Cancer Immunotherapy 237

Liposome–DNA Complexes viral particles in kidney, salivary gland, lung, and stomach. Lastly,
Bacterial DNA can also stimulate the innate immune system a clinical study of dogs with various cancer types were treated
with a recombinant form vesicular stomatitis virus (VSV), that
via its CpG oligonucleotides, particularly when complexed with
VetBooks.ir cationic liposomes, in a form known as cationic lipid–DNA expresses IFN-β and the sodium iodide symporter (NIS). 164 This
148
Complexing bacterial plasmid DNA to
complexes (CLDCs).
study was designed to assess for safety and efficacy. They deter-
liposomes allows for more efficient delivery of the CpG DNA mined that there was no viral shedding two of the five dogs (both
to the endosomal compartment of antigen presenting cells, such with T-cell lymphoma) had a transient partial response during the
as DCs, where it is released from the liposomes and binds to its 28-day observation posttreatment time period. Five of the 9 dogs
receptor, TLR-9. 149,150 In mouse studies, CLDCs stimulate the demonstrated stable disease for the same 28-day time period and
immune system largely through induction of NK cell activity and the remaining two dogs had progressive disease. One of the dogs
release of IFN-γ. 148 Moreover, CLDCs were also shown to stimu- with stable disease (anal adenocarcinoma) had resection of the
late the production of type I IFN, 151 and thus are potent nonspe- tumor after completion of the study and evidence of an unchar-
cific immunostimulants. acteristic T cell infiltration into the tumor tissue was observed,
The use of CLDCs in dogs has been evaluated in metastatic suggesting a possible immune effect of the VSV therapy.
OSA and in dogs with soft tissue sarcoma (STS). 152,153 Intrave-
nous administration of a modified CLDC that encodes for IL-2 Toll-Like Receptor and NOD-Like Receptor Agonists
was performed in dogs with stage IV OSA. 152 Dogs that received TLRs are part of the innate immune system and are proteins
the CLDC developed fevers and showed changes in their leuko- expressed on the surfaces of macrophages and dendritic cells
gram profile indicative of immune stimulation. Moreover, NK cell and serve the purpose of recognizing microbial pathogens. As
activity was observed, as assessed by target cell lysis, and monocytes discussed earlier, CLDC contains CpG DNA, which can bind
showed increased expression of B7.2 on their surface, indicating to TLR-9. Lipopolysaccharide (LPS) is a known ligand for
activation. Treatment was associated with a significant increase in TLR-4. Recently the TLR-7 agonist imiquimod was studied as
survival times compared with historical controls. Another study a topical therapy in combination with an autologous cellular
examined the use of CLDC in canine STS. 153 Administration vaccine in dogs with invasive meningioma, 165 and as a single
of CLDC, IV, once weekly for 6 weeks resulted in an objective therapy in cats with squamous cell carcinoma. 166 As noted ear-
response in 15% of the dogs and a decrease in tumor microvessel lier, MTP functions as an NOD2 receptor agonist, and can
density in half of the dogs receiving the treatment. Thus CLDC be preferentially targeted to activate macrophages by liposome
has excellent potential to be used as a stand-alone immunothera- encapsulation. 167
peutic in veterinary medicine for a variety of cancer types.
Nonspecific Tumor Immunotherapy Using
Oncolytic Viruses Recombinant Cytokine Therapy
Oncolytic viruses are defined as viruses capable of replicating in
and lysing tumor cells, thus making them likely candidates for Interleukin-2
drug or gene delivery to tumors. This section focuses on onco- IL-2 is a cytokine that is released by T cells after their activation
lytic viruses as means of directly killing the cells, and a later sec- via interactions of antigen-loaded MHC and costimulatory mole-
tion focuses on using viral vectors as a means of gene delivery. cules expressed on the surface of antigen presenting cells. Its func-
A beneficial side effect of these viruses is that they not only kill tion is to induce clonal expansion of T cells in an antigen-specific
the tumor cells, but they also cause release of tumor antigens for fashion and activate DCs, macrophages, and B cells, which in turn
processing by the immune system. With safety being the main release proinflammatory cytokines. Moreover, IL-2 stimulates NK
concern, modern genetics has allowed for modifications of the cells, thus playing an important role in inducing both the innate
virus to make them less pathogenic and also target tumor cells and adaptive arms of the immune system.
specifically. A recent review of the use of oncolytic virotherapy The therapeutic use of IL-2 in humans is fraught with toxic-
for canine cancer describes the biology behind this therapy and ity 168–170 ; however, the use of IL-2 therapy in veterinary medicine
recent veterinary studies assessing these therapies. 154 Adenoviruses holds some promise. Helfand et al demonstrated that intra-
that have undergone genetic modification of their early genes, venously injected recombinant human IL-2 (rhIL-2) activates
1A (E1A) and 1B (E1B), preferentially target rapidly dividing canine lymphocytes, causing only mild gastrointestinal toxicity,
tumor cells and have been used to target canine OSA cells. 155–157 even at high doses for 4 consecutive days. 171 Another study dem-
Canine distemper virus (CDV) has also been investigated as a onstrated the ability of rhIL-2 to induce canine lymphokine acti-
treatment for B and T cell lymphoma in dogs. 158 In vitro stud- vated killer (LAK) cells and, incidentally, showed that LAK cells
ies using fluorescently labeled, attenuated CDV and canine lym- from tumor-bearing dogs did not kill tumor cells as efficiently
phoma cells demonstrated that CDV infected lymphoid cells via compared with normal dogs. 172 Further evaluation of toxicity
binding of the cell membrane protein CD150, which is overex- and efficacy of rhIL-2 was done using dogs with primary lung
pressed on malignant B cells, and induced cellular apoptosis. 158 cancer and with lung metastases in an aerosol formulation. 173 In
More recently, many groups have begun looking at Pox viruses this study, complete regression was seen in two of the four dogs
in oncolytic viral therapy, although this research has been done with pulmonary metastases and these dogs remained disease-
only in in vitro cultures or xenograft mice. 159–162 There is also a free for at least 12 months after treatment. One of the two dogs
report on the use of an attenuated strain of Newcastle disease virus with a primary lung tumor had stabilized disease for more than
in in vitro cultures on both human and canine lymphoma cells 8 months, whereas the other dog had progressive disease. Assess-
and compared cell death with peripheral blood mononuclear cells ment of the lymphocytes obtained from bronchoalveolar lavage
(PBMCs). 163 They reported a 34% increase in cell death in canine showed increased cytolytic activity after 15 days of IL-2 treatment.
lymphoma cells compared with normal PBMCs. Furthermore, In addition, minimal toxicity was noted in this study. Finally, IL-2
this group injected one dog with a T-cell lymphoma and found gene therapy using viral vectors has been examined for treatment