Page 259 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

238 PART III Therapeutic Modalities for the Cancer Patient

of feline fibrosarcomas and canine melanoma and was shown to mount a cytolytic immune response. Moreover, IFNs have antian-
be safe and effective. 174–176 Therefore given its comparatively low giogenic properties. The IFNs are typically classified as either type
I (IFN-α, -β, and -ω) or type II (IFN-γ).
toxicity and promising effectiveness, rIL-2 therapy is a plausible
VetBooks.ir treatment for canine cancer. Interferon-α, Interferon-β, and Interferon-ω
Interleukin 12
mechanisms including interactions with cell cycle proteins (i.e.,
IL-12, produced by antigen-stimulated DCs, macrophages, and The type I IFNs can affect cellular proliferation through various
B cells, plays a role in stimulating the growth and function of c-myc and retinoblastoma) and induction of apoptosis via Bcl-2/
T cells and enhances the cytolytic activity of both T cells and Bax and TNF/Fas interactions. Their antiangiogenic proper-
NK cells. Similar to IL-2, IL-12 therapy in humans lead to seri- ties of downregulating VEGF and basic fibroblast growth factor
ous side effects, and is thus currently not used clinically. Current (bFGF) 189 make them attractive as immunotherapies and they
investigation into the use of IL-12 in veterinary medicine revolves have been used successfully to treat pediatric hemangiomas. 190
around recombinant gene therapy for treatment of canine head Clinical trials using the type I IFNs have met limited success
and neck tumors, 177 with some in vitro work looking at its use in because of the high occurrence of severe toxicity and overall lim-
feline hyperthermia-induced gene therapy. 178 More recently, in an ited response rates. Nonetheless, their effectiveness was assessed
experimental model of CTVT, intratumoral delivery of the IL-12 in melanoma, multiple myeloma, renal cell carcinoma, leukemia,
gene resulted in decreased tumor growth and complete tumor other cancers, and in conjunction with chemotherapies. The best
remission. 179 Similar studies in dogs using IL-12 electrogene response, in terms of disease-free survival, was seen in renal cell
therapy resulted in reduced tumor volume of 9 out of 11 dogs carcinoma and melanoma when used as single agents. 191,192
with mast cell tumors 180 and increases in intratumoral IFN-γ and The use of type I IFNs in veterinary medicine is limited and
antiangiogenic effects in nine dogs with various cancers, 181 and in they are used mostly for feline viral diseases. 193 One study showed
six dogs treated with concurrent metronomic chemotherapy. 182 that recombinant feline IFN-ω was safe and easy to use for treat-
However, no significant clinical responses were observed in these ing feline fibrosarcomas. As this was a safety study, the therapeutic
studies. Interestingly, both studies demonstrated increased levels effects of this treatment were not evaluated. Another recently pub-
of tumor-infiltrating lymphocytes, suggesting immune specificity lished study also used recombinant feline IFN-ω with or without
of this therapy. chemotherapy to study its effects in treating mammary tumors
in vitro. 194 This study reported that the antitumor cell effects of
Interleukin-15 recombinant IFN-ω and chemotherapy were additive and sug-
IL-15 is structurally similar to and uses similar signaling molecules gested further investigation into its clinical use as an adjuvant
as IL-2. IL-15 plays a role in stimulation of NK cells and in pro- therapy.
moting proliferation of T cells. However, from an immunother-
apy standpoint, IL-15 holds more promise than IL-2 in that (1) it Interferon-γ
does not cause activation-induced cell death of CD4+ T cells after IFN-γ plays an important role in stimulating the immune system.
prolonged periods of exposure, but rather sustains T-cell prolifera- It is secreted mostly by NK cells, DCs and antigen-activated T
tion 183 ; (2) it plays a critical role in CD8+ T cell memory forma- cells and counteracts the effects of many of the immunosuppres-
tion and maintenance 184 ; and (3) unlike IL-2, it does not appear sive cytokines. It is a physiologic activator of macrophages, leading
to play a role in the development of Tregs. 185 to increased antigen presentation and increased lysosomal func-
Clinical evaluation has been underway now in several trials tion and NO production by macrophages. NO production by
in human cancer patients. An initial safety study in nonhuman macrophages is an efficient mechanism of tumor cytolysis. IFN-
primates was recently conducted. 186 Twelve daily doses of clinical γ can also cause increased MHC Class I and II expression on a
grade human recombinant IL-15 revealed that neutropenia was variety of cells, including tumors. Increased MHC expression has
the dose-limiting and documented an increase in circulating NK been confirmed to occur on in vitro IFN-γ treated canine tumor
cells and memory CD8+ T cells. cells lines 195 and in vivo after treatment with IFN-γ. 196 Thus its
In veterinary medicine, one study combined intralesional IL-15 role in antitumor immunity is characterized by increased tumor
and IL-6 plasmid DNA injections in beagles with CTVT. 187 With cell lysis and increased tumor antigen presentation to the adaptive
this treatment, investigators observed a threefold increase in the immune response.
proportion of CD8+ T cells that infiltrated the tumors and an The use of IFN-γ in veterinary medicine is currently being
enhancement of IFN-γ-producing cells and increased cytolytic investigated. A recently published study examined the use of
activity against the tumor. Lastly, in 2015, one group reported IFN-γ in combination with a single injection of autologous,
on the generation of recombinant canine IL-15. 188 They dem- ex vivo activated DCs in dogs with various malignant or benign
onstrated that in vitro, recombinant IL-15 could expand canine tumors. 197 In the seven dogs enrolled in the study, the investi-
NK cells and could cause expansion of lymphocytes in peripheral gators noted four complete responses and two partial responses
blood when administered to dogs intravenously. Thus IL-15 ther- against malignant tumors and saw moderate partial responses
apy shows promise as an effective immunotherapy in both human against fast-growing benign tumors. Another study looked at
and veterinary medicine. the use of adenoviral IFN-γ gene transfer as an adjuvant ther-
apy to treat a dog with astrocytoma. 198 After therapy and sur-
Interferons gery, the dog was tumor free for more than 450 days. Finally, a
Interferons (IFNs) are proteins produced by lymphocytes that safety study was done in cats with fibrosarcomas using a triple
play an important role in immune responses to pathogens and gene therapy that included IFN-γ along with IL-2 and GM-
cancer. Broadly, they can influence cell proliferation, play a role CSF. 176 In this study, cats tolerated the therapy, although six
in the induction of apoptosis, upregulate antigen presentation to of the eight cats developed local recurrence of disease within 1
T cells, and enhance the ability of the adaptive immune system to year of treatment.