Page 1411 - Clinical Small Animal Internal Medicine

153 Melanoma 1349

Chemotherapy transfected with interleukin (IL)‐2 or granulocyte
VetBooks.ir Other modalities reported for local tumor control as macrophage‐colony stimulating factor (GM‐CSF), lipo-
somal‐encapsulated nonspecific immunostimulators (e.g.,
case reports and/or case series have included intrale-
sional cisplatin implants, intralesional bleomycin with L‐MTP‐PE), topical imiquimod, intralesional Fas ligand
DNA, siRNA (small interfering) against the survivin and/
electronic pulsing and many others, but widespread use or Bcl‐2 genes, bacterial superantigen approaches with
has not been reported to date. GM‐CSF or IL‐2 as immune adjuvants, pegylated tumor
In dogs with melanoma in anatomic sites predicted to
have a moderate to high metastatic rate, or dogs with necrosis factor (TNF)‐alpha, suicide gene therapy, adeno-
vector CD40 ligand and, lastly, canine dendritic cell vac-
cutaneous melanoma with a high tumor score and/or cines loaded with melanosomal differentiation antigens.
increased proliferation index through increased Ki‐67 Although these approaches have produced some clinical
expression, the use of systemic therapies is warranted due antitumor responses, the methodologies for the genera-
to the high risk for metastasis. Rassnick and colleagues tion of these products can be expensive, time consuming,
reported an overall response rate of 28% using carboplatin sometimes dependent on patient tumor samples being
for dogs with malignant melanoma. Unfortunately, only established into cell lines, and fraught with the difficulties
one dog had a minimally durable complete response (~150 of consistency, reproducibility, and other quality control
days), and the rest were nondurable partial responses. issues. Furthermore, we are just beginning to more fully
Similarly, Boria et al. reported an 18% response rate and understand the native immune dysregulation potentially
median survival time of 119 days with cisplatin and pirox- induced by the malignancy through increased T‐regula-
icam in canine oral melanoma. Other reports using sin- tory (Treg) cells, which suppress antitumor responses.
gle‐agent dacarbazine, melphalan or doxorubicin suggest The advent of DNA vaccination circumvents many of
poor or absent activity. More recently, and importantly, the previously encountered hurdles in vaccine develop-
three studies suggest that chemotherapy plays an insig- ment. DNA is relatively inexpensive and simple to purify
nificant role in the adjuvant treatment of canine mela- in large quantities. The antigen of interest is cloned into a
noma, whereas one study suggests it may provide benefit. bacterial expression plasmid with a constitutively active
While it can be argued that the studies performed to
date to evaluate the activity of chemotherapy in an adju- promoter. The plasmid is introduced into the skin or
muscle with an intradermal or intramuscular injection.
vant setting for canine melanoma have been suboptimal Once in the skin or muscle, professional antigen‐present-
for a variety of reasons, the extensive human literature ing cells, particularly dendritic cells, are able to present
suggests that melanoma is an extremely chemotherapy‐ the transcribed and translated antigen in the proper con-
resistant tumor. It is clear that new approaches to the sys- text of major histocompatibility complex and co‐stimula-
temic treatment of this disease are desperately needed. tory molecules. Although DNA vaccines have induced
One potential therapeutic avenue which has not been
significantly reported to date in canine or feline mela- immune responses to viral proteins, vaccinating against
tissue specific self‐proteins on cancer cells is clearly a
noma is the use of COX‐2 inhibitors. A number of more difficult problem. One way to induce immunity
authors have investigated the expression of COX‐2 in against a tissue‐specific differentiation antigen on cancer
canine melanoma and have found positive correlations cells is to vaccinate with xenogeneic ( different species)
of COX‐2 expression to proliferation and survival. antigen or DNA that is homologous to the cancer anti-
Further studies investigating the clinical responsiveness gen. As outlined in cartoon form in Figure 153.1, vaccina-
of canine melanoma to COX‐2 inhibitors (and potential tion with DNA encoding cancer differentiation antigens
correlation to COX‐2 expression) are encouraged.
is ineffective when self‐DNA is used, but tumor immu-
nity can be induced by DNA from another species.
Tyrosinase is a melanosomal glycoprotein, essential
Immunotherapy
in melanin synthesis and routinely found to be
Immunotherapy represents one potential logical systemic overexpressed in a wide variety of melanomas across
therapeutic strategy for melanoma. A variety of immuno- species. Immunization with xenogeneic human DNA
therapeutic strategies for the treatment of human mela- encoding tyrosinase family proteins induced antibodies
noma have been reported, with typically poor outcomes and cytotoxic T cells against syngeneic B16 melanoma
due to a lack of breaking innate or acquired immune tol- cells in C57BL/6 mice, but immunization with mouse
erance to the tumor. Immunotherapy targets and strate- tyrosinase‐related DNA did not induce detectable
gies to date in canine melanoma have used autologous immunity. In particular, xenogeneic DNA vaccination
tumor cell vaccines (with or without transfection with induced tumor protection from syngeneic melanoma
immunostimulatory cytokines and/or melanosomal challenge and autoimmune hypopigmentation. Thus,
differentiation antigens), allogeneic tumor cell vaccines xenogeneic DNA vaccination could break tolerance