Page 261 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

240 PART III Therapeutic Modalities for the Cancer Patient

cancer vaccine is based on the DNA plasmid technology. 209 The IL-10–secreting T cells. 224 However, the methods of maturation
ONCEPT Vaccine (Merial, Inc.) for canine malignant melanoma matter as well, with studies showing DCs activated with a mixture
of IFN-α, polyinosinic-polycytidylic acid, IL-1β, TNF, and IFN-
(CMM) uses xenogeneic DNA plasmids that contain the gene
VetBooks.ir encoding human tyrosinase (huTyr). Initial studies showed the γ elicit many fold more antimelanoma CTLs in vitro than the
standard IL-1β, TNF, IL-6, prostaglandin E (PGE ) cocktail.
225
development of an antibody-mediated immune response against
2
2
the huTyr protein that cross-reacted to canine tyrosinase (also Finally, new methods of targeting antigens to DCs through anti-
see Chapter 19 for more details). 210 Improved survival of dogs DC receptor (i.e., lectin receptors such as DEC-205, DC-SIGN,
treated with this vaccine compared with historical control animals or DNGR-1) antibody–TA fusions, appropriate selection of adju-
has been reported with no severe side effects noted. 209,211 Further vants to deliver antigens to DCs, and combination therapies using
studies of this plasmid DNA technology demonstrated that the chemotherapy and DC activation are being investigated. 221,223
vaccine could induce antigen-specific IFN-γ+ T cells in normal DC vaccination in veterinary medicine has been and is still
beagle dogs. 212 The same group that developed the CMM vac- currently being explored. An initial study of three dogs with oral
cine has reportedly completed Phase I trials of murine CD20 for melanoma showed that bone marrow derived DCs transduced
treatment of canine B cell lymphoma and is initiating a Phase with an adenovirus expressing human gp100 could safely be used.
II trial soon. 213 Lastly, a recently developed vaccine against the In this study, dogs received three subcutaneous vaccines over 4
dog telomerase reverse transcriptase protein, for use in canine lym- months. 226 One of the dogs, which was disease-free 4 years later,
phoma patients, has demonstrated positive results, significantly developed a robust CTL response against the gp100. Another
increasing survival in dogs with B-cell lymphoma when added to dog that relapsed after 22 months had no evidence of antigp100
conventional chemotherapy. 214,215 CTLs. A similar study performed in normal dogs was done to
assess the immune response of DCs pulsed with canine melanoma
Tumor Vaccination Using Viral Vector Vaccines cell (CMM2) lysates, where a good delayed-type hypersensitivity
As discussed earlier (section “Oncolytic Viruses”), viruses have been (DTH) response was seen against CMM2 after vaccination. 227
used to target tumor cells, in particular ones with innate oncolytic Another study described earlier (section “Interferon-γ”) saw
properties. However, viruses can also be used as vectors for expres- success using ex vivo activated DCs and IFN-γ for treating canine
sion of particular TAs. Typically, attenuated or replication-defec- solid tumors. Finally, a very recent study looked at the safety of
tive forms of the virus are used to allow for effective stimulation using a DC–mammary tumor cell fusion hybvrid vaccine. 228 In
of the innate and adaptive immune responses without the risk of this case normal dog PBMCs were used to generate DCs that were
spreading and rapidly dividing within the host. The most com- subsequently fused to canine mammary tumor cells. Injection of
monly used viral platform for both human and veterinary studies normal beagle dogs with this fusion plus CpG adjuvant resulted
is the Poxviridae family. The poxviruses are easy to work with, are in a robust antibody response against the fusion partner tumor cell
amenable to large amounts of foreign DNA, and are highly immu- line and three unrelated canine mammary tumor cells. However,
nogenic, allowing for strong immune responses against weak TAs, no CTL responses were noted. Hence, development of DC vac-
such as carcinoembryonic antigen (CEA). 216 In humans, one of cines for use in veterinary medicine is currently being explored in
the most commonly used viral vaccine platform is the canarypox various tumor models and using various strategies to optimize the
virus ALVAC. Recent published human clinical trials using ALVAC induced antitumor immune response.
include combining CEA-expressing ALVAC with chemotherapy
for metastatic colorectal cancer, 217 ALVAC expressing huGM-
CSF or IL-2 for treatment of melanoma or leiomyosarcoma, 218 Antibody Therapy for Cancer
and intranodal injection of ALVAC expressing gp100 in high-risk Monoclonal Antibodies
melanoma patients. 219 Interestingly, although all of these studies
reported that the vaccine was safe to use and that immunologic The use of mAb therapy for cancer has been studied for more than
responses were observed, the efficacy of these therapies is limited. 220 four decades after the development of hybridoma technology by
Kohler and Milstein in 1975. 229 This technique consisted of anti-
Vaccination Against Tumor Antigens Using Dendritic Cells body-producing cells fused with mouse myeloma cells, thus becom-
DCs possess very potent antigen presenting abilities and are an ing immortalized and capable of continuously producing antibody
attractive target for cancer vaccine strategies. Besides their role that can be purified out of the culture media. Initially, the use of
in vivo in processing and presenting TAs derived either naturally mAbs clinically was limited because of the responses mounted
or from tumor vaccines, there are many clinical trials published by the host against the foreign mouse proteins. However, recent
that examine the use of ex vivo activated and expanded DCs technology allowed for “humanizing” these antibodies by geneti-
injected back into the donor as a way of activating tumor-specific cally grafting the mouse hypervariable region of interest onto the
T cells in vivo. The drawback to this method is that the ex vivo human immunoglobulin, thus resulting in an antibody that is 95%
processing of DCs typically is expensive, takes about 7 to 10 days, human. Moreover, mice genetically rendered to express human
requires growth in a combination of cytokines, and can be used immunoglobulins can successfully generate 100% human antibod-
only autologously. Nonetheless, ex vivo prepared DCs have shown ies in response to various antigens. 230 Using humanized antibodies
clinical efficacy, particularly in human patients with metastatic improves antibody-dependent cell-mediated cytotoxicity (ADCC),
disease. 221,222 Recently, it has been determined that the potency of improves antibody stability, and decreases immunogenicity of the
the DCs produced ex vivo depends on the combination of cyto- antibody itself. The use of mAbs in human medicine has increased
kines used. 223 DCs generated with GM-CSF and IFN-α or GM- over the years. Table 14.3 lists those approved by the FDA for use as
CSF and IL-15 display potent priming of T-cell–mediated and human cancer treatments and some recent mAbs tested in human
CD8+ T-cell–mediated immune responses in vitro. Moreover, the clinical trials. 231 As a general guide, mAb names ending in -omab
use of mature DCs is better than use of immature DCs, as imma- are murine based, -ximab and -zumab are chimeric, and -umab are
ture DCs actually induce immune tolerance via expansion of humanized versions of the antibodies.