Page 260 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 14 Cancer Immunotherapy 239

Specific Immunotherapy for Cancer: Tumor One study out of our laboratory assessed the use of an allo-
Vaccines geneic HSA tumor lysate vaccine in combination with chemo-
202
In this Phase I/II study, 28 dogs were evaluated and
therapy.
VetBooks.ir The development of a tumor vaccine that is safe, effective, and received eight immunizations of tumor lysate plus CLDC (see
long-lasting is an ultimate goal of immunotherapy. Whereas the
the section “Liposome–DNA Complexes”) over a 22-week period
effects of traditional cancer treatments such as chemotherapy, sur- while concurrently receiving doxorubicin. The vaccine was well
gery, and radiation therapy typically result in noticeable clinical tolerated; adverse effects were limited to moderate diarrhea and
responses within hours to days after treatment, cancer vaccine anorexia. Tumor-specific antibody responses were detected in four
therapeutic responses typically take weeks to months to lead to to five of the six dogs tested, depending on which HSA cell-line
an appreciable clinical response. This difference in response time, they were screened against. Moreover, overall survival times of
coupled with the lack of congruent and objective ways to measure dogs receiving the combination treatment were significantly bet-
efficacy, make it difficult to develop tumor vaccines. ter than chemotherapy-only treated historical controls.
Nonetheless, despite the challenges to tumor vaccine develop- Whole cell and tumor lysate vaccines can also be modified to
ment, there are many different varieties of tumor vaccines currently enhance their immunogenicity. Aside from different adjuvant
in use either clinically or as part of Phase I, II, and III clinical tri- strategies, combination of these vaccines with modifiers such as
als. In fact, in April of 2010, the first FDA-approved therapeutic immunostimulatory cytokines has been examined. One clinical
cancer vaccine for human prostate cancer was approved. In the trial of 16 dogs with STS or melanoma assessed the use of an autol-
following section, we will discuss only those showing success in ogous, whole cell vaccine transfected with human GM-CSF. 203
human trials and those relevant to veterinary medicine. Three dogs in the study demonstrated objective tumor responses
that included regression of primary and metastatic lesions. On his-
Tumor Antigen Targets for Immunization tologic examination of tumor tissue in the dogs that received the
vaccine, an impressive inflammatory response was noted. Another
Tumor antigens (TAs) are proteins are other molecules that are recent study using a similar human GM-CSF adjuvanted, autol-
either unique to cancer cells or significantly more abundant in ogous vaccine looked at its efficacy in treating dogs with B cell
cancer cells compared with normal cells. These proteins include lymphoma. 204 Dogs in remission after a 19-week standard CHOP
the broad categories of oncogenes, oncofetal proteins, and can- (Cyclophosphamide, Hydroxydaunorubicin, Oncovin [vincris-
cer testes antigens. Although TAs offer potential targets for vac- tine], and Prednisone) protocol were randomized into placebo or
cine development, their downside is that some of them tend to vaccine treatment groups. No improvement in median length to
be individual or certain tumor type specific. Nonetheless, much remission, nor overall survival, was seen. Another study investi-
work has been accomplished characterizing TAs for various forms gated the use of an allogeneic melanoma vaccine in combination
of cancer and a table of currently studied TAs can be found in a with a xenogeneic melanoma protein, human glycoprotein 100
2009 publication by a panel of experts organized by the National (hpg100). 205 In this Phase II trial, the vaccine was well tolerated
Cancer Institute (NCI). 199 Although numerous TAs exist, the use and the researchers observed an overall response rate of 17% and
of these TAs in tumor vaccines is not trivial. As mentioned earlier, a tumor control rate (including complete and partial responses
the tumor is highly capable of inducing a potent, immunosup- and stable disease greater than 6 weeks duration) of 35%. Lastly,
pressive microenviroment by various mechanisms; thus standard some positive results have been seen with an autologous B cell
vaccine procedures using TAs can be rendered useless in this pow- lymphoma vaccine where the cells were transfected loaded with
erful environment. In fact, there are little data available showing a tumor RNA and activated through CD40, particularly in pro-
clear correlation between in vitro TA responses and prognosis. The longing remission duration of salvage therapy. 206
success of most tumor vaccines has been limited to animal mod-
els of induced disease. 200,201 However, through the use of better Immunization Against Defined Tumor Antigens Using
vaccine strategies and by combining therapies that can ultimately Plasmid DNA
overcome tumor immunosuppression, more promising specific Vaccines that use specific gene sequences of TAs encoded in plas-
immunotherapies are being developed. In the text that follows we mid DNA have shown some clinical promise with their ability to
will discuss the various platforms used to develop tumor vaccines. invoke both cellular and humoral immunity. The ease of working
with bacterial DNA and the ability to quickly produce large quan-
Tumor Vaccine Approaches tities of plasmid DNA make this an attractive vaccine platform.
Moreover, the DNA sequences of a majority of TAs are known
Whole Tumor Cell and Tumor Cell Lysate Vaccines and can be easily inserted into the plasmid DNA and expressed
One of the more simple approaches to tumor vaccine develop- under the control of a constitutively active bacterial promoter.
ment is through the use of whole tumor cell or tumor cell lysate Typically given intradermally or intramuscularly, the proteins
vaccines. These can either be made directly from the patient in the expressed by transcription and translation of the plasmid are read-
form of an autologous vaccine or from cell lines of similar tumor ily picked up by DCs, processed and presented in the context of
types from the same species as an allogeneic vaccine. Whole cell MHC Class I and II, thus providing a more “natural” stimulation
preparations are most often produced made by lethally irradiat- of the immune system. Moreover, the unmethylated dinucleotide-
ing tumor cells and/or tissues. Tumor lysate vaccines, including CpG residues, or CpG motifs, present in high frequency in the
membrane protein fraction vaccines, are made by mechanically bacterial DNA provide additional stimulation of DCs, triggering
disrupting the tumor cells and/or tissues. Both whole cell and them to induce a Th1-type immune response. 207
tumor-lysate vaccines are typically administered with some form No DNA vaccines have been licensed for human use yet. How-
of adjuvant to enhance the immune response. These polyvalent ever, many DNA vaccines have been tested in clinical trials and
vaccines may be superior to specific peptide or protein (subunit) results have thus far been disappointing for various reasons (see
vaccines in that they contain a heterogeneous population of TAs. review 208 ). Nonetheless, the first conditionally licensed veterinary