This understanding has lead to several promising
strategies that use the immune system to first
detect and then destroy cancer cells. Approaches
to immunotherapy include the following:
Non-specific Immunotherapy--where
bacterial agents (e.g., BCG, Corynebacterium
Parvum), natural products (Acemannan), synthetic
compounds (Muramyl tripeptide), chemical agents,
and others, are used to stimulate an immune
response. This approach is similar to that of
Coley, and is referred to as non-specific
because the target for immune recognition in the
cancer is not known. The most extensively
studied form of non-specific immunotherapy in
veterinary oncology is muramyl tripeptide (MTP).
In randomized, controlled, and placebo-blinded
trials, MacEwen et al have demonstrated
the activity of MTP against canine osteosarcoma
and canine hemangiosarcoma. Treatment of dogs
with osteosarcoma or hemangiosarcoma using MTP
plus chemotherapy resulted in significantly
longer survival times compared to chemotherapy
alone. There has been a renewed commercial
interest in the development of MTP by IDM,
who is considering the development of MTP for
pediatric osteosarcoma patients.
Specific Immunotherapy--attempts
to generate a specific immune response against a
known or unknown tumor antigen (target). A tumor
vaccine is the most common form of specific
immunotherapy. Our understanding of the immune
response against cancer suggests that the most
effective tumor vaccines will stimulate
cell-mediated responses against cancer. Clinical
trials using a number of vaccination approaches
are currently ongoing at several sites in the
United
States for dogs with melanoma,
osteosarcoma, and hemangiosarcoma. In some
cases, these treatment options do not require
travel to the sponsoring institution. More
information about these clinical trials can be
found at
www.vetcancersociety.org.
Adoptive Immunotherapy--refers
to the administration of parts of the immune
system to a patient. Monoclonal antibodies
raised against cancers represent adoptive
humoral immunotherapy. Advances in the design of
monoclonal antibodies to prevent immune
reactions against the antibody and to improve
antigen recognition have raised the potential
value of this type of therapy. The land-mark
approval of Herceptin®, an antibody that binds
the Her2/neu gene product, to treat breast
cancer in women is evidence of the progress that
has been made in this field. Since the approval
of Herceptin, a series of antibody-based
therapies have become available for the
treatment of cancer in human patients (e.g.,
Avastin, Erbitux, Rituxin). These treatment
approaches have received considerable press and
as such, interest from pet owners; however,
humanized monoclonal antibodies are not likely
to have wide application in the treatment of
canine or feline cancers since the development
of neutralizing antibodies against these human
proteins is likely to occur. Future development
of smaller fragments of antibodies, peptide
antibodies, may have greater transferability to
veterinary patients.
Cytokine Immunotherapy--refers
to the administration of products of the immune
system (cytokines) to stimulate or direct
anti-tumor immune responses. Cytokines are
released by leukocytes and function in the
activation and regulation of the immune
response. Cytokines, such as interleukin-2
(IL-2), have been used to induce significant
anti-tumor immune responses and objective tumor
responses in dogs with osteosarcoma. We have
shown in a small number of dogs with pulmonary
metastasis from appendicular osteosarcoma
(4/16), complete regression of metastases after
the inhalation IL-2. Interleukin-2 is
commercially available through most large drug
distributors. It is not likely that cytokine
therapy will become a single cancer treatment,
rather it is more likely that it will become
part of another immunotherapeutic approach
(i.e., used as a cancer vaccine adjuvant).
Information on the delivery of aerosols of IL-2
are available at :www.animalci.com.
Survival at Distant Sites
The ability of
cancer cells to survive in distant "foreign"
tissues immediately after arrest or while cancer
cells are in a dormant state is a hallmark of
successful metastasis. For most metastatic
cancers, this ability to survive is in part
regulated by internal genetic cues, but also by
signals received from the microenvironment
(growth factors). A number of small molecules
that inhibit signal transduction from growth
factor receptors have been developed as cancer
agents. Many of these agents may have a role in
treating metastases through the disruption of
critical survival signals provided by these
growth factor receptors. In work from London
et al, a small molecule inhibitor (SU11654)
of the split tyrosine kinase receptor family was
found to be active in a number of canine
cancers, including mast cell tumors, metastatic
sarcoma, and mammary carcinoma.
The split tyrosine kinase receptors that are
inhibited by SU11654 have a diversity of
biological effects. As such, their inhibition
may not be limited to preventing survival and
may be the result of the inhibition of many
steps in the metastatic cascade. As a class,
small molecular inhibitors of tyrosine kinase
receptors represent one of the most promising
types of novel therapies for cancer and cancer
metastases. Clinical trials using these agents
are underway at several veterinary referral
centers and veterinary teaching hospitals across
the United
States.
Angiogenesis
Angiogenesis
describes the generation or recruitment of new
blood vessels. It appears that new blood vessel
development is essential for tumor cells to grow
and metastasize. The new blood vessels may be
created by the tumor or may be recruited from
the surrounding normal tissues. If new blood
vessel formation or recruitment can be
inhibited, a tumor cannot progress and may cause
established tumors to regress. Therapies that
are directed against blood vessels and not tumor
cells are likely to be active against a wide
spectrum of cancers. Biological differences
between tumor associated endothelial cells and
normal endothelial cells have become apparent.
This has lead to several novel therapeutic
agents that either prevent new blood vessel
formation or survival (antiangiogenic agents),
or specifically target existing tumor-associated
blood vessels (vascular targeting agents).
Recent studies using antiangiogenic peptides of
thrombospondin-I (TSP-I) have demonstrated
surprising objective regressions of metastatic
cancers in dogs with a variety of histologies
and have significantly extended remission
duration in dogs with lymphoma when combined
with chemotherapy (demonstrated in a randomized
controlled trial). Trials with TSP-I peptides in
dogs are underway at several sites across the
United
States.
Progress that has been made in our understanding
of the basic biology of cancer has uncovered
several opportunities for the treatment of
cancer. The improved knowledge of cancer biology
has allowed differences between cancer cells and
normal cells to be identified and has uncovered
important interactions that occur between cancer
cells and the host. The cancer treatment
strategies discussed above specifically target
cancer, and as such are less likely to result in
the toxicities that are associated with
conventional cancer therapy. Effective and
non-toxic cancer therapy is therefore the goal.
In the very near future, we can expect these
novel treatments to be used in conjunction with
conventional cancer treatment modalities
(surgery, radiation therapy, and chemotherapy)
in the management of our veterinary cancer
patients.
A New Option for the Treatment of Canine Lymphoma
This article is a wonderful one as Dr.
Khanna is doing some of the leading nationwide
canine cancer research.
