Biotherapy of Cancer (and some good news in osteo research)

[chivas]

Biotherapy of Cancer
Chand Khanna, DVM, PhD, DACVM (Oncology)
Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland and
Friendship Hospital for Animals

Biotherapy (or biological therapy) refers to a diverse group of therapeutic
strategies for cancers. It is a treatment modality based on products of the
cancer, products of the host response against the cancer, and products of
the interaction between the cancer and the host. Biotherapy is the product
of the dramatic increase in our understanding of the basic biology of cancer
and cancer metastasis. It is safe to say that the next breakthrough(s) in
the treatment of cancer will come from biotherapy. A number of forms of
biotherapy are currently under investigation in the field of Veterinary
Oncology. In many cases these therapies may become available to pet animals
with cancer before they are available for treatment of human cancer
patients. Increasing awareness of biotherapy strategies by the pet owning
public has forced veterinarians to be knowledgeable about these novel forms
of cancer therapy.

For the sake of discussion, biotherapy can be divided into four major
(non-mutually exclusive) groups.

I. Immunotherapy
II. Agents that Inhibit Angiogenesis or Invasion
III. Growth Factor Modulation
IV. Small Molecules (Inhibitors of signal transduction)


Each of these groups have evolved independently as forms of cancer therapy
and have been subsequently grouped under the umbrella cancer biotherapy.

Immunotherapy.

The belief that the immune system may play a role in the treatment of cancer
has been held for over 100 years. Coley, a surgeon in the early 1900s,
observed the spontaneous regression of large ovarian tumors in women
following post-surgical bacterial sepsis. His belief that the fever
associated with the sepsis was responsible for regression of the tumor led
him to administer mixtures of bacteria to patients in the hopes of
re-creating the fever and resultant tumor regression. These bacterial
mixtures, referred to as Coley¹s toxins, were some of the first documented
attempts at cancer immunotherapy. Since the days of Coley considerable
progress in our understanding of the immune response (and lack of immune
response) against cancer has emerged. This understanding may be summarized
in the following generalizations:
Cancers differ in their sensitivity to immune
recognition and destruction (immmunogenicity). The determinants for immune
recognition of cancers are specific to each cancer type. Cancers evade
immune recognition by many different mechanisms. The cell mediated immune
recognition by many different mechanisms. Cancer immunotherapy is likely to
be most effective against small tumor Burdens (microscopic disease).

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 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) delivered in a long
acting lipid encapsulated formulation. In randomized, controlled, and
placebo-blinded trials, MacEwen et al has 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. The
commercial availability of MTP is uncertain at this time; however, the
recent demonstration of MTP activity in childhood cases of osteosarcoma may
stimulate commercial interest in this form of immunotherapy.

Specific Immunotherapy. Attempts to generate a specific immune response
against a known or unknown (whole cell approach) 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. The use of autologous tumor vaccines based on genetically modified
tumor cells (using gene therapy) or purified factors from the tumor (heat
shock proteins) are currently under investigation in dogs and cats with
cancer. Preliminary results from these trials and human clinical trials
using these autologous tumor vaccine approaches are encouraging.
Adoptive Immunotherapy. Refers to the administration of parts of the immune
system to a patient. Monoclonal antibodies raised against cancer represent
adoptive humoral immnunotherapy. 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 recent release of Herceptin®, an antibody that binds the epidermal
growth factor receptor, to treat breast cancer in women is evidence of the
progress that has been made in this field. In dogs, the canine lymphoma
antibody MoAb221® has been approved for use in dogs. The activity in this
antibody in randomized trials has not been demonstrated to date. The
conjugation of monoclonal antibodies to chemotherapeutic agents or cellular
toxins will be the next step in the evolution of this work. Adoptive
cellular immunotherapy, where stimulated immune effector cells (e.g. LAK ?
lymphokine activated killer cells) are administered to the patient, has not
been extensively evaluated in dogs. Logistically, this type of therapy
presents problems for both human and veterinary cancer 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 system. 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.

Growth Factor Modulation.

Normal tissues utilize signals from growth factors to regulate specific
cellular functions. In tumors the normal response to growth factors is
dys-regulated. This may result in the abnormal dependence of a tumor cell
on a growth factor or a growth factor pathway. In either situation the
blockage of the growth factor/growth factor receptor pathway may prevent
tumor cell growth or progression. As discussed above, the realization that
many breast cancers were dependent on the epidermal growth factor receptor
pathway resulted in the development of an antibody to block this growth
factor receptor. The result of epidermal growth factor receptor blockade is
a profound decrease in tumor cell growth and metastasis. Work is
currently underway to identify tumors in dogs and cats that are dependent on
the epidermal growth factor pathway, such that this antibody may be used in
veterinary cancer patients. In osteosarcoma the insulin like growth factor
(IGF-I) has been shown to be essential (in both dogs and humans). This
growth factor appears to provide a life signal to osteosarcoma cells. This
life signals prevents these cells from dying even after receiving normally
lethal doses of chemotherapy. We have recently completed accrual of dogs
with osteosarcoma to a clinical trial that evaluated the benefit of IGF-1
inhibition plus chemotherapy compared to chemotherapy alone. In this trial
the inhibition of IGF-1 was well tolerated and did not increase the toxicity
of carboplatin chemotherapy. Preliminary analysis of the data suggested
improved survival in dogs receiving IGF-1 plus chemotherapy that approached
statistical significance (p=0.10). Further analysis of this data is
expected by the fall of 2000. Feline vaccine associated sarcomas may share
similar dependence on the IGF-1 pathway and may be responsive to therapies
that inhibit IGF-1.
Agents that inhibit angiogenesis or invasion.
Our understanding of the process of cancer progression and metastasis has
increased dramatically. What is clear, is that tumor cells interact closely
with their host and their immediate environment (microenvironment) and in
many cases recruit host cells or enzymes to facilitate their spread. This
understanding has lead to the development of two novel cancer treatment
strategies, anti-angiogenesis and anti-invasion.
Angiogenesis describes the generation or recruitment of new blood vessels.
It appears that new new blood vessel development is essential for tumor
cells to grow beyond a size of 1mm. Because such therapies would be
directed against blood vessels and not tumor cells, their use could be
imagined against all cancers as opposed to a specific cancer type. Such
therapies may lack normal tissue toxicity since most adult tissues do not
require new blood vessel formation. Several human and veterinary clinical
trials are currently underway to evaluate the activity of antiangiogenic
agents. Endostatin® and Angiostatin® are the best known of these agents.
Other antiangiogenic agents include thrmbospondins, thalidomide, and
interleukin-12. Our preliminary experience with thalidomide as an
anti-angiogenic treatment for dogs has been disappointing. Thalidomide
treatments were undertaken in dogs with advanced disease (bulky tumors). The
failure to see objective tumor responses in this trial speaks to the
importance of evaluating these novel agents in animals with small if not
microscopic tumor burden.
The process of cancer invasion within tissues and across tissue boundaries
(basement membranes) is essential to cancer metastasis. The recent
understanding of the determinants for invasion by cancer cells has lead to
the development of a number of agents that inhibit cancer invasion. Matrix
metalloproteinases (MMPs) have been identified as critical enzymes that
facilitate tumor invasion. Natural and synthetic inhibitors of MMPS have
been defined and developed as potential inhibitors of cancer progression.
Several classes of MMP inhibitors are currently under investigation in
pre-clinical models and in veterinary cancer patients. No data on the
effectiveness of these agents is yet available.

Small Molecules ? Describe a class of novel anti-cancer agents that target
signaling pathways in a cell. Signaling pathways describe the biochemical
pathways that are responsible for all cellular responses (i.e. cellular
growth, death, motility, adherence, invasion, etc). Small molecules
interfere with biochemical pathways in a highly selective manner. The
potential to target a specific biochemical pathway in a cancer cell carries
great potential. The small molecule may be viewed as the ³switch that turns
the cancer cell off². Such selective therapies focus on the important basic
differences in the biology of cancer cells and normal cells.

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 the host. The cancer treatment
strategies (biotherapy) discussed above specifically target cancer and as
such are less likely to result in the tonicities that are associated with
conventional cancer therapy. Effective and non-toxic cancer therapy is
therefore the goal. Several forms of biotherapy, that share this goal, are
now under investigation in the field of veterinary oncology. In the very
near future we can expect biotherapy to be used in conjunction with
conventional cancer treatment modalities (surgery, radiation therapy, and
chemotherapy) in the management of our veterinary cancer patients.