What
are biological therapies?
These
are man made proteins which alter the growth and replication of a cancer cell by
interfering with its specific biological pathways. Biological agents aim to find
chemical or genetic processes which are present in the cancer cell but not the
normal cells. In this way they are more targeted than conventional chemotherapy
which generally kills rapidly dividing cells. They can also have an anticancer
effect by stopping the growth of new blood vessels into a tumour mass thus
depriving it of oxygen and a means to grow and spread (angiogenesis).
Biological agents, once attached to a cancer cell can also make the cell
more vulnerable to the bodies own immune system - that is why they have
previously been known as immunotherapy. One of the 1st observations of an
immunotherapy reaction was seen at the turn of the 20th century, when a patient's breast cancer shrunk following a severe skin infection.
Her bodies defenses where so greatly stimulated to fight the infection they also attacked the
tumour. There has been major strives to enhance this reaction
by identifying specific tumour targets.
Biological
agents sometimes work in partnership chemotherapy. The chemotherapy kills the DNA and
the biological agent stops the cells from repairing themselves.
In summary the modes of anti cancer action are:
- They can bind to receptor
proteins on the surface or inside cancer cells which block pathways which reduce
the cells ability to grow, spread, invade other organs.
- They interfere with
new tumour blood vessel formation blocking its ability to grow
- They can stimulate and recruit the bodies own immune system including natural killer (NK)
cells to attack the cells.
- They can carry poisons
to a target more commonly found on tumour cells - targeted therapy
What
are the main categories of biological agents?
The two main categories of biological agents are:
Tyrosine kinase inhibitors.
These are small molecules which can interfere with the intracellular or extra
cellular section of a biological protein which is involved in triggering various
essential biological functions of the cell.
Monoclonal
antibodies (Mab).
These are large natural proteins which are a normal part of the bodies defense
against foreign organism. Although cancer cells come from our own bodies and
hence not detected as foreign by our immune system there may be some supple
difference which can be exploited in the immunity against them is enhanced.
Antibodies are mass-produced in the lab by fusing a
myeloma (a type of bone marrow cancer) cell from a mouse with a mouse B
cell that makes a specific antibody. Because the antibodies are all
identical clones produced from a single (mono) hybridoma cell, they are called monoclonal
antibodies ( MAbs). In
some cases, Mab can been congugated or
joined to another substance which kills the tumour cells. This could be a
chemotherapy drug, radioactive particle, or a toxin (a substance that poisons
cells).
Commonly
available biological agents and mode of action?
Monoclonal
antibodies:
Rituximab (MabThera):
Non-Hodgkin’s lymphoma. Targets
the CD20 antigen found in excess on lymphoma cells. extensively used
in both low and high grade lymphomas as long as they are shown to over
express CD20 proteins.
Trastuzumab (Herceptin);
Breast cancer.
An intravenous agent, attacking the HER-2 receptor (activity is greatest
in tumours also over expressing cMYC, PTEN or TOPO 11.
Cetuximab (Erbitux);
Colorectal cancer
head and neck cancers;
An intravenous inhibitor of erbB1(EGFR) k-ras mutations should not be
present.
Bevacizumab (Avastin);
Breast and colorectal cancer plus others in development.
An intravenous humanised Mab attaches to and inhibits vascular
endothelial growth factor which then prevents new blood vessels forming
in cancers (angiogenesis)
Panitumumab;
Colorectal cancer. A humanised mab against EGFR under investigation.
Alemtuzumab (Campath):
Chronic lymphocytic leukemia;
Active against low grade lymphoma and CLL attacks the CD56 antigen.
Ibritumomab tiuxetan (Zevalin)
Non-Hodgkin’s lymphoma;
A Mab which has a
radioactive molecule attached to it shown activity in patients with low
grade NHL transforming into higher grade tumours
Tositumomab (Bexxar);
Non-Hodgkin’s lymphoma;
A Mab which has a radioactive molecule attached to it shown activity in
low grade NHL.
Tyrosine Kinase inhibitors:
Gefitinib (Irissa); Lung & pancreas;
Inhibits a mutated EGFR (p-Akt).
Erlotinib (Tarceva): Lung & pancreas;
Inhibits a mutated EGFR
Imatinib (Gleevec);
GIST & CML;
An oral agent. Inhibits EGFR with the KIT mutation found in CML and
gastrointestinal stromal tumours
Lapatinib (Tyverb);
Breast;
An oral, dual inhibitor of EGFR (erbB1) & HER2 (ErbB2)
Sunitinib (Sutent); Renal cell; An oral multi-targeted tyrosine kinase inhibitor with activity against
vascular epidermal growth factor receptor (VEGFR), platelet derived
growth factor receptor, KIT, RET and FLT3 having anti-tumour and anti-angiogenesis activity.
Sorafeneib (Nexxava); Renal cell; An oral agent with multiple targets against the tryosine kinase
inhibitor.
Bortezomib (Velcade); Myeloma; Attacks a structure called the
protosome.
Preparation for
biological
therapy.
As these are specific treatments your
doctor needs to find out if your tumour expresses the necessary target before
even considering treatment. This is usually achieved by re-analysing a section 
of
your original tumour (from the time of your original surgery or biopsy). Occasionally,
your doctor will need a more recent tumour for analysis and recommend a further
biopsy. In either case the tumour is usually send to a lab which specialises in
specific testing for antigens (targets) called immunohistochemistry. A report
will be issued by the pathologist on whether your tumour over expresses the
target and to what degree. For example, Herceptin treatment for breast cancer
requires the tumour to be HER-2+ve and on a scale of 1-3 it should be 3 to
ensure a likely subsequent clinical response. More recently it has been
discovered that certain mutations within the cancer cell can predict a likely
response to biological agents. For example, the K-ras mutation found in 20% of
cells from colorectal cancer, if present it means there will be little or no therapeutic
response to Erbitux given to that patient.
How are Mab administered? Most tryrosine
tynase inhibitors are oral drugs taken once or twice a day. Mab on the
other hand cannot be taken orally as they would be
destroyed by your stomach. They are therefore infused into a vein usually over a
few hours. Occasionally, as with all protein based drugs it is possible to 
get
an allergic reaction. The nurses will therefore be checking how you are
feeling and measuring your breathing, pulse and blood pressure blood
regularly. If all goes well the infusion can last 1-2 hours, sometimes, in
response to mild reaction, it may have to be slowed down over several hours.
Rarely if there allergic reaction is prominent it has to be stopped altogether
and abandoned. To avoid a mild reaction often paracetamol and an antihistamine
are given before the infusion. If you are are able to tolerate the first
infusion it will be repeated thereafter, either at the same or a lower dose, on
regular intervals. The specific regimen (ie weekly, 3 weekly) will be explain to
you by the doctors and nurses and depends on the specific Mab used. Mab are
often given in conjunction will chemotherapy the administration schedule and
side effect also depend on these drugs.
Are there side effects to Mab therapy?
Compared with side effects of standard chemotherapy, the side effects of naked
MAbs are usually relatively mild. They can be broadly split into three
categories:-
The early effects often related to an
"allergic" reaction. If they do occur, it is often while the drug is
being infused or . Potential side effects include:
- Fever and sweating
- Chills
- Skin flushing - redness
- Tightness in the chest or difficulty breathing
- Discomfort in the throat
- Agitation
Particularly if associated with a fast pulse and lower blood pressure these
symptoms indicate an early allergic reaction. As mentioned above if these
symptoms are prominent the infusion has to be slowed down or abandoned
altogether. To avoid a mild reaction often paracetamol and an antihistamine are
given before the infusion.
The ongoing effects may occurs over the
entire period of time whilst you are receiving the Mab - usually weeks to
months. these are usually worse a day or two after the infusion and could
include:-
- Weakness, lethargy or tiredness
- Headache
- Sore eyes
- Joint pains
- Nausea and rarely vomiting
- Diarrhoea
- Skin rashes
- Shortness of breath on exertion
- Very occasionally MAbs can also affect the bone marrow in a way similar to what most
chemotherapy drugs can do. This can result in lower levels of blood cells, which
can lead to an increased risk of bleeding and infection in some people.
Late side effects may occur occur after
receiving Mab for some time - usually months. These include heart & lung
damage - they are rare but this is the reason why patients receiving prolonged
Mab therapy have special monitoring including Heart test.
Further
information The book Lifestyle
After Cancer summarises the lifestyle evidence from around the world
and provides practical advice for all stages in the cancer journey. A detailed
film available in English, Italian, Urdu,
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