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In no particular order, here are some drugs in clinical trials or in pre-clinical trial status, that may one day have
a role in treating CLL:
SDX-101 (R-etodolac)
This drug is now in phase II clinical trial. SDX-101 is a special form of the anti-inflammatory drug etodolac.
The trial is taking place in Sweden, Germany, and the UK.
SDX-101 has been found to cause apoptosis (organized cell death) in malignant lymphocytes.
The phase I trial showed that a maximum of 48% of absolute lymphocyte count reduction was achieved, but the ALC rose
after the cessation of treatment. This has led researchers to propose adding the older drug chlorambucil to SDX-101
for some of the patients in the phase II trial.
More information can be found on the Salmedix, Inc. website at:
Xcellerated T cells
3-05 Update: The company is actively conducting trials in CLL. However,
the latest trial in patients who had previously used Campath has been put on hold, and now the company is shedding employees.
A bit of background: T lymphocytes function to help the immune system fight disease. These lymphocytes are
different from B lymphocytes, which are the cells which can turn cancerous and led to the most common form of CLL. T
lymphocytes are so named because they mature in the thymus gland.
It is thought that in CLL the T lymphocytes don't work as well as they should, or are too low in number. The technology
behind Xcellerated T cells is that some of a CLL patient's own T cells are removed, activated to fight CLL, and
then 'expanded' or multiplied outside of the body.
These activated T cells, many more numerous than present in the patient, are infused back into the patient's bloodstream.
Preliminary results from the phase I/II trial were presented at the 2003 annual meeting of the American Society for Hematology.
Few serious side effects were encountered, and positive results were found in most patients, leading to significant declines
in CLL cell numbers. Lymph node size was also generally reduced, in one case, dramatically so.
The company website is at:
PT-100 (Talabostat)
The mechanism of PT-100 is unknown, but the company believes it interacts with an enzyme located in the bone marrow and
lymph nodes. This interaction may boost production of certain cellular signaling proteins and growth factors, which may cause
an enhanced innate immune system reaction against tumors. PT-100 may also work to increase the activity of T lymphocytes.
The company believes the drug may improve the efficacy of monoclonal antibodies such as rituximab, by an effect called
'antibody-dependent cell-mediated cytotoxicity'.
The company website can be found here:
http://www.pther.com/
Depsipeptide(FK228, FR901228):
Depsipeptides are a class of peptides.*
The compound under clinical review in cancer is FK228 or FR901228, commonly called Depsipeptide. It is one of a new
class of chemotherapeutic drugs (histone deacytylase (HDAC) inhibitors) that cause growth arrest and apoptosis of cancer cells.
These drugs may help either killed or 'normalize' cancer cells by down-regulating cellular signals needed
for survival, differentiation, or apoptosis. Depsipeptide was found to be safe in humans
and has been shown to induce apoptosis in various cancers.
Depsipeptide in currently in clinical trials for CLL and other cancers including non-Hodgkin's lymphoma and acute leukemias.
* A compound of two or more amino acids
Hu1D10 (Apolizumab)
Hu1D10 is a humanized monoclonal antibody that seems to cause apoptosis in B cell malignancies that express the 1D10 antigen.
Apparently not all CLL cells express this antigen.
Some good responses have been seen in patients with lymphoma. There are several trials currently recruiting patients for
study of this drug, and several more have recently closed or have been completed.
Oncolytic viruses
As their name suggests, these are viruses that infect only cancer cells. After they infect a cancer cell, they behave as
all other viruses do; they hijack the cell's machinery to help produce multiple copies of themselves, so much so that the
cell eventually bursts, and thousands of newly made viruses are available to infect nearby cells. Since oncoviruses only infect
cancer cells, the newly-minted viruses float around looking for malignant cells to infect. Unlike normal viruses, they do
not replicate in normal cells, thus sparing the body from a widespread infection.
Interestingly, there are naturally-occuring viruses that can perform such a seemingly miraculous feat. These include the
Newcastle Disease virus, Autonomous Parvovirus, and the Reovirus. These viruses attack and destroy certain types of tumor
cells, and do not have the ability to fight all cancers.
Scientists are trying to do nature one better by developing new strains of ordinary viruses. These engineered viruses are
made by genetically modifying the DNA or RNA in existing strains, so that they will replicate only in targeted cancer cells.
There are three main avenues that researchers are following to develop new oncoviruses.
1. Cellular Membrane Targeting. In this line of research, the existing viral membrane is modified so that the virus will
selectively attack cancer cells, and ignore healthy cells.
2. Replication in Cells Lacking Specific Tumor Suppressor Genes. A virus is modified so that it will only replicate in
cells that lack a specific anti-tumor gene such as p53. The virus can still get into normal cells, but as long as that cell
has a functioning p53 gene, the virus will not replicate.
3. Replication under Certain Cellular Conditions. In this situation, the virus will only grow in cells that display certain
selected antigens.
Advantages:
The use of therapeutic oncolytic virus theoretically allows a selective 'smart bomb' approach to cancer therapy. The virus
is designed to attack only cells which manifest certain characterists, as outlined above.
Oncolytic viruses, like other virus, replicate inside cells, ultimately killing the cell by simple bursting, a process
known as lysis. The newly hatched viruses float around, seeking other suitable host cells, in this case other cancer cells.
They then infect that cell, replicate, destroy the cell, repeating the process over and over again until, in theory, all of
the cancer cells are eliminated.
Once all of the cancer cells have been destroyed, the body's natural immune functions eliminate the virus.
Experiments have demonstrated high specificity; perhaps as high as 100,000 to one, meaning that 100,000 cancer cells are
lysed for every normal cell that is killed.
Some oncolytic viruses have been tested with conventional therapies, and seem to function well. The additive effects of
the therapies together have demonstrated very effective effectiveness.
Disadvantages:
The immune system has been primed through evolution to detect and eliminate viruses from the body. This can be accomplished
too efficiently, causing the removal of the oncolytic virus before the cancer is completely destroyed.
The body protects itself from future infection by producing memory lymphocytes. This natural immunity might preclude retreatment
with the same oncolytic virus.
Currently, most testing has been done via intratumoral delivery. This would preclude the use of the virus in systemic cancers
such as CLL and NHL.
Currently, there are about 20 phase I/II trials of oncolytic viruses ongoing, and several different companies are producing
these therapeutic agents.
See http://oncolyticvirus.org/
LMB-2 (anti-Tac(Fv)-PE38)
LMB-2 is a recombinant immunotoxin that has a fragment of Pseudomonas Exotoxin attached to an antibody that in turns
attaches to the CD25 receptor that may exist on B lymphocytes, including CLL cells.
The theory behind this drug is similar to other conjugated antibodies, such as Bexxar and Zevalin (which are drugs that
attach to CD20 receptors, as does rituximab, but have a 'payload' of radioactive material attached to them). The payload
in this case is a toxin.
It currently is in a phase II clinical trial, sponsored by the National Cancer Institute.
The hope is that the conjugated toxin will enhance the killing power of the monoclonal antibody.
Besides CLL, the drug has shown responses in hairy cell leukemia and cutaneous T cell lymphoma. The drug seems
more effective in those diseases than CLL.
CCI-779 (Temsirolimus)
CCI-779 is an analog of the antifungal rapamycin. It is an inhibitor of mammalian target of rapamycin
(mTOR), through the inhibition of its kinase activity. Ultimately, the drug interfers with messenger RNA activity,
leading to cell cycle arrest.
In addition, it may work to curb the growth of new blood vessels which are necessary to support the growth of tumors.
The drug is attractive because it has shown previous efficacy in a number of cancers, and has a good safety profile.
It currently is the subject of a phase II trial in recurrent or refractory CLL and NHL, and has been granted 'fast track'
designation by the FDA for its activity against certain solid tumors.
Two other rapamycin analogs, RAD001, and AP23573, are also the subject of studies in hematologic cancers.
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