autologous blood and marrow transplantation - Blog Science ...

636 Chapter 13: Immunotherapy
tumor or leukemia targeting module. Preliminary studies show that immunostimulatory
conjugates can be produced, isolated, and transferred to both cell lines and
primary leukemia and solid tumor cells. Functional studies in murine systems and
using human leukemias are underway.
INTRODUCTION
Background
The acute leukemias, and specifically AML, are particularly good examples of
the development of chemotherapeutic resistance and the consequences of
increasing drug dose intensification. 1-4
Although induction chemotherapy is
capable of effecting disease remission in 60-80% of patients with AML, long-term
survival is achieved in only a minority. 5
There remains a great need for the
development of alternative treatment approaches for patients with leukemia and
other malignancies that are designed to 7) circumvent drug resistance mechanisms,
2) demonstrate specificity for cancer cells, and 3) avoid toxic injury to normal
tissues.
Several approaches have been designed to block or inhibit molecular pathways
leading to chemotherapeutic resistance as demonstrated in the case of the Pglycoprotein
drug transporter. 1
"* 6
" 12
However, these studies have not proven to be
less toxic and have shown that in most instances other drug resistance pathways are
selected, thus reducing the regimen's ultimate effectiveness. 6-13
Other studies have
used the ability of monoclonal antibodies (mAbs) or cytokines to target bacterial
toxins or radiochemical conjugates to tumor cells. 14-18
Although such toxin
conjugates have shown some encouraging results, they ultimately depend on the
ability of the toxin to kill the malignant cells, which can develop toxin resistance
or downregulate targeted surface molecules. 19-23
In addition, normal cells
expressing the protein to which the conjugated toxin is targeted will also be
exposed and potentially damaged by the toxin. 19-23
An alternative approach to
eradicating tumor cells is to use the specificity of the immune system for unique
immunostimulatory tumor antigens, thus providing a means to circumvent drug
resistance mechanisms, avoid toxicity of either drugs or toxins from targeted
conjugate molecules, eradicate minimal residual disease, and possibly maintain
long term antitumor immunity.
Enhancing antitumor immunity
Recent experiments have demonstrated that the modification of both murine and
human tumor cells to express a wide variety of cytokines results in the rejection of
genetically modified malignant cells as well as preexisting non-genetically