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Targeting Immunotherapy for the Treatment of
Leukemia and Solid Tumors
Michael McGuinness, Robert J. Arceci
Hematology/Oncology, Children's Hospital Medical Center, Cincinnati, OH
ABSTRACT
The prognosis for patients with leukemia and solid tumors remains poor in large
part due to high relapse rates and significant toxicity from intensive combination
chemotherapy. The development of more effective treatment strategies that do not
depend entirely on the use of chemotherapeutic agents would be extremely useful.
Recent advances in tumor immunology have provided the possibility of using
antitumor immune responses in the treatment of patients. These advances are based
on an increased understanding of T lymphocyte activation and tumor antigen
expression. T lymphocytes, to become fully activated and functional, need at least
two critical signals. The first is the recognition of foreign antigen through the T cell
receptor, and the second is signaling through a costimulation receptor system. As
many tumor cell types do not express costimulation receptors, it has been hypothesized
that the lack of costimulation by the tumor cells may represent an important
mechanism of escaping immune recognition and killing. To test this hypothesis for
leukemia, murine models for acute myeloid leukemia (AML) have been used.
Retroviral transfer and expression of the B7-1 (CD80) costimulation receptor has
been shown to specifically stimulate the host immune system to develop effective
antileukemic responses in these models. Further experiments have demonstrated
that the antileukemic effect is primarily due to a CD8 +
cytolytic T cell response to
one or more as-yet-unidentified MHCI restricted leukemia antigens. This response
protects animals following subsequent exposure to B7 negative leukemia and is
also able to cure animals with established leukemia in its early stages. Although
promising, such viral-mediated approaches have several significant problems
including safety, complicated implementation for the methodologies, and relatively
low efficiencies of gene transfer and expression in cells derived from the human
hematopoietic system such as leukemia. To this end, our laboratory has begun to
develop alternative approaches designed to avoid these problems by targeting
immunostimulatory protein conjugates to leukemia cells (as well as solid tumors)
to generate specific antileukemic immune responses. This targeting approach uses
the construction of chimeric proteins consisting of three different modular domains
including 1) a T cell costimulatory module, 2) a linker or hinge module, and 3) a
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