Immunotherapy in AML
|Michael A. Caligirui, MD
Associate Professor of Medicine,
Roswell Park Cancer Institute
Immunotherapy following achievement of complete remission in AML would logically seem capable of eliminating a minimal number of malignant stem cells displaying intrinsic resistance to chemotherapy. Presumably, immune-mediated cytolysis utilizes a pathway to cell death that is distinct from that of chemotherapy. But while this may, indeed, be the case in the graft-versus-leukemia (GVL) effect observed in chronic myelogenous leukemia (CML),1-4 recent advances in cellular and molecular biology suggest limitations in the application to AML.
Principles of immunotherapy may be limited when applied to AML (v CML) for the following reasons:
- In contrast to CML, AML is quite heterogeneous at the molecular level. The host of genetic alterations characterized to date support the concept of multiple mechanisms of leukemogenesis.5, 6
- Given the variety of genetic alterations seen in AML, some blasts may be susceptible to T-cell mediated lysis,7 others to natural killer (NK) cell-mediated lysis,8 and others may escape all methods of immune-mediated cytotoxicity precisely because of their resistance to chemotherapy, as explained below.
The premise of noncross-resistance between chemotherapy-induced and immunotherapy-induced cell kill may not be as valid as was once thought. The long-standing notion was that cancer chemotherapy killed rapidly dividing cells, and that resistance to these agents could be classified by mechanism of drug action: preventing penetration into the cell by mdr-1 gene amplification; increasing the activity of DNA repair enzymes; decreasing in the rate of DNA damage; and direct attention in the targets of drugs. However, it now appears that regardless of initial mechanism of action, these "distinct" pathways of cell kill converge at a later time point onto a common, genetically encoded pathway of cell death (apoptosis), with characteristic morphologic and biochemical changes (See figure).9
A diverse group of genetically encoded elements are known to regulate apoptosis, including growth factor receptors and their ligands, signal transducing molecules, and nuclear factors that control cell growth and differentiation. It also appears that a major form of tumor resistance to chemotherapy occurs through genetic alterations that impede the process of apoptosis. The consequent delay in cell death results in a survival advantage for neoplastic cells over normal cells, which may in turn provide time for additional programs of drug resistance to emerge.10
Elucidation of this very important mechanism of resistance to chemotherapy has both discouraging and encouraging implications with regard to immunotherapy for AML:
- Currently, induction of apoptosis is a critical component of NK cell- and T cell-mediated cytotoxicity (both perforin-dependent and Fas-mediated mechanisms), antibody-dependent cellular cytotoxicity, antibody-toxin mediated cytotoxicity, radiolabeled antibody therapy, and growth factor deprivation through soluble receptor therapy. Thus, there is likely to be considerable overlap between resistance to chemotherapy and resistance to certain forms of immunotherapy.
- In the long term, however, as has been shown experimentally,11,12 gene-based therapies targeting defects in the programmed cell death pathway may provide opportunity for improvement in cell kill via chemotherapy and/or immunotherapy.
- In addition, certain forms of immunotherapy currently under development may make it possible to kill leukemic cells by mechanisms distinct from apoptosis:
- Humanized monoclonal antibodies directed against CD33+ AML blasts that can evade the human-anti-mouse-antibody response may have the potential to kill cells by complement mediated lysis.13
- Use of cytokines, such as interleukin-2, has shown promise even in the face of drug resistance, through mechanisms that have yet to be explained.14
- Recent engraftment of human AML and identification of a "leukemia stem cell" in the SCID mouse model may allow the study of resistance to apoptosis in subsets of blasts that are critical targets for successful eradication of the disease15
- Realization that pathways of cell kill previously thought to be distinct actually converge into a common, genetically encoded program of cell death (apoptosis) has important implications.
- At the molecular level, AML is a heterogeneous disease likely to have evolved multiple mechanisms of resistance to apoptosis.
- Redirecting our efforts toward understanding the molecular mechanisms controlling apoptosis may allow for the development of new and effective strategies to cure AML by chemotherapy, immunotherapy, and gene-based therapy.
- Promising forms of immunotherapy are currently under development that may make it possible to achieve tumor cell kill by mechanisms distinct from apoptosis.
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- Rhee Fv, Lin F, Cullis JO, et al. Relapse of chronic myeloid leukemia after allogeneic bone marrow transplant: the case for giving donor leukocyte transfusions before the onset of hematologic relapse. Blood. 1994;83:3377-3383.
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- Lowe SW, Ruley HE, Jacks T, Housman DE. p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell. 1993;74:957-967.
- Fuchs EJ, Bedi A, Jones RJ, Hess AD. Cytotoxic T cells overcome BCR-ABL-mediated resistance to apoptosis. Cancer Res 1995; 55:463-466.
- Caron PC, Jurcic JG, Scott AM, et al. A phase 1B trial of humanized monoclonal antibody M195 (anti-CD33) in myeloid leukemia: specific targeting without immunogenicity. Blood. 1994;83:1760-1768.
- Meloni R, Foa R, Vignetti M, et al. Interleukin-2 may induce prolonged remissions in advanced acute myelogenous leukemia. Blood. 1994;84:2158-2163.
- Lapidot T, Sirard C, Vormoor J, et al. Development of an in vivo assay for human AML stem cells by transplantation into SCID mice. Nature. 1994;367:645-648.
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