Acute myelogenous leukemia blasts as accessory cells during T lymphocyte activation: possible implications for future therapeutic strategies

Abstract

Both clinical and experimental evidence indicate that T lymphocytes can mediate antileukemic effects in acute myelogenous leukemia (AML). These antileukemic effects can be either nonspecific cytotoxicity (killer cell activity) or reactivity against leukemia-specific antigenic peptides presented by self-HLA molecules. The antigen-specific T cell activation requires recognition of specific peptides together with costimulatory signalling. For most patients the AML blasts express both HLA class I and class II molecules for antigenic presentation, but patients are heterogeneous with regard to: (1) expression of costimulatory binding molecules; (2) expression of receptors/counterreceptors involved in induction of apoptosis; (3) constitutive release of immunomodulatory soluble mediators. This heterogeneity suggests that the ability of AML blasts to initiate an antileukemic T cell response will differ between individual patients. Thus, clinical approaches for immunotherapy in AML have to overcome three major problems. First, the therapy should reduce the patient heterogeneity so that therapeutic effects become more predictable; or alternatively one should define patient subsets which are likely to benefit from immunotherapy. Second, immunotherapy should enhance antileukemic T cell reactivity or blast susceptibility to immune attacks. Third, the therapeutic procedures must be safe and suitable for routine use. All three problems probably have to be solved before immunotherapy can become a routine treatment.

New Strategies for the Treatment of Acute Myelogenous Leukemia: Differentiation Induction—Present Use and Future Possibilities

“…Although native AML blasts with a phenotype consistent with progenitors of dendritic Langerhans' cells have been described [78], this phenotype seems to be very rare. Native AML blasts usually express only some of the membrane molecules needed for initiation of T cell activation, including the peptide-presenting HLA class I and class II molecules and the T cell binding CD58 molecule, but in most cases the AML blasts do not express the costimulatory B7 (CD80 and CD86) and CD45 molecules [72,79]. One possible approach for enhancement of AML-specific T cell reactivity would therefore be to induce a dendritic cell phenotype in AML blasts, and thereafter to use these modulated cells for presentation of leukemia-specific antigens to T cells (Table 2).…”

New Strategies in the Treatment of Acute Myelogenous Leukemia (AML): In Vitro Culture of AML Cells—The Present Use in Experimental Studies and the Possible Importance for Future Therapeutic Approaches

“…Studies of in vitro cultured acute myelogenous leukemia (AML) cell lines and native blasts have been important for the characterization of proliferation, differentiation, and apoptosis in leukemic hematopoiesis, and for our understanding of chemotherapy effects in AML [1][2][3][4][5][6]. One would also expect experimental studies to become important in the future characterization of genetic abnormalities as pathogenetic factors in AML [3,4], and based on the in vitro results several new therapeutic strategies have already been suggested [1,5,6].…”

“…One would also expect experimental studies to become important in the future characterization of genetic abnormalities as pathogenetic factors in AML [3,4], and based on the in vitro results several new therapeutic strategies have already been suggested [1,5,6]. Furthermore, in vitro growth characteristics of native AML blasts may be useful as a prognostic parameter in AML…”

Transduction of acute myeloid leukemia cells with third generation self-inactivating lentiviral vectors expressing CD80 and GM-CSF: effects on proliferation, differentiation, and stimulation of allogeneic and autologous anti-leukemia immune responses

“…For most patients, AML cells express both MHC class I and class II molecules required for antigen presentation. 8,9 However, they lack the expression of co-stimulatory ligands or inflammatory cytokines to promote strong immune responses. In fact, expression of the co-stimulatory ligand CD80 has been reported to occur in less than 10% of analyzed AML samples.…”