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INTRODUCTION

SUMMARY

Since their discovery in the early 1970s, dendritic cells (DCs) and natural killer (NK) cells have tantalized immunologists and cancer researchers with their immunotherapeutic potential to control certain neoplasms, including the hematologic malignancies. The current generation of DC-based vaccinations against acute myelogenous leukemia and myeloma has demonstrated promise in this regard. Early-phase clinical trials of allogeneic NK cells, both in haploidentical allogeneic hematopoietic stem cell transplant and as a stand-alone treatment, have also found encouraging results. Future directions of research will include efforts to augment the immune response to DC-based vaccination and allogeneic NK cells. These approaches are in clinical trials. Further laboratory research is exploring the nature, function, and regulation of DCs and NK cells in the tumor microenvironment. These efforts should result in more efficient and effective DC- and NK cell–based immune effector cell therapies with enhanced clinical activity against the hematologic malignancies.

Acronyms and Abbreviations

BCMA, B-cell maturation antigen; BiKE, bispecific killer engager; BiTE, bi-specific T-cell engager; BMT-CTN, bone marrow transplant clinical trials network; CAR, chimeric antigen receptor; cDC, conventional dendritic cell; CTLA4, cytotoxic T lymphocyte associated protein 4; DC, dendritic cell; GVHD, graft versus host disease; HLA, human leukocyte antigen; HSCT, hemopoietic stem cell transplantation; hTERT, human telomerase reverse transcriptase; IL, interleukin; KIR. Killer immunoglobulin-like receptor; LAK, lymphokine-activated killer; NK, natural killer; MGUS, monoclonal gammopathy of undetermined significance; MHC, major histocompatibility complex; MUC1, mucin 1 cell surface associated gene; NCR, natural cytotoxic receptor; pDC, plasmacytoid dendritic cell; PD-1, programmed cell death protein 1; PR-1, pathogenesis-related protein 1; Treg. Regulatory T cell; TGFb, transforming growth factor beta; TNF tumor necrosis factor; TiKE, trispecific killer engager; WT1, Wilm’s tumor 1 gene

An important feature of malignancy is a progressive immune dysregulation, resulting in the loss of immune surveillance and the promotion of tolerance toward the clonal tumor population.1 The nature of this dynamic interaction between tumor cells and host immunity is fostered by a microenvironment in which immunosuppressive elements such as regulatory T cells, immature myeloid-derived suppressor cells, and tolerogenic macrophages and dendritic cell (DC) populations gain dominance.2 The unique interactions between stroma and tumor cell and corresponding activation of immunoregulatory pathways within both cell populations result in the release of endogenous factors that induce T-cell exhaustion and senescence, inhibition of migration of tumor-reactive clonal T-cell populations, and a metabolic environment that fosters tumor proliferation.3 The evolution of myeloma offers an example of this process. Mutational events associated with the emergence of myeloma may be present in the premalignant state of monoclonal gammopathy of undetermined significance (MGUS). Disease progression is not necessarily associated with the accumulation of additional mutational events but rather with changes in the tumor microenvironment, including increased presence of immunosuppressive elements and the corresponding loss of tumor antigen-specific T cells4,5 (Chaps 105 and 106).

The enhanced understanding of the complex interactions between tumor cells and the ...

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