Novel immunotherapeutic approaches for the treatment of acute leukemia (myeloid and lymphoblastic)

Abstract

There have been major advances in our understanding of the multiple interactions between malignant cells and the innate and adaptive immune system. While the attention of immunologists has hitherto focused on solid tumors, the specific immunobiology of acute leukemias is now becoming defined. These discoveries have pointed the way to immune interventions building on the established graft-versus-leukemia (GVL) effect from hematopoietic stem-cell transplant (HSCT) and extending immunotherapy beyond HSCT to individuals with acute leukemia with a diversity of immune manipulations early in the course of the leukemia. At present, clinical results are in their infancy. In the coming years larger studies will better define the place of immunotherapy in the management of acute leukemias and lead to treatment approaches that combine conventional chemotherapy, immunotherapy and HSCT to achieve durable cures.

Keywords: immune-editing; immunotherapy; leukemia.

Figure 1.

Immune evasion mechanisms seen in acute leukemia. Multiple immune pathways and functions are targeted by acute leukemia. Leukemic blasts directly and indirectly inhibit the host’s immune response by inducing phenotypic changes in T cells and NK cells by: modifying milieu toward hostile environment for immune system to function; inducing suppressor cells; and promoting immune checkpoint and coinhibitory pathways. The magnitude to which each pathway contributes to leukemia’s immune escape ability remains to be elucidated. Studies are mostly done in AML and immune evasion mechanisms applicable to ALL are less well understood. ALL, acute lymphoblastic leukemia; AML, acute myeloblastic leukemia; CD4/8, costim, costimulatory; GITR, glucocorticoid-induced tumor necrosis factor-related protein; IDO, indolamine 2,3-dioxygenase; KIR, killer immunoglobulin-like receptor; LAG3, lymphocyte-activation gene 3; MDSC, myeloid-derived suppressor cells; MHC, major histocompatibility complex; MIC, major immunogene complex; NK, natural killer; NKG2D, natural killer group 2, member D; NOS, nitric oxide synthase; PD1, programmed death 1; PD-L1, programmed death–ligand 1; STAT3, signal transducer and activator of transcription 3; TIM3, T-cell immunoglobulin domain and mucin domain 3; Treg, regulatory T cell.

Figure 2.

Exploiting therapeutic effects by targeting leukemia’s immune evasion mechanisms. The immune evasion mechanisms described in Figure 1 can be targeted for therapeutic effects. Some therapeutic modalities have more than one mechanism of action and overlap with other types of immunotherapy: for instance, improvement of hostile milieu by IDO inhibitor works partly by blocking Treg pathways. Combination of different immunotherapies may augment the effect of one another: examples include providing cell therapy in combination with Treg blockade to augment the effect of adoptively transferred cell products. ALL, acute lymphoblastic leukemia; AML, acute myeloblastic leukemia; BiTE, bispecific T-cell engagers; CAR, chimeric antigen receptor; CIK, cytokine induced killer; CTLA-4, cytotoxic T lymphocyte antigen-4; DC, dendritic cell; IDO, indolamine 2,3-dioxygenase; IMiDs, immunomodulatory drugs; NK, natural killer; PD1, programmed death 1; PD-L1, PDL1, programmed death–ligand 1; STAT3, signal transducer and activator of transcription 3; TCR, T-cell receptor; Treg, regulatory T cell.

Figure 3.

Timing of immunotherapy application in the course of leukemia progression. It is important to identify the most efficacious timing for each immunotherapeutic strategy. The immune environment is not static, and is actively modified by the status of the leukemia and the host, most dramatically in the context of HSCT. Thus the same treatment may not have the same effect depending on the environment in which it was administered. Novel therapies have been frequently tested first in relapsed or refractory disease in phase I studies. Accumulating evidences provide some rationale to choose the timing and combination of multiple therapeutic modalities for better effect. CAR, chimeric antigen receptor; CR1, complement receptor 1; DLI, donor lymphocytes infusion; HSCT, hematopoietic stem-cell transplant; IMiDs, immunomodulatory drugs; NK, natural killer.