Immunotherapy for acute myeloid leukemia (AML): a potent alternative therapy

Abstract

The standard therapy of AML for many years has been chemotherapy with or without stem transplantation. However, there has not been any tangible improvement in this treatment beyond induction through chemotherapy and consolidation with allogeneic stem cell transplantation or chemotherapy. Residual AML cells which later cause relapse mostly persist even after rigorous standard therapy. It is imperative therefore to find an alternative therapy that can take care of the residual AML cells. With a better understanding of how the immune system works to destroy tumor cells and inhibit their growth, another therapeutic option immunotherapy has emerged to address the difficulties associated with the standard therapy. Identification of leukemia-associated antigens (LAA) and the fact that T and NK cells can be activated to exert cytotoxicity on AML cells have further introduced diverse immunotherapeutic development strategies. This review discusses the merits of current immunotherapeutic strategies such as the use of antibodies, adoptive T cells and alloreactive NK cell, and vaccination as against the standard therapy of AML.

Introduction

Acute myeloid leukemia (AML) also called acute myelocytic leukemia, acute myelogenous leukemia, acute granulocytic leukemia, or acute non-lymphocytic leukemia is a kind of leukemia that starts in the myeloid cells. These cells are capable of self-renewing and sustaining malignant populations as well as producing subclones [1]. Acute myeloid leukemia (AML) is considered acute because it progresses quickly if no suitable intervention is found, and can be very fatal in a short period [2]. Available data point to the fact that AML is the most common acute leukemia among adults, and its incidence increases with age [3], [4]. Acute myeloid leukemia (AML) is reported to account for roughly 1.2% of cancer deaths in the United States although relatively rare [5], [6]. Notwithstanding, the incidence of AML is expected to increase as the population ages. Considering these alarming indicators, it is imperative to devote time and resources in finding appropriate interventions, and creating awareness.

The symptoms of AML are as a result of the replacement of normal bone marrow with leukemic cells which causes a drop in red blood cells, white blood cells and platelets [7], [8]. Early and common symptoms associated with AML are fatigue, dypnoea, ostealgia, arthralgia, hemorrhage, and increased risk of infection [9]. There are other signs which are peculiar to the individual. Typical example is the swelling of the gingivae which may be experienced by some patients due to infiltration of leukemic cells into the gum tissue [10]. Interestingly, some patients do not exhibit any of these symptoms, therefore the condition is discovered accidentally during a routine blood test. A number of risk factors have been implicated in AML development, however, blood disorders, chemical exposures, ionizing radiation, and genetics are the most cited risk factors [11].

Treatment of AML is divided into induction phase and consolidation phase. Induction phase of AML treatment seeks to clear the blood of blasts and reduce the number of blasts in the bone marrow. Currently, the induction phase involves high dose induction chemotherapy with cytarabine and an anthracycline [12], [13], [14]. Consolidation chemotherapy is then administered to destroy residual leukemic cells after the patient has recovered from induction [15]. Although chemotherapy with remission and induction phases is the first option, this treatment mode is usually associated with high toxicity and high risk of relapse [16]. This is because, the AML stem cell is reportedly resistant to chemotherapy and responds to different selection pressures from chemotherapeutic drugs [17], [18]. Stress cells including cancer cells express stress proteins which are recognized by the immune system through immunosurveillance. This leads to the elimination of these stress cells. Nevertheless, cancer cells are able to escape this immunosurveillance through various mechanisms including the shedding of the stress proteins [19], [20]. Therefore, for cancer conditions such as AML, the best therapeutic option is immunotherapy, where specific immune cells are activated to re-establish the immunosurvielling activity of the immune system against these cancer cells.

Unlike chemotherapy and radiotherapy, immunotherapy is more specific in its activity and therefore associated with low toxicity [21]. This specificity is the core of immunotherapy that eliminates cancer cells without harming normal cells. Immunotherapeutic agents specifically inhibit cancer cell proliferation, recruit effector cells to eliminate the cancer cells or induce apoptosis in the cancer cells [22]. More importantly, many suitable AML associated antigens that can be targeted by immunotherapy to exert its activity have been identified, translating into construction and production of more efficient immunotherapeutic agents.