Novel and Emerging Strategies
Autologous T-Cell Infusion
In an important clinical case report, researchers isolated T cells from a CLL patient and genetically modified them to target and kill leukemia cells. The modification of the T cells gave them a receptor that specifically binds to the CD19 molecule present on both normal and malignant B cells. Reinfusion of these modified T cells into the patient induced remission that persisted through follow-up at 10 months after the treatment. Although similar experimental treatments have been attempted in the past for several types of cancer, they did not have a clear effect on tumors, as the modified T cells would lose their ability to divide and did not persist inside the body for a sufficient length of time. In this instance, specific genetic modifications gave the T cells the ability to multiply several times. In fact, these modified T cells were found at high levels for 6 months in the patient’s blood and bone marrow and continued to express the specialized receptor (Porter 2011; Urba 2011; Peggs 2011).
Another clinical study, on two children with relapsed refractory pre-B-cell ALL, also showed encouraging results. T cells modified to produce an anti-CD19 antibody and another signaling molecule were administered, with complete remission in both patients; one patient remained in remission 11 months after therapy (Grupp 2013). In a clinical trial of modified T-cell therapy in 16 ALL patients who relapsed or whose leukemia had not responded to previous treatment, there was an 88% overall complete response rate, including those with high-risk BCR-ABL mutations. (“Complete response” refers to the disappearance of all signs and symptoms of cancer.) Only two patients did not respond to treatment (Davila 2014).
A potential limitation of this therapy, resulting from the persistence of the modified T cells, is its effect on normal B cell populations. Because both normal and malignant B cells are destroyed, immune suppression and increased risk of infection is considered a likely outcome. In the patient mentioned above, B cells were not present in blood or bone marrow for at least six months after the T cell infusion (Davila 2013).
Omacetaxine mepesuccinate (Synribo) is a substance derived from the evergreen tree Cephalotaxus harringtonia, which is native to China (Chen 2010). This drug was originally identified more than 35 years ago, and initial studies for CML showed promise (Wetzler 2011). Recently, omacetaxine has been shown to effectively kill leukemia stem cells in laboratory and animal studies. Omacetaxine was able to kill more than 90% of leukemic stem cells in leukemia cell lines bearing BCR-ABL mutations. In contrast, imatinib and dasatinib were only able to kill less than 9% and 25% of leukemic stem cells, respectively. Omacetaxine given to mice with CML and mutant BCR-ABL resulted in a marked reduction in both leukemia stem cells and total leukemia cells (Chen, Hu, Michaels 2009).
Targeting Leukemia Stem Cells
One of the most intriguing areas of current cancer research is the study of cancer stem cells. Stem cells represent a self-renewing reservoir of progenitor cells capable of sustaining a large population of mature cells. Healthy stem cells are essential for the maintenance and repair of tissue throughout the body. Cancer stem cells function much the same as healthy stem cells, but have become deregulated and, instead of giving rise to healthy cells, act as progenitors to malignant cells (Crews 2013; Ravandi 2006; SSM 2014).
Contemporary theory proposes that one of the problems with conventional cancer treatment is its failure to eliminate cancer stem cells (Crews 2013). Standard chemotherapeutic agents destroy rapidly dividing cells, such as cancer cells. However, cancer stem cells are able to become dormant; therefore, even if chemotherapy eliminates the bulk of existing tumor cells, it often cannot kill cancer stem cells, which eventually produce new cancer cells, causing relapse (Crews 2013; Ravandi 2006). Some evidence suggests that mature leukemia cells may be capable of reverting to leukemia stems cells, allowing them to evade cytotoxic chemotherapeutic agents (Crews 2013; Ravandi 2006; SSM 2014).
Research indicates that the key to eliminating cancer stem cells may be combination therapies that target multiple pathways. One of the goals of this type of treatment would be to act on cancer stem cells, but leave normal adult stem cells unaffected. Since cancers of the blood (eg, leukemias) allow for easier identification of cancer stem cells than do solid tumors, a great deal of scientific inquiry is focusing on leukemia stem cells, and several promising therapies are being developed on the basis of the findings from studies (Crews 2013).
One evolving area of leukemia stem cell research focuses on developing ways to prevent CML stem cells from becoming resistant to TKI therapy. Bcl-2 proteins help leukemia stem cells avoid destruction by TKIs, and several drugs that target these proteins are in development (Crews 2013; Ng 2012). Another opportunity is in the development of drugs that target signaling pathways involved in leukemia stem cell self-renewal, especially the Wnt/β-catenin and “Hedgehog” pathways. Laboratory evidence shows that administering an experimental Wnt/β-catenin inhibitor along with imatinib leads to an additive or synergistic inhibitory effect on CML cell proliferation (Nagao 2011). Several inhibitors of the hedgehog signaling pathway are being explored as possible therapeutic options for leukemia. Vismodegib (Erivedge), which is FDA-approved for the treatment of basal cell carcinoma, a type of skin cancer, is one of these (see Off-Label Use of Drugs that May Target Leukemia Stem Cells) (Crews 2013).
Numerous additional agents that target leukemia stem cells are in development, and some are being studied in clinical trials (Crews 2013). Since therapies that target leukemia stem cells are not yet widely available, individuals with treatment-resistant leukemia may wish to talk with their physicians about participating in a clinical trial. Information about ongoing clinical trials of leukemia stem cell therapies and other anti-leukemia agents can be accessed at www.clinicaltrials.gov.
Off-Label Use of Drugs that May Target Leukemia Stem Cells
Zileuton (Zyflo), an FDA-approved drug used to treat asthma (Watkins 2007), specifically inhibits the enzymatic activity of the inflammatory enzyme 5-LOX, the product of the ALOX5 gene (Sirois 1991; Knapp 1990). 5-LOX-inhibiting substances, including zileuton, have been shown to suppress proliferation and induce apoptosis (regulated cell death) in human CML cell lines (Anderson 1996; Anderson 1995). ALOX5 regulates the function of leukemia stem cells in mice with CML (Chen, Hu, Zhang 2009). In a rodent model, zileuton prolonged survival of CML mice with the T315I BCR-ABL mutation more effectively than imatinib alone, and the combination of the two was more effective than either alone. Zileuton deserves further attention for its potential role in leukemia treatment and leukemia stem cell-targeting.
Vismodegib was recently approved by the FDA to treat adult patients with basal cell carcinoma. Vismodegib inhibits hedgehog signaling (Fellner 2012). The hedgehog signaling pathway is essential for the maintenance of leukemia stem cells, and loss of this pathway impairs leukemia progression (Dierks 2008; Zhao 2009). In one preclinical trial, vismodegib in combination with ponatinib eliminated therapy-resistant T315I BCR-ABL1-positive leukemia cells (Katagiri 2013; Dao 2013). A phase II clinical trial is underway as of the time of this writing to determine the safety and efficacy of vismodegib in patients with relapsed/refractory AML (Hoffmann-La Roche 2014).
Aurora Kinase Inhibitors
Aurora kinases are a group of proteins required for the normal process of cell division. However, aurora kinases have been found to be overexpressed in various cancers, including leukemia (Goldenson 2014). Aurora kinase inhibitors have recently entered testing for leukemia treatment. One drug in development, danusertib, targets several aurora kinases, giving it the ability to target multiple cancer cell division pathways (Xie 2013). A 2012 study tested danusertib on a variety of acute lymphoblastic leukemia cells including the Philadelphia chromosome-positive (Ph-positive) ALL subclass. The researchers concluded, danusertib “represents an alternative drug for the treatment of both Ph-positive and negative ALL, although combined treatment with a second drug may be needed to eradicate the leukemic cells” (Fei 2012).
Aurora kinases A and B are present in excessive numbers in pediatric ALL and AML (Hartsink-Segers 2013). In a phase I study, AT9283, an inhibitor of aurora kinases A and B, was administered to leukemia patients and led to moderately successful results, with a more than 38% decrease in bone marrow blasts in almost one-third of AML patients. However, the drug showed serious side effects including myocardial infarction, hypertension, cardiomyopathy, tumor lysis syndrome, pneumonia, and multi-organ failure (Foran 2014). The toxicity and efficacy of an aurora B-specific inhibitor, barasertib (AZD1152), were tested in phase I and II clinical trials in patients with adult AML (Kantarjian 2013; Dennis 2012; Löwenberg 2011; Tsuboi 2011). Barasertib led to a better clinical response when used in combination with Ara-C compared to Ara-C alone (Kantarjian 2013). Alisertib (MLN8237), a novel inhibitor of aurora kinase A, is being tested for safety and efficacy in a phase I clinical trial in patients with blood-related malignancies (Hartsink-Segers 2013; Kelly 2013).