ASH 2009

American Society of Hematology (ASH) 2009 Recap

Every day, pediatric patients, families and their health care teams put on their armor to fight childhood cancer in the Children's Cancer Hospital at The University of Texas MD Anderson Cancer Center. While patients are receiving their treatment at the hospital, research teams are working in laboratories to find better ways to combat childhood cancer.

This December, researchers from the Children’s Cancer Hospital were selected to present their newest lines of defense at the 51st American Society of Hematology (ASH) Annual Meeting. Their weapons come in the form of drugs and antibodies, and the soldiers carrying the weapons are the patients’ own immune cells.

Weapons Against Cancer

New Function of Valproic Acid Increases Potential Uses

In recent years, researchers have been investigating the effectiveness of valproic acid, an inexpensive drug commonly used in the treatment of epilepsy and bipolar disorder, which has also shown promise in treating various cancers.

Valproic acid has been identified as a histone deacetylase (HDAC) inhibitor, which causes anti-tumor activity in certain cancers. However, in the most recent study conducted by Shiguo Zhu, Ph.D., and Dean Lee, M.D., Ph.D., from the Children's Cancer Hospital, valproic acid was also found to be a STAT3 phosphorylation inhibitor. Several drug companies have STAT3 phosphorylation inhibitors in development, but VPA is already approved, its few side effects are well-known, and it is very inexpensive.

By discovering this trait, researchers hope to be able to use VPA to specifically target cancers for which STAT3 phosphorylation is important for tumor growth.

Decreasing Cardiotoxicity of Anthracyclines

The overall survival of pediatric cancer patients has greatly improved over the last 40 years, due in part to the introduction of a class of chemotherapy agents called anthracyclines. Although these drugs are effective against many cancers, including breast cancer, sarcoma, lymphoma and pediatric leukemia, anthracyclines are very toxic to a patient’s cardiovascular system.

Looking at acute leukemia cell lines, investigators from the Children’s Cancer Hospital Joy Fulbright, M.D., and Joya Chandra, Ph.D., found that a new anthracycline, amrubicin, causes less cardiotoxicity than other drugs in its class.

The researchers know that anthracyclines cause damaging oxidative stress but are trying to see how large a role this stress plays in cardiotoxicity and if it relates to the amrubicin’s ability to be less toxic.

In their laboratory research, Fulbright and Chandra have shown that by using an antioxidant when administering amrubicin, they are able to decrease oxidative stress and still kill cancer cells, which they hope will lead to less cardiotoxicity overall when using this class of drugs. Their study is funded by Pharmion Corporation.

Lower Dosage of Decitabine Could Be Better for Patients

Decitabine is an epigenetic drug commonly used against acute myeloid leukemia, myelodysplastic syndrome, and after patients receive stem cell transplants. A recent investigation by Lisa Kopp, D.O., and Dean Lee, M.D., Ph.D., at the Children's Cancer Hospital, found that this drug, while effective against leukemia, also can be highly toxic to natural killer cells, important cancer-fighting cells within a person’s immune system.

At lower doses, the drug has little impact on natural killer cells, but at high doses, it causes significant damage to the cells. With this new knowledge, future studies will investigate the best dosage of decitabine, which will allow the drug to be effective against leukemia cells while minimizing its damage to natural killer cells.

An Army of Cancer Fighters

Historically, cancer therapies have consisted of administering drugs to a patient’s body that go in and kill any quickly growing cells, both normal and cancerous. The price of curing cancer using these therapies can come with a list of side effects and late effects.

Researchers now are focusing on new treatments, such as cell therapy, that are less toxic to the patient and better tolerated. Cell therapy harnesses the power of a patient’s own immune system, or the transfused immune cells of a donor, to attack tumors without harming healthy cells. Investigators at the Children’s Cancer Hospital are researching methods of better training these armies of immune cells to be better fighters.

Vamping up T Cells Before Infusion

Interleukin drugs are often given with immune cell infusions to supercharge the immune cells to grow and live longer to fight cancer cells. However, this class of drugs has also been known to cause harsh side effects when administered to patients. A new interleukin drug, Interleukin-7 (IL-7), has been found to be highly effective in growing T cells, but the drug is not readily available for mass distribution.

For the first time, Children’s Cancer Hospital researchers Lenka Hurton, M.S., and Laurence Cooper, M.D., Ph.D., have devised a way to use a small amount of IL-7 in the laboratory to charge up T cells before they are infused into the patient. These supercharged T cells developed in the labratory could potentially negate the need to transfuse patients directly with IL-7, thus decreasing the risk of harsh side effects.

New Process Puts Receptor in NK Cells that Targets Leukemia

Acute myeloid leukemia (AML) is an aggressive leukemia that has a low survival rate of 50 percent. Many standard chemotherapy regimens fail patients, which is why researchers have focused on cell therapies to make a difference against this difficult blood disease.

AML cells have a protein called CD33 present on their cell surface. Children’s Cancer Hospital researchers Jeffrey Friesen and Dean Lee, M.D., Ph.D., discovered a means to put an antibody against CD33 inside a natural killer cell, which zeroes in on the CD33+ AML cells. Currently, doctors use a chemotherapy agent that has an antibody on it that functions in the same way, except the chemotherapy agent is also toxic to the liver. Researchers hope that by using the antibody to direct natural killer cells to the AML cells, patients could potentially avoid the side effects of harsh agents.

Gene Modification Allows NK Cells to Better Target Neuroblastoma

Similar to the AML study, researchers Srinivas Somanchi, Ph.D., and Dean Lee, M.D., Ph.D., from the Children’s Cancer Hospital have developed a method that modifies NK cells to carry a different antibody targeting neuroblastoma. In this study, the NK cells carry a chimeric antigen receptor that seeks out GD2 antigens commonly expressed on neuroblastoma cells.

Currently, there are drugs that can be administered that stimulate NK cells to seek out neuroblastoma cells. However, these drugs are very limited in supply. By using a laboratory procedure, researchers hope to create a similar result without needing to administer more drugs to the patient.

Using Receptors to Enhance T Cell Growth and Fighting Capability

In addition to using chimeric antigen receptors to enable natural killer cells to target specific cancer cells, researchers Harjeet Singh, Ph.D., and Laurence Cooper, M.D., Ph.D., have long been able to use CARs to grow T cells. In their latest study, they showed that adding certain signaling molecules to the CAR-modified T cells not only increased the ability of T cells to last longer, but it also caused them to grow more rapidly than previous modified T cells.

Increasing NK Cells to Army Strength

Although researchers have found many potential benefits for using natural killer (NK) cells as immunotherapy against cancer, one challenge has been obtaining enough NK cells to be sufficient for infusing them into patients. The current method requires a donor to spend numerous hours donating NK cells through a process called apheresis, which collects the necessary white blood cells.

Recently, however, Cecele Denman, M.S., and Dean Lee, M.D., Ph.D., from the Children’s Cancer Hospital, have found a way to generate 100 times the amount of NK cells than the traditional apheresis method, starting from just eight teaspoons of a donor’s blood. Denman and Lee separate the white blood cells and mix them with genetically-engineered artificial antigen presenting cells, which stimulate the NK cells to grow and multiply. This technology could potentially allow doctors in the future to infuse more NK cells, more often, at a lower cost and at less risk to the donor.

Understanding Notch and Duplicating How it Attacks Certain Leukemias

Previous studies done at the Children’s Cancer Hospital have illustrated the importance that Notch signaling has on suppressing B-cell leukemia and acute myeloid leukemia (AML). Notch is a receptor found on both normal and leukemia cells, and when turned on by a certain ligand, the receptor causes certain cancerous cells to die.

Most recently, Children’s Cancer Hospital researchers Sankaranarayanan Kannan, Ph.D., and Patrick Zweidler-McKay, M.D., Ph.D., discovered the mechanics behind Notch’s ability to induce cell death. From their study, they found a way to imitate the behaviors of Notch using a synthetic peptide developed in their laboratory. Future studies will test this novel peptide in mouse models to see if it will turn on the Notch signal in B-cell leukemia and AML and induce cell death.

A Defense Strategy

With a range of therapies coming down the pipeline, pediatric oncologists are continuously studying which patients might respond best to the various options available.

Lymphocytes Help Predict Which Patients Will Do Better or Worse

Patrick Zweidler-McKay, M.D., Ph.D., from the Children’s Cancer Hospital, has found another prognostic factor that may further assist physicians in strategizing what treatments to prescribe.

Previously, Zweidler-McKay discovered the importance of the absolute lymphocyte count (ALC) and how it affected a patient’s prognosis. He has expanded his research to include a retrospective analysis of pediatric patients from hospitals across the nation. By studying ALC data along with another prognostic factor, minimal residual disease (MRD), researchers were able to predict prognosis even more efficiently. Patients who tested negative for MRD and had a high ALC at diagnosis had a 99 percent 7-year survival rate. On the other side of the spectrum, those who tested positive for MRD and had a low ALC had a 41 percent overall survival rate.

Zweidler-McKay will co-chair a Children’s Oncology Group study in 2010 that will investigate a large cohort of patients prospectively and look at the influence of the prognostic tools. With information gathered from the study, he hopes to better determine which patients have a poor prognosis at diagnosis so that physicians can develop a more aggressive treatment strategy from the start.

Prepared for Battle