Researcher – Dr. Miguel-Angel Perales
Facility – Memorial Sloan – Kettering Cancer Center
Location – New York, NY
Amount – $50,000

Overview: Dr. Perales describes his research entitled “T-cell Precursors in Allogeneic Hematopoietic Stem Cell Transplant” in the following manner:

Approximately one-third of the nearly 4000 acute lymphoblastic leukemia (ALL) cases in the United States occur in adults.  Although remission rates are nearly equivalent in children (> 90%) and adults (> 78%), the overall cure rate is much lower in adults than children (< 40% versus 80%).  Patients with relapsed or refractory leukemia have a dismal prognosis with a short survival.  Allogeneic hematopoietic stem cell transplant (HSCT), where stem cells are obtained from the blood or bone marrow of a donor, is a curative therapy for many patients with leukemia.  However transplants are associated with delays in recovery of the immune system, which results in increased risks of infection and leukemia relapse.  We are working on new strategies to enhance immune recovery after transplant and improve overall outcomes.  The immune system is made up of white blood cells and includes B cells that make antibodies and T cells that are responsible for killing cells infected with viruses.  T cells are also able to kill tumor cells in some cases.  Recently, we have developed a novel approach to promote T cell recovery based on the transfer of T cell precursors that can be grown in the laboratory.  The T cell precursors are derived from cord blood and will develop into T cells once they are transferred into the patient who is undergoing a transplant.  We have developed a specialized “Notch-based” culture system to grow T cell precursors in the laboratory and are able to further enhance the anti-leukemia activity of these cells by engineering them to express receptors specific for CD19, a marker present on the surface of most ALL and non-Hodgkin lymphoma (NHL).  The specialized receptor is called a chimeric antigen receptor or CAR.  The goal of this proposal is to establish an FDA-approved culture system for the generation of human T cell precursors engineered to express a CAR targeting human CD19.  We will then conduct a phase I clinical trial to evaluate the T cell precursors in patients undergoing an allogeneic transplant for advanced ALL or NHL.  The project draws on the resources and expertise of several teams at MSKCC, including members of the Bone Marrow Transplant and Leukemia Services, and the Gene Transfer and Somatic Cell Engineering Facility.  The study represents an innovative immunotherapeutic approach for patients with advanced leukemia, including relapsed or refractory ALL.

Researcher – Dr. Omar Abdel-Wahab
Facility – Memorial Sloan – Kettering Cancer Center
Location – New York, NY
Amount – $50,000

The Problem: The research project of mine which was funded in part by When Everyone Survives was a study of the biological and clinical importance of mutations in a gene called “ASXL1.” This gene was found to be mutated in 20-30% of patients with the disease MDS (myelodysplastic syndrome) and a 10-20% of patients with elderly AML (acute myeloid leukemia) in 2009. Despite the frequency of mutation, very little was known about the function of this gene. We felt it was important to study this gene because mutations in this gene appeared to be associated with worsened patient outcome.

What Did We Learn? The findings were two-fold:

1. Clinically, ASXL1 mutations clearly confer an adverse overall survival in patients with AML. This was published recently in a study by our group in the New England Journal of Medicine: Patel, JP, Gonen, M, Figueroa, M, Fernandez, HF, Zhuoxin, S, Van Vlierberghe, P, Dolgalev, I, Thomas, S, Aminova, O, Huberman, K, Cheng, J, Viale, A, Socci, ND, Heguy, A, Cherry, A, Vance, G, Higgins, R, Ketterling, R, Gallagher, R, Litzow, M, van den Brink, M, Lazarus, H, Rowe, J, Luger, S, Ferrando, AF, Paietta, E, Tallman, MS, Melnick, AM, Abdel-Wahab, O (co-last author), and Levine, RL. Prognostic and therapeutic relevance of integrated genetic profiling in AML. N Engl J Med. 2012; 22; 366(12):1079-89.

2. Biologically, ASXL1 appears to regulated the Polycomb Group of Proteins and the mutations in ASXL1 result in a decrease in the repressive activity of the Polycomb proteins. This was published in a study in Cancer Cell by our group recently: Abdel-Wahab O, Adli M, Lafave LM, Gao J, Hricik T, Shih AH, Pandey S, Patel JP, Chung YR, Koche R, Perna F, Zhao X, Taylor JE, Park CY, Carroll M, Melnick A, Nimer SD, Jaffe JD, Aifantis I, Bernstein BE, Levine RL. ASXL1 Mutations Promote Myeloid Transformation through Loss of PRC2-Mediated Gene Repression. Cancer Cell. 2012 Aug 14;22(2):180-93. PMCID: PMC3422511

Where do we go from here? Now that we have some initial idea about the function of these mutations and their clinical relevance the ultimate goal is to utilize this information to attempt to improve therapy for MDS/AML patients. There are several new small molecule drugs which may inhibit the downstream effects of ASXL1 loss. This includes small molecule inhibitors of the proteins UTX and JMJD3. We are now testing a number of compounds in cell lines, patient samples, and mouse cells with loss of Asxl1 in hopes of using these for treatment of patients with ASXL1 mutations.

In addition to the above, by allowing me to continue my research funding from the When Everyone Survives Foundation also helped me to get long-term NIH-funding in the form of a K08 Mentored Physician Scientist Award. Based on this work and this funding I am now starting my own laboratory at MSKCC and have become a tenure-track faculty member in the Human Oncology and Pathogenesis Program here.

Chairman’s Choice Award *

Researcher – Sara Day, RN, PhD
Facility – St. Jude Children’s Research Hospital
Location – Memphis, TN
Amount – $25,000

Overview - Although 80% of children with acute lymphoblastic leukemia in high-income countries are cured, most children live in low-income countries where cure rates are much lower.  In these countries, deaths due to side effects of treatment (toxicity of treatment) and missed appointments during active treatment (abandonment of treatment) are the two most common causes of treatment failure and occur even more frequently than relapse.  Improved supportive care and family education can address these problems, and the role of the pediatric oncology nurse is therefore critical. Well-trained nurses prevent infection through rigorous infection control efforts and reduce mortality by early detection of symptoms and prompt intervention. They also can reduce abandonment by educating patients and families and increasing their confidence in the health system.

Unfortunately in low-income countries there is inadequate nursing education, and one nurse is often required to care for 10 to 20 patients.   The purpose of this study is to assess the impact of improved nursing education and staffing on toxic death and treatment abandonment in children with acute leukemia at the National Pediatric Oncology Unit in Guatemala, where 350 children with newly-diagnosed cancer are treated annually. The effect of nursing education and better nurse staffing on patient outcomes has been extensively researched; however, almost all studies were conducted in high-income countries.  This will be the first study to attempt to establish a relationship between abandonment of treatment and toxic death and interventions specifically related to nursing in a low-income country.

* A funding request that does not fit our typical laboratory based research request, however, is a compelling humanitarian effort.