Leukemia and lymphoma are blood cancers that are a major cause of death in children. Many of these cancers are curable with chemotherapy, but in some people the cancer comes back and is harder to cure. A new treatment called CAR-T cells involves genetic engineering of a cancer patient's own immune system cells to fight cancer, and can cure many people. However, this treatment still does not work well enough in about half the people who get it. Dr. Pauerstein proposes improving the sensitivity of CAR-T cells to cancer using engineered cell adhesion molecules, a type of molecular glue between two cells. CAR-T cells do not attach to cancer cells as strongly as normal T cells do, and this limits their ability to find and kill cancer cells. An engineered adhesion will be used in combination with CARs to improve the ability of CAR-T cells to kill cancer. Dr. Pauerstein and team will also study how changes in cell adhesion affect how CAR-T cells kill cancer. This work should improve cell-based treatments for blood cancers.

Hepatoblastoma is the most common liver tumor diagnosed in early childhood, and new therapies are urgently needed to improve survival and reduce treatment related morbidity. Immunotherapy is a type of cancer treatment that harnesses the body's own immune system to target and attack cancer cells. While some immunotherapies have been very successful against certain tumor types in adult patients, they have been largely unsuccessful in treating pediatric tumors. This demonstrates how little we know about how the pediatric immune system responds to tumors. Using samples and models of hepatoblastoma, Dr. Cabric's research aims to identify the key immune cells involved in recognizing and responding to hepatoblastoma. Identifying the key immune cells involved in tumor immunity, and mechanisms that allow tumors to escape detection and deletion by the immune system, will allow us to find novel targets for future immunotherapies that work in children.

Neuroblastoma is a devastating pediatric cancer, with only 50% survival in aggressive "high-risk" disease. Survivors are burdened with life-long side effects from chemotherapy and radiation. Newer therapies, such as cancer vaccines, provide an opportunity to mobilize a patient's own immune system to find and destroy cancer cells. Identifying the unique genetic signature of an individual patient's tumor allows scientists to formulate a personalized vaccine to stimulate the immune system to recognize tumor-specific mutations, called "neoantigens". Dr. Spear has developed a new tool to identify these unique genetic signatures (neoantigens) and test the effectiveness of the neoantigen vaccine in modes. These findings will lay the groundwork to develop a clinical trial using personalized vaccines for high-risk neuroblastoma and other pediatric cancers.

Brain tumors are the leading cause of cancer related death in children. The outcomes for high-grade gliomas in children are dismal. Chimeric antigen receptor (CAR) T cells are genetically engineered cells programmed to target cancer cells with high precision. The application of CAR T cells in brain tumors in children is still limited compared to leukemia. One challenge is that CAR T cells need multiple hits to kill brain tumor cells compared with leukemic cells, where a single hit is sufficient. Dr. Abu Arja and team discovered a subset of CAR T cells that are more potent and can more proficiently kill brain cancer cells by increasing their lethality, making a second hit unnecessary. In this project, Dr. Abu Arja is studying the cellular program of this unique subset of potent killer CAR T cells to better understand why they are superior killers. Dr. Abu Arja plans to use these findings to genetically engineer new enhanced CAR T cells to eliminate tumors in children with brain cancers.

Chimeric Antigen Receptor (CAR)-T cells have been clinically effective in patients with leukemias and lymphomas. Dr. Venkataraman’s goal is to bring similar success in treating a fatal brain tumor in children called DIPG (Diffuse Intrinsic Pontine Glioma). A major obstacle in treating brain tumors with CAR-T cell therapy is a lack of antigens which are tumor specific, or which are absent on normal vital tissues that can lead to off-target toxicities. To overcome this risk, Dr. Venkataraman and colleagues have successfully generated and tested the functionality of a novel “logic-gated” CAR-T cells targeting two distinct antigens, CD99 AND B7H3 that are highly expressed on DIPG but present singly on certain normal cells. This gated “AND” CAR-Ts will have full-activation against DIPG cells having both the antigens while sparing the single antigen expressing normal cells and will now investigate the safety, preclinical efficacy of these CAR-T cells against DIPG and evaluate its translational relevance to DIPG patients.

Children, adolescents and young adults with recurrent or refractory Osteosarcoma have a very poor prognosis, with a dismal 6mo overall survival of less than 5%. Presumably, this poor prognosis is in large part secondary to the development of resistance to chemotherapy and radiation. More recent studies employing therapies that release and activate the patients’ immune cells, called T-cells, and even targeted T-cells have not improved this poor prognosis. Dr. Cairo proposes to investigate novel and innovative methods of combinatorial immunotherapy to circumvent known mechanisms of resistance. Together with colleagues, he proposes to investigate at the bench (in the laboratory) and in models with osteosarcoma alternative methods of combination immunotherapy including natural killer cells (NK) that we have been engineered in the laboratory to also circumvent mechanisms of resistance and to additionally express a single or dual target that are present on the osteosarcoma cells.

They further plan to investigate the efficacy of adding other immunotherapies to enhance the function and persistence of these targeted NK cells with antibodies, and two different NK activating cytokines. They will also investigate the optimal combination of this immunotherapy in children, adolescents and young adults with recurrent or refractory osteosarcoma to determine the safety and efficacy of this approach. Finally, Dr. Cario and team will determine what are the genetic and immune mechanisms of resistance after these novel combinatorial immunotherapy approaches utilizing state-of-the-art laboratory techniques. The goal of this grant is to develop novel combinatorial immunotherapy that will significantly increase the overall survival in children and adolescents with poor risk osteosarcoma.

To make a significant impact for kids fighting osteosarcoma, five funders have banded together with St. Baldrick’s to support this grant – The Helping Osteosarcoma Patients Everywhere (HOPE) Super grant supported by Battle Osteosarcoma, the Faris Foundation, the Zach Sobiech Osteosarcoma Fund of Children’s Cancer Research Fund, the Children’s Cancer Fund NY (supporting the Maria Fareri Children’s Hospital and New York Medical College) and Nationwide Children’s Hospital.

CAR-T cell immunotherapies, treatments that use T cells constructed to recognize tumors and kill them, revolutionized how doctors treat children with B cell leukemia (B-ALL). These killer T cells recognize a specific protein expressed on the surface of the leukemic cells. Unfortunately, leukemia frequently relapses and often finds ways to "switch off" the expression of this protein, making T cells unable to track and kill them. This notion is called "antigen escape," as the tumor finds a way to escape the immune treatment. Dr. Aifantis plans to identify ways to avoid antigen escape by boosting the expression of the surface recognition protein. The study aims to validate such mechanisms in an organism using CAR-T cell models and sequencing patient cells. At the same time, Dr. Aifantis will design screens that will help identify surface antigen-specific regulators, so researchers can one day create combinatorial protocols using CAR-T cells and targeting specific antigen surface expression regulators.

Genes instruct cells to do their jobs through making specific proteins. In our body, all cells store this what-to-do manual in a set of higher-order structures called chromosomes. When chromosomes break off, the broken pieces sometimes exchange their places to build new chromosomes. These errors, known as translocations, could have no effect on our bodies, but in many cases they might cause problems as severe as cancer. Dr. Su's research focuses on learning how chromosomal translocations promote tumor formation in children and young adults, as well as looking for clinically useful approaches to correct their pathogenic activities and cure these deadly diseases.

This institution is a member of a research consortium which is being funded by St. Baldrick's: Treehouse Childhood Cancer Project. For a description of this project, see the consortium grant made to the lead institution: University of California, Santa Cruz, Santa Cruz, CA.

Acute Lymphoblastic Leukemia (ALL) are aggressive cancers of B- and T- immune cells. ALL is most common in children but also affects adolescents and young adults. 90% of childhood ALL is curable. However, ~10% of children and ~30% of adolescents and young adults with ALL are not cured. To combat hard-to-treat ALL, Dr. Swaminathan will harness the body’s natural anti-cancer defense mechanism: a type of immune cell called a natural killer (NK) cell. He will also find defective NK cells in children with ALL. Those with fewer defective NK cells tend to survive longer and spend more of their lives free from disease compared to patients with high levels of abnormal NK cells. These findings will inform the development of NK cells as affordable therapies to cure pediatric ALL.

Each year, approximately 1000 Americans aged 20 years or younger are diagnosed with acute myeloid leukemia (AML). Currently, even the most effective targeted drug BCL2 inhibitor-venetoclax (VEN) cannot eradicate all leukemia cells. The remaining cells cause disease recurrence and result in a very low overall survival rate for AML patients. In preliminary studies, Dr. Li found that targeting an enzyme called ADSS2 promotes pediatric AML cells sensitivity to VEN induced mitochondrial apoptosis, resulting in a synthetic lethality. This study will ask how ADSS2 preserves AML cells fitness and test the effectiveness of a first-in-class ADSS2 inhibitor combined with VEN or other BCL2 family protein MCL1 inhibitor in models of AML. If successful, this could lead to a clinical trial with potential impact for childhood AML patients.

Ewing sarcoma (EwS) is a malignant cancer of bone and soft tissues that occurs mainly in children, adolescents and young adults. If the tumors spread, fewer than 1/3 will survive. For some pediatric cancers, recent progress has led to new treatments that use one's own immune system to target cancer cells. However, immunotherapy has not been successful for EwS because we don't know enough about how EwS tumor cells evade the immune system. The tumor microenvironment (TME) is an intricate ecosystem consists of cancer cells and the host's immune system. Dr. Kuo's project will focus on dissecting the TME of EwS, to understand how tumors develop. Using EwS tumors removed from pediatric patients during their cancer diagnosis and treatment, Dr. Kuo will use newly-developed techniques to map the TME and use a genetic model of EwS developed at CHLA to examine tumor/immune cell interactions in living tissue. The long-term goal of this work is to identify new treatment options for children with EwS.

This grant is funded by and named for The Shohet Family Fund for Ewing Sarcoma Research. In his freshman year of college, Noah was diagnosed with Ewing sarcoma. He endured many months of chemotherapy and had limb salvage surgery. Able to return to school, Noah had no evidence of disease for 2½ years until April 2018 when routine scans revealed he had relapsed. He passed away in May 2021 at the age of 25. Noah and his family were always passionate about the need for curative treatments for diseases of the AYA population. The Shohet family intends to raise funds for this Hero Fund in Noah's memory to find cures for Ewing sarcoma and to carry on his legacy of possibilities and hope.

This institution is a member of a research consortium which is being funded by St. Baldrick's: Malignant Germ Cell Tumors International Consortium (MaGIC). For a description of this project, see the consortium grant made to the lead institution: Dana–Farber Cancer Institute, Boston, MA.

High-Risk neuroblastoma (HR-NB) is an aggressive pediatric cancer, with only half of patients surviving. New Approaches to Neuroblastoma Therapy (NANT) headquartered at Children’s Hospital Los Angeles is the only group focused on new treatments based on lab data for HR-NB. NANT includes a team of 18 children’s hospitals across nationally and internationally working together to design new treatments, treat patients, and use what is learned to design the next treatments. New treatments include helping patients’ own immune system kill tumor by increasing and activating immune cells. Another treatment uses radiation therapy focused on the tumor combined with medicines to help the immune system recognize tumor. Trials include special tests on patients’ blood and bone marrow to understand how treatments work, find tiny amounts of tumor and new therapy targets. NANT trials help kids with aggressive NB that has come back. Funds administered by Children's Hospital Los Angeles.

This grant is named for the LukeStrong a Force Against Neuroblastoma Childhood Cancer Fund. When Luke was 5 years old, he was diagnosed with high-risk neuroblastoma. He is now in his teens and still in active treatment for relapsed neuroblastoma. Since 2014 Luke’s “Never tell me the odds” attitude has inspired his family and friends to shave their heads, fundraise with St. Baldrick’s, and help conquer childhood cancers.

This institution is a member of a research consortium which is being funded by St. Baldrick's: New Approaches to Neuroblastoma Therapy (NANT) Consortium. For a description of this project, see the consortium grant made to the lead institution: Children's Hospital Los Angeles, Los Angeles, CA.

Diffuse intrinsic pontine glioma (DIPG) is a deadly pediatric brain cancer, and there is a dire need to develop new therapeutic strategies to improve the terrible outcomes for these patients. Looking at genes that are turned on or off in a cancer can be helpful to figure out what is causing cancer growth. While looking at genes that are turned on in DIPG, Dr. Tsai found a gene called FOXR2 that is turned on at very high levels in a subset of DIPGs. FOXR2 is usually turned off, and turning on FOXR2 makes tumors grow very quickly. FOXR2 is actually capable of turning on an entire set of genes that are called ETS transcription factors (TFs). This is surprising as these genes have never been shown to be activated in DIPGs. Others have shown that ETS TFs can turn on the MAPK signaling pathway. Dr. Tsai also has found that FOXR2 is able to activate MAPK signaling. The goal is to determine exactly how FOXR2 and ETS TFs cooperate together to turn on MAPK signaling to make DIPGs grow. This grant was awarded at Dana-Farber Cancer Institute and transferred to Children's Hospital of Los Angeles.

A portion of this grant is generously supported by Griffin's Guardians, a St. Baldrick's partner. Griffin's Guardians was created by the Engles in memory of their son, Griffin. Their mission is to provide support and financial assistance to children battling cancer in Central New York, raise awareness about pediatric cancer and provide funding for research.

This institution is a member of a research consortium which is being funded by St. Baldrick's: Treehouse Childhood Cancer Project. For a description of this project, see the consortium grant made to the lead institution: University of California, Santa Cruz, Santa Cruz, CA.

This institution is a member of a research consortium which is being funded by St. Baldrick's: Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium. For a description of this project, see the consortium grant made to the lead institution: Baylor College of Medicine, Houston, TX.

This institution is a member of a research consortium which is being funded by St. Baldrick's: Malignant Germ Cell Tumors International Consortium (MaGIC). For a description of this project, see the consortium grant made to the lead institution: Dana–Farber Cancer Institute, Boston, MA.

This institution is a member of a research consortium which is being funded by St. Baldrick's: Malignant Germ Cell Tumors International Consortium (MaGIC). For a description of this project, see the consortium grant made to the lead institution: Dana–Farber Cancer Institute, Boston, MA.