Beyond traditional treatment for AML

The Press On Fund Collaborates with the Leukemia & Lymphoma Society (LLS) by granting $100,000 to Dr. Soheil Meshinchi’s Specialized Center of Research Grant.

Immunotherapeutic Targeting of AML Targets in Infants and Children

Pediatric acute myeloid leukemia (AML) is among the most lethal cancers in children, with an overall mortality rate of 60 percent from the disease or its treatment. Recent advances in AML therapies for adults have not benefited pediatric patients, as the childhood disease has a distinct biology from adult AML. Recognizing this unmet medical need, Press On decided to continue its collaboration with LLS by making significant investments in pediatric-focused research through The Dare To Dream Project.

In March of 2023, Press On gave $100,000 to the The Dare To Dream Project allowing LLS to award a Specialized Center of Research (SCOR) grant to Dr. Soheil Meshinchi. SCOR grants are LLS’s largest ($5 million over 5 years) and most prestigious grants. They support teams of researchers from one or several institutions, representing different disciplines who are engaged in collaborative efforts to discover new approaches to treat patients with blood cancers. The SCOR project under Dr. Meshinchi’s leadership advances a comprehensive and coordinated strategy to develop the very first immunotherapies for childhood AML. Dr. Meshinchi’s application was the top-rated SCOR application when evaluated by a panel of leukemia experts, garnering a near-perfect score. His program builds on robust previous studies conducted over a decade, which were supported by Target Pediatric AML, a previous Press On Fund collaboration with multiple parent driven philanthropic groups, and by LLS, in which Dr. Meshinchi and colleagues analyzed samples from almost 3,000 pediatric AML patients and identified targets that are uniquely expressed in AML cells and not expressed in normal blood cells, thus providing new opportunities to develop novel therapies that will kill AML cells but leave normal cells unharmed.

His SCOR project is focused on the most promising target candidates and is undertaking preclinical evaluation and development of immunotherapies that target these novel proteins on pediatric AML cells. Distinct yet coordinated projects are simultaneously developing three different types of immunotherapies attacking these same targets. This cooperative, multi-modal approach will provide “multiple shots on goal,” expediting the path to clinical trials—including LLS’s Pediatric Acute Leukemia (PedAL) Master Clinical Trial. Ultimately, the goal of this SCOR is to create an arsenal of immunotherapies for children with AML. Dr. Meshinchi’s program is composed of a highly integrated system of four projects and supporting cores to rapidly translate new therapeutic targets into clinical application. The grant began in October 2021 and runs through September 2026.

Following are descriptions of each of the four projects and the progress made to date.

PROJECT 1: Dr. Meshinchi is exploring the promising new approach of engineering natural killer (NK) cells so that they produce chimeric antigen receptors (CARs). NK cells are another kind of white blood cell, and like T cells, when made to produce CARs, their ability to kill cancer is greatly increased. In addition, CAR-NK cells have the distinctive characteristic of rarely killing healthy cells of patients who did not donate the NK cells. So, CAR-NK cells engineered using cells from a donor could be used to treat many different patients. Thus, Dr. Meshinchi believes this can provide a readily available “off-the-shelf” immunotherapy. In collaboration with Deverra Therapeutics, Dr. Meshinchi’s team is focusing their efforts on optimizing a key part of the process called transduction where DNA is transferred to NK cells to enable them to target AMLspecific proteins. Efficient transduction is critical for developing a clinically viable product. The NK cells are being extracted from cord blood stem cells, a convenient source of white blood cells. The team is currently working on producing CAR-NK cells that target the protein mesothelin that is abundant on pediatric AML cells; they expect to begin pre-clinical testing of these engineered cells within the next year.

PROJECT 2: This project focuses on improving CAR T cells designed to target the protein FOLR1 that is abundant on AML cancer cells. This project has moved rapidly and outpaced the anticipated timeline originally outlined in the grant application. Studies have been completed that were necessary to support qualification of the designed cells (FOLR1 CAR-T cells) as an Investigational New Drug (IND) by the FDA and thus start the process towards clinical trials of the therapy.

The FOLR1 CAR-T cells are the first CAR T cells developed exclusively for treatment of pediatric/infant AML. The team is currently optimizing the process for producing the CAR T cells efficiently and expects to complete these efforts and submit an IND application by spring 2023. The clinical team is in place and the researchers intend to run a 10-patient trial anticipated to begin in the third quarter of 2023.

PROJECT 3: Another way to target cancer is with bi-specific T-cell engagers (BiTEs), in which two different antibodies are linked together. One antibody recognizes and binds to a protein on the surface of T cells and the other binds to a protein on the surface of cancer cells. This brings the cancer cells together within close proximity of T cells so that the T cells can more readily destroy the malignant cells. In Project 3, Dr. Olson’s team has created an improved, fully human antibody against FOLR1 and has incorporated it into a BiTE. Their initial experiments have shown the new FOLR1 BiTE has strong potency for killing cancer cells. One of the SCOR project core labs has produced animals with human cancer tumors and these will be used in experiments testing the ability of the optimized BiTE to fight cancer.

PROJECT 4: Dr. Meshinchi is collaborating with Dr. Le in Project 4 to find and validate more proteins that may be candidate targets for new immunotherapies. This would allow researchers to attack cancer from new and different angles. Not all proteins are viable for targeting. For example, proteins need to be found on the surface of cancer cells where CAR T cells or BiTEs can find and bind to them. They must also be abundant in malignant cells while being absent or present at only low levels in healthy cells, so that the therapy only targets and kills the cancer cells and not healthy cells. Working closely with the computational biology core to analyze cellular data such as gene activity levels, the team has identified several new promising candidate proteins that include Lamp5 as well as members of the C-lectin family of proteins. These proteins will be further studied in more extensive experiments, and Drs. Le and Meshinchi anticipate that this effort will identify the next generation of targets for therapeutic development.