Project Stella: Targeted Therapies
Dr Meshinchi explains the history behind Project Stella and why targeted therapies are so imperative in treating this disease.
Current Treatments
Current therapies for many forms of childhood AML follow a fairly standard treatment protocol of several rounds of chemotherapy followed by a stem cell transplant. Chemotherapy is designed to kill fast-growing cells, both cancer cells and many types of healthy cells the immune system is reliant upon. Each round of chemotherapy leaves a child open to a variety of life-threatening infections, with no functional immune system to fight them. Furthermore, the vast majority of chemotherapies used in pediatric applications today are decades old and were developed for adult patients. Pediatric AML is an entirely different set of cancers, with different genetic makeups and treatment targets. As a result, they are not only toxic to the bodies of small children, but are largely ineffective because they fail to recognize the unique attributes of pediatric AML.
This is especially true with CBF-GLIS AML. Traditional AML chemotherapies wipe out all cells, both healthy and cancerous, but yet the cancer persists. This means a child is subjected to multiple rounds of toxic chemo to fight it. Even if remission is secured and the child moves on to a stem cell transplant, the cancer itself hasn’t been adequately targeted and therefore is almost certain to come back. In essence, the lack of tailored and targeted treatments up front sets a transplant up for failure in the end.
Image at right: Aspen battling Veno-occlusive disease (VOD), one of the many life-threatening side effects of chemotherapy and bone marrow transplants.
A New Approach to Treatment
In contrast to traditional treatment, targeted therapies like those being researched at Project Stella are designed to identify and kill only cancer cells. This leaves the body resilient and healthy; equipped to fight infections and illness. Most importantly, they are tailored to target mutations within the cancer cell itself, making it far more capable long term. They leverage what we know through genomic sequencing to understand and predict cancerous behavior to cure the child, for good.
Project Stella works closely with Dr. Soheil Meshinchi, a world-renowned pediatric AML expert at Fred Hutch Cancer Center to expedite precision medicine research. Dr. Meshinchi runs one of the only labs in the country developing cures for children facing the devastating diagnosis of high-risk AML. His research is tailored to pediatric cancers, aimed specifically at patients under 5 years old. Dr. Meshinchi’s research is focused on finding a treatment protocol that targets the cancer and does not bring the irreversible side effects. Moreover, these therapies will be brought to children on an expedited time frame, bypassing the decades it often takes to bring novel treatments to pediatric cancer patients.
What is CAR T cell therapy?
CAR T cell therapy is a tailored form of immunotherapy that works by modifying the body's own T cells, a type of immune system cell that hunts and destroys abnormal cells. Scientists harvest T cells from patients, genetically alter them, then infuse the resulting CAR T cells into patients to attack cancerous cells. The CAR T cells then act as a "living drug" against cancer cells. When they come in contact with their targeted antigen on a cell, CAR T cells bind to it and become activated, then proliferate and become cytotoxic. In other words, they are cancer-fighting smart missiles.
Creating an effective CAR T is contingent on first identifying a suitable target. For safety, CAR T cells are engineered to be specific to an antigen expressed on a tumor that is not expressed on healthy cells. This is another reason genomic sequencing is so critical. Under the leadership of Dr. Meshinchi, sequencing has become part of pediatric AML protocol - advanced significantly in partnership with the LLS PEDAL initiative. Sequencing helps us understand the mutations underlying the disease, so vulnerabilities can be identified. As a result of Project Stella and the Hutch having the largest repository of pediatric leukemia samples, the Meshinchi Lab has identified several proteins that are highly expressed in AML RAM, like FOLR-1. Because FOLR-1 is found in high expressions on the outside of the cancer cell, it is ideally suited for immunotherapies. Moreover, it is not found on healthy cells.
Image: Leukemia & Lymphoma Society (LLS)
Phase Two: Manufacture The CAR T Cells
We have completed the actual manufacturing phase of the CAR T.
The manufacturing process for engineered T cells follows many complex and labor-intensive procedures.
The video below describes many of the steps required to manufacture CAR T cells to meet the FDA’s requirements.
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