Novel CD7 CAR T-cells for refractory T-cell malignancies affecting pediatric and AYA patients
Rayne Rouce
MDBaylor College of Medicine
Project Term: July 1, 2024 - June 30, 2027
T-cell leukemias and lymphomas have devastating outcomes if they recur after or don’t respond to standard treatment, with the only hope of cure being bone marrow transplant (BMT). Unfortunately, many pediatric, adolescent and young adult (AYA) patients are unable to achieve clinical remission (and thus unable to proceed to BMT) with standard salvage therapies, which are often even more toxic than upfront therapies. Available treatment options for patients with relapsed or refractory T-cell malignancies (particularly pediatric and AYA patients) are lacking, thus 3-year survival rates are <15% for these patients. This proposal aims to study a less toxic, targeted approach using patient or donor-derived T-cells engineered to target an antigen expressed on over 90% of T-cell malignancies that affect pediatric and AYA patients (CD7 Chimeric Antigen Receptor T-cells).
Chimeric Antigen Receptor T-cells are a type of personalized, targeted therapy that involves equipping an immune cell (T-cell) with a specialized receptor that targets a protein or antigen on the surface of a cancer. CAR T-cells have been very effective in patients with difficult-to-treat B-cell blood cancers but have lagged behind in T-cell blood cancers. This is because the tumor antigens targeted in T-cell cancers are also present on normal T-cells, making it difficult for these cells to grow in the lab and raising safety concerns. We have identified a strategy to create CAR T-cells engineered to target CD7, an antigen expressed on most aggressive T-cell leukemia and lymphoma, particularly types that affect children, adolescents and young adults (AYA). CD7 is also present on most T-cell lymphoma. The goal of this first-in-human clinical trial is to determine whether we can safely administer CD7 CAR T-cells to children and AYA (12 months and up) with CD7+ T cell leukemia or lymphoma that has come back or never gone away. We will make the CD7 CAR-T either from the patient’s own blood that we collect from a blood draw, or from a patient’s prior bone marrow transplant (BMT) donor who shares the same tissue type. We will test 3 different doses of CD7 CAR T-cells, starting with the lowest dose in the first patients treated and increasing the dose in the next patients only if the lower dose is considered safe and patients do not have worrisome side effects. We will determine the safest dose of CD7 CAR-T and track any expected or unexpected side effects. We will also measure whether our CD7 CAR-T are able to eliminate leukemia and lymphoma cells and enable patients to proceed to curative bone marrow transplant. We will perform additional research tests that will help us better understand how the CD7 CAR-T work, such as how long they survive in patients’ blood and what effect they have on other normal cells. We expect that treatment with CD7 CAR-T will be safe and well-tolerated. If CD7 CAR-T are successful in eliminating participants’ cancer, patients previously ineligible for BMT due to residual cancer will now be able to undergo this curative treatment. Our study also has the potential for even broader impact: our hope is that we will obtain preliminary evidence that CD7 CAR-T can eliminate T-cell leukemia and lymphoma long term, without being toxic to normal cells, which could replace the need for BMT and reduce overall complications while improving quality of life.
We have extensive experience in safely moving cellular immune therapies such as CAR-T from the research lab to the clinic. Our study fills a noticeable gap and provides a potentially less toxic, targeted approach for our most vulnerable pediatric/AYA, underrepresented, and low resource patients. Our approach is novel, feasible, and would have wide-reaching benefits for these often-neglected blood cancers.