Patients with B-cell leukemia can benefit tremendously from the latest generation of targeted cellular immunotherapies where their own killer cells (called T-cells) are engineered with special molecules called chimeric antigen receptors (CARs) which recognize and kill tumor cells. In stark contrast, patients with T-cell leukemia (T-ALL) lack any options for those life-saving treatments and mostly have to rely on conventional chemotherapies, which can be toxic and not always effective. Developing CAR T-cell therapies for patients with T-ALL is very challenging because the protein targets that the CARs can recognize are often present on vital tissues, including T-cells themselves. This can lea...

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Patients with B-cell leukemia can benefit tremendously from the latest generation of targeted cellular immunotherapies where their own killer cells (called T-cells) are engineered with special molecules called chimeric antigen receptors (CARs) which recognize and kill tumor cells. In stark contrast, patients with T-cell leukemia (T-ALL) lack any options for those life-saving treatments and mostly have to rely on conventional chemotherapies, which can be toxic and not always effective. Developing CAR T-cell therapies for patients with T-ALL is very challenging because the protein targets that the CARs can recognize are often present on vital tissues, including T-cells themselves. This can lead to life-threatening toxicities. To overcome this limitation, we developed CAR T-cells that kill T-ALL by recognizing a protein called CD5. We have recently tested this novel therapy in patients with T-ALL and T-cell lymphoma. We found that CD5 CAR T-cell infusions were very safe and well-tolerated, and even produced complete tumor regression in some patients with lymphoma. Unfortunately, responses in T-ALL patients were still not durable, and leukemia eventually relapsed. In this proposal, we will engineer a special protein which can be combined with the CD5 CAR to boost anti-tumor activity of CD5 CAR T-cells in T-ALL while preserving their favorable safety profile. For that, we analyzed leukemic cells from >100 patients with T-ALL and found two promising protein targets that are highly present on tumor cells but not on healthy T-cells. We will now create a molecule that will bind to one of those proteins and help CD5 CAR T-cells kill leukemia. At the same time, modified CD5 CAR T-cells will not touch any other cell that does not have CD5 thus preserving their selectivity and safety. If successful, this approach can dramatically improve outcomes of CD5 CAR T-cell therapy in patients with refractory or relapsed T-ALL, who otherwise do not have any other effective treatments.

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