TCR directed immunotoxins and antibody drug conjugates for the treatment of T cell malignancies
Suman Paul
MBBS PhDThe Johns Hopkins University School of Medicine
Project Term: July 1, 2022 - June 30, 2025
Few treatment options are available for T cell leukemias and lymphomas, collectively called T cell cancers that affect ~100,000 patients worldwide each year. The current proposal will generate new antibodies attached to drugs and toxins that kill the T cell cancers. Importantly, the antibodies will preserve enough healthy T cells to maintain a functioning immune system. These modified antibodies may improve patient outcome and limit side effects associated with traditional chemotherapies.
T cell leukemias and lymphomas, collectively known as T cell cancers, affect ~100,000 patients worldwide each year. The T cell cancers are frequently resistant to chemotherapies that are currently available for treatment. As a result, only 7% to 38% of the T cell cancer patients remain alive 5 years after their diagnosis. Immunotherapies such as antibodies linked to drugs or toxins that specifically kill cancer cells while sparing the healthy cells are highly effective in treating a range of human cancers. Thus, T cell cancer patients particularly need such drug or toxin-linked antibodies in order to improve patient survival. However, developing such therapies is challenging, as the treatment will have to preserve some of the healthy T cells, as the healthy T cells are required to maintain a functioning immune system, which is required for human survival. T cells express the T cell receptor (TCR) on the cell-surface. Although all T cells express TCR, they can be distinguished based on the TCR beta chain constant region (TRBC) which is derived from one of two gene segments, TRBC1 or TRBC2. My team demonstrated that in healthy T cell populations, about 45% of cells express TRBC1 while the other 55% express TRBC2. However, the T cell cancers express either TRBC1 or TRBC2 (Paul et al., Sci. Transl. Med. 2021). Thus, for patients suffering from T cell cancers that express TRBC1, toxin or drug-linked antibodies targeting TRBC1 will eradicate the T cell cancers and ~45% of the healthy T cells (the TRBC1+ healthy T cells), while preserving the rest 55% healthy T cells (the TRBC2+ healthy T cells). We have now developed toxin or drug-linked TRBC1-targeting antibodies that kill TRBC1+ T cell cancers in the laboratory. We need to test these therapies in animal models before administering them in human patients. Our proposed research will generate mouse models of T cell cancers by injecting mice with human cancer cells. We will then test if these toxin or drug-linked TRBC1-targeting antibodies can kill the TRBC1+ T cell cancers inside mice and thereby improve mice survival. We will also examine if the remaining healthy TRBC2+ T cells retain the entire immune cell subsets required for a functioning immune system. Based on previous observations we expect our treatment will eliminate the T cell cancers from mice and the remaining healthy T cells will be sufficient for a functioning immune system. The second part of the proposal will generate toxin or drug-linked antibodies that kill TRBC2+ T cell cancers, as such TRBC2-targeting antibodies are currently unavailable. We will then similarly test the TRBC2-targeting antibodies in mice harboring human T cell cancers that express TRBC2. We expect our therapies will eliminate the TRBC2+ T cell cancers while retaining the healthy TRBC1+ T cells. Successful preclinical testing of our antibodies will allow us to proceed with human clinical trials and may fill an unmet need for the treatment of T cell cancer patients.