Researchers at Ludwig Johns Hopkins, including graduate students Emily Han-Chung Hsiue and Jacqueline Douglass, Co-directors Bert Vogelstein and Kenneth Kinzler, and investigators Shibin Zhou, Nick Papadopoulos and Chetan Bettegowda, as well as their Johns Hopkins colleagues Katharine Wright and Sandra Gabelli developed and demonstrated a new strategy for immunotherapy that targets specific genetic alterations commonly associated with cancer, including those of the TP53 tumor suppressor gene and cancer-driving RAS genes to generate a therapeutic immune response. The strategy and its preclinical evaluation in mouse models were described in two March papers in Science Immunology and Science.
The Ludwig Johns Hopkins team first developed antibody fragments to recognize the targeted mutant antigens, called neoantigens, and used them to design bispecific antibodies that recognize two distinct molecules: the antigens bound to the protein machinery that presents them to the immune system’s T cells, known as HLA, and a receptor on T cells that is critical to their function. By linking the two, the bispecific antibodies prompted the T cells to kill the cancer cells presenting the targeted antigens. The researchers demonstrated that the immune attack elicited by the bispecific antibodies is restricted to cancer cells bearing the neoantigens, does not affect healthy cells and prompts the destruction of human cancer cells harboring TP53 and RAS mutations in xenograft mouse models.
The strategy’s success depends on a cancer expressing at least one targeted neoantigen and the patient having the particular HLA type that presents that antigen to the immune system. It has several advantages. Importantly, neoantigens derived from genetic alterations represent the most specific targets possible. Therefore, targeting these antigens minimizes the chances of causing so called “on-target, off-tissue” toxicities observed when targeting tumor-associated antigens that can also be expressed in certain normal tissues.
Another potential benefit would be that such products could work on a wide variety of patients, so long as they have the HLA subtype and any type of cancer that expresses the mutant TP53 or RAS gene—both of which are very common drivers of cancer. The antibody-based approach should also be comparatively simple to apply because it does not entail any isolation and engineering of patient immune cells. The researchers are now further studying the strategy to assess its potential toxicities and adapting their approach to target other common cancer-related mutations.
In a third March paper published in Science Translational Medicine, the team led by Bert Vogelstein and a Johns Hopkins colleague Suman Paul devised similar bispecific antibodies to target T-cell lymphomas. In this approach, the target antigen is a T-cell receptor (TCR) instead of a neoantigen. Each normal T cell expresses a unique TCR type generated from one of approximately 30 different TCR β chain variable gene families. But all cancer cells in a patient express one particular TCR type because all cancer cells are derived from a single original T cell. By targeting the particular cancer cell-expressed TCR, the new approach would kill all cancer cells and only a very small fraction of normal T cells. The efficacy and specificity of this approach were shown both in culture dishes and in mouse models of the disease.
This article appeared in the August 2021 issue of Ludwig Link. Click here to download a PDF (2MB).