MIT Koch Institute
November 5, 2024
A new therapeutic approach from the Wittrup lab uses reactive oxygen species-induced cancer cell death to help jumpstart anti-tumor immune responses and synergize with existing immunotherapies for improved treatment of many solid tumor types.
Reactive oxygen species are naturally occurring highly reactive chemical molecules formed from diatomic oxygen (O2), water, and hydrogen peroxide. These molecules act as biochemical switches that turn biological processes on and off, including certain cell death and immune functions.
Within tumors, heightened levels of reactive oxygen species (ROS) are often associated with a suppressive tumor microenvironment. However, under certain conditions ROS can contribute to tumor elimination. For example, some chemotherapies, radiation protocols and other treatment approaches increase cancer cell ROS levels, which influences the mechanism of cell death by which the tumor cells are killed and thereby their subsequent recognition by the immune system. Furthermore, activated myeloid cells, a type of immune cell that circulates in the blood, rapidly generate ROS upon encountering pathogens or infected cells in order to eliminate disease. Recently, this same function has been noted in cancer as well. Thus, ROS-induced cancer cell death may help initiate immune responses against tumors and synergize with current approved immunotherapies to better treat cancer.
Researchers in the Wittrup lab have developed an approach, published in Molecular Cancer Therapy, that uses a targeted enzyme to effectively harness ROS-induced cell death against solid tumors.
The researchers used glucose oxidase--an enzyme that produces hydrogen peroxide, which is a type of ROS--to therapeutically mimic the oxidative burst normally seen from myeloid cells, in order to promote antigen generation within the tumor microenvironment. These antigens can then serve as flags to alert, inform and engage immune responses.
Moreover, the Wittrup team engineered their enzyme to target pan-tumor expressed integrins--cell adhesion receptors that can play a role in immune cell activation--both as a broadly applicable tumor-agnostic therapeutic approach and as a strategy to prolong local enzyme activity following administration within the tumor. They found the targeted enzyme potently induced cancer cell death and enhanced cross-presentation by dendritic cells in cell models of cancer, and further combined with a clinically used immunotherapy called interferon alpha for long-term tumor control in mouse models of colorectal cancer.
Importantly, by optimizing single-dose administration of their enzyme and administering it directly into the tumor, the researchers were able to overcome limitations and immunogenicity-related challenges noted for other pro-oxidant enzyme approaches. Many of these strategies require repeated dosing and conjugation of the enzyme to an antibody or delivery material in order to precipitate tumor accumulation and activity, resulting in levels of immunogenicity that limit their clinical translation.
Overall, results from this study, published in Molecular Cancer Therapies, suggest that ROS-induced cell death can be harnessed for tumor control and highlight the potential use of designed enzyme therapies alongside immunotherapy against cancer.