Investigating the immunomodulatory effects of drug combinations with PSMA targeted radiopharmaceuticals
Anticancer radioligand therapies (RLT) such as 177Lu-PSMA show great promise in the treatment of metastatic castration resistant prostate cancer. However, despite many patients experiencing an initial response to RLT it is currently a non-curative treatment. One potential strategy to enhance this molecularly targeted systemic treatment is to combine it with immune checkpoint inhibitors (ICI) which amplify the immune response towards cancer cell associated-neoantigens that are released upon radiation-induced cell death. However, due to the complexity and timing of potential cell death events during the extended exposure to radiation that is associated with RLT compared to conventional external beam radiotherapy, the release of neo-antigens and immune stimulation appears to be modest following RLT treatment. We have discovered that a number of immunomodulatory chemotherapeutics are able to redirect and orchestrate 177Lu-PSMA therapy towards certain types of cell death and outcomes. Recent data suggest that these drugs could greatly enhance the combination of RLT plus immune therapeutics such as checkpoint inhibitors and CAR-T therapy.
The central goal of this project is to investigate immunomodulatory chemotherapy combinations with therapeutic radionuclides including lutetium-177. In addition, it is planned to investigate alpha particle-emitting RLTs, which have a particularly potent anticancer effect and so constitute a promising class of agents. This programme of in vitro and preclinical research will, in due course, be used to inform the design of clinical trials.
This project is a collaboration between the O’Neill (Nuffield Department of Surgery) and Vallis (Oncology) research groups and will provide training and experience in the development and radiobiology of radionuclide therapy. Methods used in the execution of the project include radiosynthesis, preclinical therapy and imaging, confocal microscopy, drug screening and ex vivo analysis techniques. As a result of the therapeutic success of agents like 177Lu-PSMA the field of radiopharmaceuticals is advancing very rapidly. Healthcare systems and research organisations are having to adapt to this new demand and researchers with experience in RLT find growing opportunities within the pharmaceutical industry and academia within the UK and worldwide.
O'Neill, E., Mosley, M. and Cornelissen, B., 2023. Imaging DNA damage response by γH2AX in vivo predicts treatment response to Lutetium-177 radioligand therapy and suggests senescence as a therapeutically desirable outcome. Theranostics, 13(4), p.1302.
Dias, G., Able, S., Skaripa-Koukelli, I., Anderson, R., Wilson, G. and Vallis, K.A., 2023. Evaluation of anti-tumor immunity in response to [177Lu] Lu-PSMA in a mouse model of prostate cancer. Cancer Research, 83(7_Supplement), pp.5038-5038.
Chan, T.G., O’Neill, E., Habjan, C. and Cornelissen, B., 2020. Combination strategies to improve targeted radionuclide therapy. Journal of Nuclear Medicine, 61(11), pp.1544-1552.