The Radiobiology of Radiopharmaceuticals

Abstract

Radiopharmaceutical therapy or targeted radionuclide therapy (TRT) is a well-established class of cancer therapeutics that includes a growing number of FDA-approved drugs and a promising pipeline of experimental therapeutics. Radiobiology is fundamental to a mechanistic understanding of the therapeutic capacity of these agents and their potential toxicities. However, the field of radiobiology has historically focused on external beam radiation. Critical differences exist between TRT and external beam radiotherapy with respect to dosimetry, dose rate, linear energy transfer, duration of treatment delivery, fractionation, range, and target volume. These distinctions simultaneously make it difficult to extrapolate from the radiobiology of external beam radiation to that of TRT and pose considerable challenges for preclinical and clinical studies investigating TRT. Here, we discuss these challenges and explore the current understanding of the radiobiology of radiopharmaceuticals.

Figure 1

The radiobiological effects of TRT on tumor cells and the tumor-immune microenvironment are multifaceted and change with the type, range, rate, and dose of radiation emitted from a given radionuclide. In tumor cells (upper right), DNA damage (1) is thought to be the primary mechanism of TRT-induced cell death. In addition, lower doses of radiation from TRT may elicit sublethal DNA damage that is detected by the sensor cGAS and leads to the production of type I interferon. (2) Type I interferon may help to prime tumor antigen (TA)-specific T cells by inducing antigen uptake and maturation of antigen presenting cells (APC) such as dendritic cells. (3) Cellular debris is phagocytosed by APC’s and (4) presented to T cells. (5) T cells mount an adaptive response to the tumor antigen which can lead to local and distant tumor cell killing. (6) Radiation also impacts the tumor microenvironment by increasing leukocyte infiltration into tumor tissue by changing vessel structure (ie, normalization), increased adhesion molecule expression on endothelium, and by triggering the expression and release of chemokines and cytokines. (7) Radiation from TRT may also kill or alter the function of immune cells in the tumor microenvironment. The radiobiological effects of dose rate and LET associated with TRT on tumor cells and the tumor microenvironment are poorly understood. A-C illustrate the dosimetric envelope for (A) medium range (millimeter), (B) long range (centimeter), and (C) short range (micrometer) radiation emitted from a tumor cell selective TRT in the tumor microenvironment. Figure graciously provided by Dr. Bryan Bednarz, University of Wisconsin.