Combined Targeted Radiopharmaceutical Therapy and Immune Checkpoint Blockade: From Preclinical Advances to the Clinic

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized cancer care, but many patients with poorly immunogenic tumors fail to benefit. Preclinical studies have shown that external beam radiotherapy (EBRT) can synergize with ICI to prompt remarkable tumor regression and even eradication. However, EBRT is poorly suited to widely disseminated disease. Targeted radiopharmaceutical therapy (TRT) selectively delivers radiation to both the primary tumor and the metastatic sites, and promising results achieved with this approach have led to regulatory approval of certain agents (e.g., 177 Lu-PSMA-617/Pluvicto for metastatic prostate cancer). To further improve therapeutic outcomes, combining TRT and ICI is a burgeoning research area, both preclinically and in clinical trials. Here we introduce basic TRT radiobiology and survey emerging and clinically translated TRT agents that have been combined with ICI.

Fibroblast activation protein targeted radiotherapy induces an immunogenic tumor microenvironment and enhances the efficacy of PD-1 immune checkpoint inhibition

“…In addition to direct cytotoxic effects, radiation-based therapeutics can promote inflammatory signals and increase tumor immunogenicity. Evidence from preclinical and clinical studies suggest that TRT can promote an immune-privileged TME [ 11 ]. In a previous report with beta-particle emitting radionuclides, radiation induced DNA damage was demonstrated to upregulate pro-inflammatory cytokines such as interferons through activation of the stimulator of interferon genes (STING) pathway [ 12 ].…”

Metastatic castration-resistant prostate cancer and immune checkpoint inhibitors

“…Особенно это было заметно у пациентов с мутациями репарации повреждений ДНК, что указывает на то, что пациенты с этими мутациями могут получить дополнительный положительный эффект при сочетании иммунотерапии и лечения ингибиторами ПАРП. Несмотря на то что было проведено несколько исследований комбинаций ИИКТ с радиолигандной терапией, возможно, стоит дополнительно изучить радиолигандную терапию как вариант повышения чувствительности иммунологически «холодных» опухолей предстательной железы к ИИКТ [34]. В исследовании PRINCE фазы 1b/II применения пембролизумаба в комбинации с 177-Lu-PSMA-617 у пациентов с мКРРПЖ показана частота ПСА-ответа 76 % и объективного ответа 78 %.…”

Theranostic Nuclear Medicine with Gallium-68, Lutetium-177, Copper-64/67, Actinium-225, and Lead-212/203 Radionuclides

“…259 While these effects have largely been investigated in relation to external beam radiation therapies, the advent of systemic radiotherapies such as radioimmunotherapy and targeted α-therapy provide a new avenue for activating the immune system for cancer treatment. 260 Several metallic "matched pairs" have the physical and chemical characteristics that warrant further investigation. 9,261,262 An emphasis of this Focus Review was placed on the significant potential of copper-64/67 theranostics that have the potential to offer viable alternatives to lutetium-177based therapeutics with gallium-68 based companion diagnostics.…”

“…The bystander effect (whereby irradiated cells have toxic effects on neighboring nonirradiated cells) and the abscopal effect (when the irradiation of a tumor causes toxic effects in distant sites of disease) are thought to be due to the immunostimulatory effects following irradiation of a tumor . While these effects have largely been investigated in relation to external beam radiation therapies, the advent of systemic radiotherapies such as radioimmunotherapy and targeted α-therapy provide a new avenue for activating the immune system for cancer treatment …”