Radionuclide imaging and therapy directed towards the tumor microenvironment: a multi-cancer approach for personalized medicine

Abstract

Targeted radionuclide theranostics is becoming more and more prominent in clinical oncology. Currently, most nuclear medicine compounds researched for cancer theranostics are directed towards targets expressed in only a small subset of cancer types, limiting clinical applicability. The identification of cancer-specific targets that are (more) universally expressed will allow more cancer patients to benefit from these personalized nuclear medicine-based interventions. A tumor is not merely a collection of cancer cells, it also comprises supporting stromal cells embedded in an altered extracellular matrix (ECM), together forming the tumor microenvironment (TME). Since the TME is less genetically unstable than cancer cells, and TME phenotypes can be shared between cancer types, it offers targets that are more universally expressed. The TME is characterized by the presence of altered processes such as hypoxia, acidity, and increased metabolism. Next to the ECM, the TME consists of cancer-associated fibroblasts (CAFs), macrophages, endothelial cells forming the neo-vasculature, immune cells, and cancer-associated adipocytes (CAAs). Radioligands directed at the altered processes, the ECM, and the cellular components of the TME have been developed and evaluated in preclinical and clinical studies for targeted radionuclide imaging and/or therapy. In this review, we provide an overview of the TME targets and their corresponding radioligands. In addition, we discuss what developments are needed to further explore the TME as a target for radionuclide theranostics, with the hopes of stimulating the development of novel TME radioligands with multi-cancer, or in some cases even pan-cancer, application.

Keywords: Cancer stroma; Pan-cancer therapy; Radionuclide imaging and therapy; Theranostics; Tumor microenvironment.

Fig. 1

Targets in the TME suitable for radionuclide imaging and/or therapy. This includes altered TME processes and the EMC (left) and cellular components of the TME (right)

Fig. 2

The concept of using [¹⁸F]FDG amine for pH-dependent (pH < 6.5) release of [¹⁸F]FDG. The [¹⁸F]FDG amine cage is cleaved at low extracellular pH. Consequently, [.¹⁸F]FDG is released, which then enters tumor cells through the GLUT receptor, enabling visualization of acidic lesions on PET scans. The figure is based on Flavell et al. [52]

Fig. 3

PET/CT scans of 1/5 responding Hodgkin’s lymphoma patients treated with the TNC-A1-targeting radioligand [¹³¹I]I-F16SIP (Tenarad). a Maximum intensity projection image of the baseline FDG PET/CT scan (left), the [¹³¹I]I-F16SIP SPECT/CT scan 24 h post-injection (middle), and the FDG PET/CT scan 4 weeks after [¹³¹I]I-F16SIP treatment (right). b Whole-body images at different time points after 3.33 GBq [¹³¹I]I-F16SIP administration, demonstrating uptake in tumor lesions. A: anterior view, P: posterior view. The figure was originally published in EJNNMI by Aloj et al. [65]. Radioimmunotherapy with Tenarad, a 131I-labeled antibody fragment targeting the extradomain A1 of tenascin-C, in patients with refractory Hodgkin's lymphoma (2014) Vol 41(5):867–877

Fig. 4

Pre-targeting system for imaging of ECM remodeling. Protective antigen binds to the cell membrane in the presence of MMP-2, -9, and/or -14 allowing to form a pore in the membrane. Hereafter, an indium-111 labeled LF.^E687A is administered which selectively binds to the cleaved protective antigen, and enters the cells via the created pore. The figure is based on Xavier et al. [84]

Fig. 5

[⁶⁸Ga]Ga-FAPI-04 PET/CT scans in 15 different cancer types demonstrating the pan-cancer potential of FAP-targeting radionuclide imaging. Ca cancer; CCC clear cell carcinoma; CUP carcinoma of unknown primary; MTC medullary thyroid cancer; NET neuroendocrine tumor NSCLC non-small cell lung cancer. The figure was originally published in JNM. Kratochwil et al. [95]. ⁶⁸Ga-FAPI PET/CT: Tracer Uptake in 28 Different Kinds of Cancer (2019) Vol. 60(6): 801–805

Fig. 6

Chemical structures of several monomeric (i.e., [¹⁸F]Galacto-RGD, [¹⁸F]RGD-K5, [⁶⁸Ga]NOTA-RGD, [¹⁸F]Fluciclatide) and dimeric (i.e., [¹⁸F]FPPRGD2, [⁶⁸Ga]NOTA-PRGD2, [¹⁸F]Alfatide, [¹⁸F]Alfatide II) RGD-based PET radioligands. The figure was originally published in Theranostics by Chen et al. [144]. Clinical application of radiolabeled RGD peptides for PET imaging of integrin αvβ3 (2016) Vol. 6(1): 78–92

Fig. 7

[¹²³I]I-VEGF₁₆₅ SPECT/MRI of a grade IV glioma in a 60-year-old patient. a Acial T1-weighted MRI for anatomical reference of the tumor lesion. b [¹²³I]I-VEGF SPECT imaging before radiation therapy and c lower radioligand accumulation 1 week post-radiation therapy. White arrows indicate the tumor lesion. The figure was originally published in EJNMMI by Rainer et al. [163]. The prognostic value of [¹²³I]-vascular endothelial growth factor ([.¹²³I]-VEGF) in glioma (2018) Vol. 45(13): 2396–2403

Fig. 8

Chemical structures of [⁶⁸Ga]Ga-Pentixafor and [¹⁷⁷Lu]Lu-Pentixather. Originally published in Theranostics by Schottelius et al. [185]. [.¹⁷⁷Lu]pentixather: Comprehensive Preclinical Characterization of a First CXCR4-directed Endoradiotherapeutic Agent (2017) Vol. 7(9): 2350–2362