Although positron emission tomography (PET) imaging with 18-Fluorodeoxyglucose (¹⁸F-FDG) is a promising technique in multiple myeloma (MM), the development of other radiopharmaceuticals seems relevant. CD138 is currently used as a standard marker for the identification of myeloma cells and could be used in phenotype tumor imaging. In this study, we used an anti-CD138 murine antibody (9E7.4) radiolabeled with copper-64 (⁶⁴Cu) or zirconium-89 (⁸⁹Zr) and compared them in a syngeneic mouse model to select the optimal tracers for MM PET imaging. Then, 9E7.4 was conjugated to TE2A-benzyl isothiocyanate (TE2A) and desferrioxamine (DFO) chelators for ⁶⁴Cu and ⁸⁹Zr labeling, respectively. ⁶⁴Cu-TE2A-9E7.4 and ⁸⁹Zr-DFO-9E7.4 antibodies were evaluated by PET imaging and biodistribution studies in C57BL/KaLwRij mice bearing either 5T33-MM subcutaneous tumors or bone lesions and were compared to ¹⁸F-FDG-PET imaging. In biodistribution and PET studies, ⁶⁴Cu-TE2A-9E7.4 and ⁸⁹Zr-DFO-9E7.4 displayed comparable good tumor uptake of subcutaneous tumors. On the bone lesions, PET imaging with ⁶⁴Cu-TE2A-9E7.4 and ⁸⁹Zr-DFO-9E7.4 showed higher uptake than with ¹⁸F-FDG-PET. Comparison of both 9E7.4 conjugates revealed higher nonspecific bone uptakes of ⁸⁹Zr-DFO-9E7.4 than ⁶⁴Cu-TE2A-9E7.4. Because of free ⁸⁹Zr’s tropism for bone when using ⁸⁹Zr-anti-CD138, ⁶⁴Cu-anti-CD138 antibody had the most optimal tumor-to-nontarget tissue ratios for translation into humans as a specific new imaging radiopharmaceutical agent in MM.

Objectives. A phase I pretargeted radioimmunotherapy trial (EudractCT 200800603096) was designed in patients with metastatic lung cancer expressing carcinoembryonic antigen (CEA) to optimize bispecific antibody and labelled peptide doses, as well as the delay between their injections. Methods. Three cohorts of 3 patients received the anti-CEA x anti-histamine-succinyl-glycine (HSG) humanized trivalent bispecific antibody (TF2) and the IMP288 bivalent HSG-peptide. Patients underwent a pre-therapeutic imaging session S1 (44 or 88 nmol/m2 of TF2 followed by 4.4 nmol/m2, 185 MBq, of 111In-labelled IMP288), and, 1-2 weeks later, a therapy session S2 (240 or 480 nmol/m2 of TF2 followed by 24 nmol/m2, 1.1 GBq/m2, 177Lu-labeled IMP288). The pretargeting delay was 24 or 48 hours. The dose schedule was defined based on pre-clinical TF2 pharmacokinetic studies, on our previous clinical data using the previous anti-CEA pretargeting system and on clinical results observed in the first patients injected using the same system in the Netherlands. Results. TF2 pharmacokinetics (PK) was represented by a two-compartment model in which the central compartment volume was linearly dependent on the patient's surface area. PK were remarkably similar, with a clearance of 0.33 +/- 0.03 L/h per m2. 111In- and 177Lu-IMP288 PK were also well represented by a two-compartment model. IMP288 PK were faster (clearance 1.4 to 3.3 l/h). The central compartment volume was proportional to body surface area and IMP288clearance depended on the molar ratio of injected IMP288 to circulating TF2 at the time of IMP288 injection. Modelling of image quantification confirmed the dependence of IMP288 kinetics on circulating TF2, but tumour activity PK were variable. Organ absorbed doses were not significantly different in the 3 cohorts, but the tumour dose was significantly higher with the higher molar doses of TF2 (p < 0.002). S1 imaging predicted absorbed doses calculated in S2. Conclusion. The best dosing parameters corresponded to the shorter pretargeting delay and to the highest TF2 molar doses. S1 imaging session accurately predicted PK as well as absorbed doses of S2, thus potentially allowing for patient selection and dose optimization.

Although the concept of theranostics is neither new nor exclusive to nuclear medicine, it is a particularly promising approach for the future of nuclear oncology. This approach is based on the use of molecules targeting specific biomarkers in the tumour or its microenvironment, associated with optimal radionuclides which, depending on their emission properties, allow the combination of diagnosis by molecular imaging and targeted radionuclide therapy (TRT). Copper-64 has suitable decay properties (both β⁺ and β- decays) for PET imaging and potentially for TRT, making it both an imaging and therapy agent. We developed and evaluated a theranostic approach using a copper-64 radiolabelled anti-CD138 antibody, [⁶⁴Cu]Cu-TE1PA-9E7.4 in a MOPC315.BM mouse model of multiple myeloma. PET imaging using [⁶⁴Cu]Cu-TE1PA-9E7.4 allows for high-resolution PET images. Dosimetric estimation from ex vivo biodistribution data revealed acceptable delivered doses to healthy organs and tissues, and a very encouraging tumour absorbed dose for TRT applications. Therapeutic efficacy resulting in delayed tumour growth and increased survival without inducing major or irreversible toxicity has been observed with 2 doses of 35 MBq administered at a 2-week interval. Repeated injections of [⁶⁴Cu]Cu-TE1PA-9E7.4 are safe and can be effective for TRT application in this syngeneic preclinical model of MM.

PD-L1 (programmed death-ligand 1, B7-H1, CD274), the ligand for PD-1 inhibitory receptor, is expressed on various tumors, and its expression is correlated with a poor prognosis in melanoma. Anti-PD-L1 mAbs have been developed along with anti-CTLA-4 and anti-PD-1 antibodies for immune checkpoint inhibitor (ICI) therapy, and anti-PD-1 mAbs are now used as first line treatment in melanoma. However, many patients do not respond to ICI therapies, and therefore new treatment alternatives should be developed. Because of its expression on the tumor cells and on immunosuppressive cells within the tumor microenvironment, PD-L1 represents an interesting target for targeted alpha-particle therapy (TAT). We developed a TAT approach in a human melanoma xenograft model that stably expresses PD-L1 using a ²¹³Bi-anti-human-PD-L1 mAb. Unlike treatment with unlabeled anti-human-PD-L1 mAb, TAT targeting PD-L1 significantly delayed melanoma tumor growth and improved animal survival. A slight decrease in platelets was observed, but no toxicity on red blood cells, bone marrow, liver or kidney was induced. Anti-tumor efficacy was associated with specific tumor targeting since no therapeutic effect was observed in animals bearing PD-L1 negative melanoma tumors. This study demonstrates that anti-PD-L1 antibodies may be used efficiently for TAT treatment in melanoma.

The CRCI²NA inaugural symposium, a meeting on tumor and immune ecosystems, took place in the vibrant and picturesque city of Nantes. The meeting gathered world‐renowned experts in cancer biology and immunology. It showcased the most advanced science on mechanisms driving cellular heterogeneity, plasticity, and signaling in normal and cancer cellular ecosystems, which contribute to cancer development, progression, and therapeutic resistance. Recent developments in cancer immunotherapy and anti‐tumor strategies were also discussed to collectively assess new therapeutic vulnerabilities to defeat cancer.