Developments in Combining Targeted Radionuclide Therapies and Immunotherapies for Cancer Treatment

Targeted radionuclide therapy (TRT) and immunotherapy are rapidly growing classes of cancer treatments. Basic, translational, and clinical research are now investigating therapeutic combinations of these agents. In comparison to external beam radiation therapy (EBRT), TRT has the unique advantage of treating all disease sites following intravenous injection and selective tumor uptake and retention—a particularly beneficial property in metastatic disease settings. The therapeutic value of combining radiation therapy with immune checkpoint blockade to treat metastases has been demonstrated in preclinical studies, whereas results of clinical studies have been mixed. Several clinical trials combining TRT and immune checkpoint blockade have been initiated based on preclinical studies combining these with EBRT and/or TRT. Despite the interest in translation of TRT and immunotherapy combinations, many questions remain surrounding the mechanisms of interaction and the optimal approach to clinical implementation of these combinations. This review highlights the mechanisms of interaction between anti-tumor immunity and radiation therapy and the status of basic and translational research and clinical trials investigating combinations of TRT and immunotherapies

Clinical Imaging and Dosimetry of a Pan-Cancer Targeting Alkylphosphocholine Analog, [¹²⁴I]I-NM404

The purpose of this study was to assess organ dosimetry and clinical use of [124I]I-NM404, a radiotheranostic alkylphosphocholine (APC) analog, for accurate detection and characterization of a wide variety of solid primary and metastatic malignancies anywhere in the body. Methods: Patterns of [124I]I-NM404 uptake were quantitatively analyzed and qualitatively compared with [18F]FDG PET/CT in 14 patients (median age, 61.5 years; 7 males, 7 females) with refractory metastatic cancer who were enrolled in one of two Phase I imaging studies. Primary cancer types included bronchogenic (n = 7), colorectal (n = 1), prostate (n = 1), triple-negative breast (n = 1), head and neck (n = 2), pancreatic (n = 1) carcinoma, and melanoma (n = 1). Patients were administered [124I]I-NM404 and imaged via PET/CT at 1–2, 4–6, 24, and 48 h and at 5–10 days post injection, from top of the skull to mid-thigh. Volumes of interest were drawn over lungs, heart, liver, kidneys, and whole body for dosimetry estimation using OLINDA 1.1 Representative metastatic index lesions were chosen when applicable for each case with active sites of disease to calculate maximum and mean tumor-to-background ratios (TBRmax, TBRmean), using the adjacent normal organ parenchyma as background when possible. Results: Administrations of [124I]-NM404 were safe and well-tolerated. The organs with the highest estimated absorbed dose (mean ± SD) were the lungs (1.74 ± 0.39 mSv/MBq), heart wall (1.52 ± 0.29 mSv/MBq), liver (1.28 ± 0.21 mSv/MBq) and kidneys (1.09 ± 0.20 mSv/MBq). The effective dose was 0.77 ± 0.05 mSv/MBq. Preferential uptake within metastatic foci was observed with all cancer subtypes, TBRmax ranged from 1.95 to 15.36 and TBRmean ranged from 1.63 to 6.63. Robust sensitive imaging of lesions was enhanced by delayed timing (2–6 days after single injection of [124I]I-NM404, respectively) due to persistent tumor retention coupled with progressive washout of background activity. NM404 uptake was evident in pulmonary, nodal, skeletal, CNS, and other metastatic sites of disease. Radiation related injury or necrosis were NM404 negative, whereas certain small number of metastatic brain lesions were false negative for NM404. Conclusions: In addition to being well tolerated, selective tumor uptake of NM404 with prolonged retention was demonstrated within a broad spectrum of highly treated metastatic cancers

Phospholipid ether analogs for the detection of colorectal tumors.

The treatment of localized colorectal cancer (CRC) depends on resection of the primary tumor with adequate margins and sufficient lymph node sampling. A novel imaging agent that accumulates in CRCs and the associated lymph nodes is needed. Cellectar Biosciences has developed a phospholipid ether analog platform that is both diagnostic and therapeutic. CLR1502 is a near-infrared fluorescent molecule, whereas 124/131I-CLR1404 is under clinical investigation as a PET tracer/therapeutic agent imaged by SPECT. We investigated the use of CLR1502 for the detection of intestinal cancers in a murine model and 131I-CLR1404 in a patient with metastatic CRC. Mice that develop multiple intestinal tumors ranging from adenomas to locally advanced adenocarcinomas were utilized. After 96 hours post CLR1502 injection, the intestinal tumors were analyzed using a Spectrum IVIS (Perkin Elmer) and a Fluobeam (Fluoptics). The intensity of the fluorescent signal was correlated with the histological characteristics for each tumor. Colon adenocarcinomas demonstrated increased accumulation of CLR1502 compared to non-invasive lesions (total radiant efficiency: 1.76×10(10) vs 3.27×10(9) respectively, p = 0.006). Metastatic mesenteric tumors and uninvolved lymph nodes were detected with CLR1502. In addition, SPECT imaging with 131I-CLR1404 was performed as part of a clinical trial in patients with advanced solid tumors. 131I-CLR1404 was shown to accumulate in metastatic tumors in a patient with colorectal adenocarcinoma. Together, these compounds might enhance our ability to properly resect CRCs through better localization of the primary tumor and improved lymph node identification as well as detect distant disease

A Phase 1 Study of ¹³¹I-CLR1404 in Patients with Relapsed or Refractory Advanced Solid Tumors: Dosimetry, Biodistribution, Pharmacokinetics, and Safety

<div><p>Introduction</p><p>¹³¹I-CLR1404 is a small molecule that combines a tumor-targeting moiety with a therapeutic radioisotope. The primary aim of this phase 1 study was to determine the administered radioactivity expected to deliver 400 mSv to the bone marrow. The secondary aims were to determine the pharmacokinetic (PK) and safety profiles of ¹³¹I-CLR1404.</p><p>Methods</p><p>Eight subjects with refractory or relapsed advanced solid tumors were treated with a single injection of 370 MBq of ¹³¹I-CLR1404. Whole body planar nuclear medicine scans were performed at 15–35 minutes, 4–6, 18–24, 48, 72, 144 hours, and 14 days post injection. Optional single photon emission computed tomography imaging was performed on two patients 6 days post injection. Clinical laboratory parameters were evaluated in blood and urine. Plasma PK was evaluated on ¹²⁷I-CLR1404 mass measurements. To evaluate renal clearance of ¹³¹I-CLR1404, urine was collected for 14 days post injection. Absorbed dose estimates for target organs were determined using the RADAR method with OLINDA/EXM software.</p><p>Results</p><p>Single administrations of 370 MBq of ¹³¹I-CLR1404 were well tolerated by all subjects. No severe adverse events were reported and no adverse event was dose-limiting. Plasma ¹²⁷I-CLR1404 concentrations declined in a bi-exponential manner with a mean t_½ value of 822 hours. Mean Cmax and AUC(0-t) values were 72.2 ng/mL and 15753 ng•hr/mL, respectively. An administered activity of approximately 740 MBq is predicted to deliver 400 mSv to marrow.</p><p>Conclusions</p><p>Preliminary data suggest that ¹³¹I-CLR1404 is well tolerated and may have unique potential as an anti-cancer agent.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="http://clinicaltrials.gov/ct2/show/NCT00925275?term=CLR1404&rank=1" target="_blank">NCT00925275</a></p></div

Renal clearance of ¹³¹I-CLR1404.

<p>The cumulative fraction of ¹³¹I-CLR1404 within the urine is shown following a single dose injection of 370 MBq of ¹³¹I-CLR1404. The top graph shows each subject individually while the bottom graph shows the average of the group with the standard deviation represented with error bars. These data are used as input into OLINDA/EXM for dosimetry calculations.</p

Plasma pharmacokinetics of ¹²⁷I-CLR1404.

<p>The remaining fraction of ¹²⁷I-CLR1404 within the plasma is plotted over time. The top graph shows each individual subject while the bottom graph shows the average of the group with the standard deviation represented with error bars.</p