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.

We characterize the in vivo biodistribution and tumor selectivity of ⁸⁶Y-NM600, a theranostic alkylphosphocholine radiometal chelate with broad tumor selectivity, in a variety of preclinical cancer models. Methods: Mice bearing flank tumors (representative of lung, pancreatic, prostate, liver, skin, and lymphoid cancers) were injected intravenously (IV) with 9.25 MBq of ⁸⁶Y-NM600 and imaged longitudinally over 4-5 days using microPET/CT. Percent injected activity per gram (%IA/g) for each volume-of-interest (VOI) was measured at each time point for the organs of interest. Mice were euthanized after the final time point and the tumor and organs of interest were counted with an automatic gamma counter. Absorbed doses delivered by ⁹⁰Y-NM600 per injected activity (Gy/MBq) were estimated. Mice bearing B78 flank tumors were injected with a prescription of ⁹⁰Y-NM600 that delivered 2.5 Gy of absorbed tumor dose and was compared to an equivalent absorbed dose delivered via external beam radiotherapy (XRT) using tumor volume as a measure of response. Histology and complete blood counts (CBC) were analyzed in naïve C57BL/6 mice who were injected with 9.25 MBq of ⁹⁰Y-NM600 at 5, 10, and 28 days post injection (p.i.). Results: PET imaging showed consistent tumor accumulation and retention across all tumor models investigated with little off-target retention of NM600 except for in the liver, which is characteristic of hepatobiliary metabolism. The tumor uptake was highest in the pancreatic and lymphoid cancer models, reaching peak concentrations of 9.34 ± 2.66%IA/g (n = 3) and 9.10 ± 0.13 %IA/g (n = 3), respectively, at approximately 40-48 hr post injection. These corresponded to tumor dose estimates of 2.72 ± 0.33 Gy/MBq and 2.67 ± 0.32 Gy/MBq, respectively. In the toxicity study, there were no visible signs of acute toxicity by histology, and perturbation of hematological parameters was transient when observed, returning to pre-therapy levels after 28 days. Conclusion: NM600 is a theranostic agent with a unique ability to selectively target a variety of cancer types, presenting a unique opportunity for PET image guided TRT and combination with immunotherapies.

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. 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. 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. Preliminary data suggest that ¹³¹I-CLR1404 is well tolerated and may have unique potential as an anti-cancer agent. ClinicalTrials.gov NCT00925275

We have previously developed a model that provides relative dosimetry estimates for targeted radionuclide therapy (TRT) agents. The whole-body and tumor pharmacokinetic (PK) parameters of this model can be noninvasively measured with molecular imaging, providing a means of comparing potential TRT agents. Parameter sensitivities and noise will affect the accuracy and precision of the estimated PK values and hence dosimetry estimates. The aim of this work is to apply a PK model for TRT to two agents with different magnitudes of clearance rates, NM404 and FLT, explore parameter sensitivity with respect to time and investigate the effect of noise on parameter precision and accuracy. Twenty-three tumor bearing mice were injected with a 'slow-clearing' agent, (124)I-NM404 (n = 10), or a 'fast-clearing' agent, (18)F-FLT (3'-deoxy-3'-fluorothymidine) (n = 13) and imaged via micro-PET/CT pseudo-dynamically or dynamically, respectively. Regions of interest were drawn within the heart and tumor to create time-concentration curves for blood pool and tumor. PK analysis was performed to estimate the mean and standard error of the central compartment efflux-to-influx ratio (k(12)/k(21)), central elimination rate constant (k(el)), and tumor influx-to-efflux ratio (k(34)/k(43)), as well as the mean and standard deviation of the dosimetry estimates. NM404 and FLT parameter estimation results were used to analyze model accuracy and parameter sensitivity. The accuracy of the experimental sampling schedule was compared to that of an optimal sampling schedule found using Cramer-Rao lower bounds theory. Accuracy was assessed using correlation coefficient, bias and standard error of the estimate normalized to the mean (SEE/mean). The PK parameter estimation of NM404 yielded a central clearance, k(el) (0.009 ± 0.003 h(-1)), normal body retention, k(12)/k(21) (0.69 ± 0.16), tumor retention, k(34)/k(43) (1.44 ± 0.46) and predicted dosimetry, D(tumor) (3.47 ± 1.24 Gy). The PK parameter estimation of FLT yielded a central elimination rate constant, k(el) (0.050 ± 0.025 min(-1)), normal body retention, k(12)/k(21) (2.21 ± 0.62) and tumor retention, k(34)/k(43) (0.65 ± 0.17), and predicted dosimetry, D(tumor) (0.61 ± 0.20 Gy). Compared to experimental sampling, optimal sampling decreases the dosimetry bias and SEE/mean for NM404; however, it increases bias and decreases SEE/mean for FLT. For both NM404 and FLT, central compartment efflux rate constant, k(12), and central compartment influx rate constant, k(21), possess mirroring sensitivities at relatively early time points. The instantaneous concentration in the blood, C(0), was most sensitive at early time points; central elimination, k(el), and tumor efflux, k(43), are most sensitive at later time points. A PK model for TRT was applied to both a slow-clearing, NM404, and a fast-clearing, FLT, agents in a xenograft murine model. NM404 possesses more favorable PK values according to the PK TRT model. The precise and accurate measurement of k(12), k(21), k(el), k(34) and k(43) will translate into improved and precise dosimetry estimations. This work will guide the future use of this PK model for assessing the relative effectiveness of potential TRT agents.

Assessment of targeted radionuclide therapy (TRT) agent effectiveness based on its pharmacokinetic (PK) properties could provide means to expedited agent development or its rejection. A broad PK model that predicts the relative effectiveness of TRT agents based on the relationship between their normal body (k₁₂, k₂₁) and tumor (k₃₄, k₄₃) PK parameters has been developed. A classic two-compartment open model decoupled from a tumor was used to represent the body. Analytically solved differential equations were used to develop a relationship that predicts TRT effectiveness. Various PK scenarios were created by pairing normal body PK parameters of 38 pharmaceuticals found in the literature with estimated tumor PK parameters. Each PK scenario resulted in a maximum permissible injected activity that limited the whole-body dose to 2 Gy and yielded a maximum delivered tumor dose. The model suggests that a k₃₄:k₄₃ ratio greater than 5 and a k₁₂:k₂₁ ratio less than 1 is effective at delivering doses that ensure sufficient solid tumor control. It was also shown that there is no direct relationship between tumor dose and acid dissociation constant (pK_a), lipophilicity (log P), and fraction unbound (fu), which are important physicochemical properties. This study suggests that although effective TRT may be difficult to achieve for solid tumors, good TRT agents must have extremely desirable normal body PKs in conjunction with very high tumor retention. The developed PK TRT model could serve as a tool to compare the relative dosimetric effectiveness of existing TRT agents and novel TRT agents early in the developmental phase to potentially reject those that possess unfavorable PKs.

Biologically effective dose (BED) may be more of a relevant quantity than absorbed dose for establishing tumour response relationships. By taking into account the dose rate and tissue-specific parameters such as repair and radiosensitivity, it is possible to compare the relative biological effects of different targeted radionuclide therapy (TRT) agents. The aim of this work was to develop an analytical tumour BED calculation for TRT that could predict a relative biological effect based on normal body and tumour pharmacokinetics. This work represents a step in the direction of establishing relative pharmacokinetic criteria of when the BED formalism is more applicable than absorbed dose for TRT. A previously established pharmacokinetic (PK) model for TRT was used and adapted into the BED formalism. An analytical equation for the protraction factor, which incorporates dose rate and repair rate, was derived. Dose rates within the normal body and tumour were related to the slopes of their time-activity curves which were determined by the ratios of their respective PK parameters. The relationships between the tumour influx-to-efflux ratio (k(34):k(43)), central compartment efflux-to-influx ratio (k(12):k(21)), central elimination (k(el)), and tumour repair rate (μ), and tumour BED were investigated. As the k(34):k(43) ratio increases and the k(12):k(21) ratio decreases, the difference between tumour BED and D increases. In contrast, as the k(34):k(43) ratios decrease and the k(12):k(21) ratios increase, the tumour BED approaches D. At large k(34):k(43) ratios, the difference between tumour BED and D increases to a maximum as k(el) increases. At small k(34):k(43) ratios, the tumour BED approaches D at very small k(el). At small μ and small k(34):k(43) ratios, the tumour BED approaches D. For large k(34):k(43) ratios, large μ values cause tumour BED to approach D. This work represents a step in the direction of establishing relative PK criteria of when the BED formalism is more applicable than absorbed dose for TRT. It also provides a framework by which the biological effects of different TRT agents can be compared in order to predict efficacy.