Publications by authors named "Steven M Larson"

270 Publications

Optimizing reconstruction parameters for quantitative I-PET in the presence of therapeutic doses of I.

EJNMMI Phys 2021 Jul 12;8(1):50. Epub 2021 Jul 12.

Department of Medical Physics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.

Background: The goal of this work was to determine the quantitative accuracy and optimal reconstruction parameters for I-PET imaging in the presence of therapeutic levels of I. In this effort, images were acquired on a GE D710 PET/CT scanner using a NEMA IEC phantom with spheres containing I and increasing amounts of I activity in the background. At each activity level, two scans were acquired, one with the phantom centered in the field of view (FOV) and one 11.2 cm off-center. Reconstructions used an ordered subset expectation maximization algorithm with up to 100 iterations of 16 subsets, with and without time-of-flight (TOF) information. Results were evaluated visually and by comparing the I activity relative to the scan performed in the absence of I.

Results: I within the FOV added to the randoms rate, to dead time, and to pile-up within the detectors. Using our standard clinical reconstruction parameters, the image quality and quantitative accuracy suffered at I activities above 1.4 GBq. Convergence rates slowed progressively in the presence of increasing amounts of I for both TOF and nonTOF reconstructions. TOF reconstructions converged more quickly than nonTOF but often towards erroneous concentrations. Iterating nonTOF reconstructions to convergence produced quantitatively accurate images except for the off-center phantom at the very highest level of background I tested.

Conclusions: This study shows that quantitative PET is feasible in the presence of large amounts of I. The high randoms fractions resulted in slow reconstruction convergence and negatively impacted TOF corrections and/or the accuracy of TOF information. Therefore, increased iterations and nonTOF reconstructions are recommended.
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http://dx.doi.org/10.1186/s40658-021-00398-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273044PMC
July 2021

Engineered Cells as a Test Platform for Radiohaptens in Pretargeted Imaging and Radioimmunotherapy Applications.

Bioconjug Chem 2021 04 5;32(4):649-654. Epub 2021 Apr 5.

Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, United States.

Pretargeted imaging and radioimmunotherapy approaches are designed to have superior targeting properties over directly targeted antibodies but impose more complex pharmacology, which hinders efforts to optimize the ligands prior to human applications. Human embryonic kidney 293T cells expressing the humanized single-chain variable fragment (scFv) C825 (huC825) with high-affinity for DOTA-haptens (293T-huC825) in a transmembrane-anchored format eliminated the requirement to use other pretargeting reagents and provided a simplified, accelerated assay of radiohapten capture while offering normalized cell surface expression of the molecular target of interest. Using binding assays, biodistribution, and imaging, we demonstrated that radiohaptens based on benzyl-DOTA and a second generation "Proteus" DOTA-platform effectively and specifically engaged membrane-bound huC825, achieving favorable tumor-to-normal tissue uptake ratios in mice. Furthermore, [Y]Y-DOTA-Bn predicted absorbed dose to critical organs with reasonable accuracy for both [Lu]Lu-DOTA-Bn and [Ac]Ac-Pr, which highlights the benefit of a dosimetry-based treatment approach.
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http://dx.doi.org/10.1021/acs.bioconjchem.0c00595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284561PMC
April 2021

A simple strategy to reduce the salivary gland and kidney uptake of PSMA-targeting small molecule radiopharmaceuticals.

Eur J Nucl Med Mol Imaging 2021 07 25;48(8):2642-2651. Epub 2021 Jan 25.

Department of Radiology, Memorial Sloan Kettering Cancer Center, MSKCC Zuckerman Building, 417 E 68th St, New York, NY, 10065, USA.

Purpose: Peptide-based prostate-specific membrane antigen (PSMA) targeted radionuclide therapy (TRT) agent [Lu]-PSMA-617 has emerged as leading TRT candidate for treatment of castration-resistant prostate cancer (mCRPC). [Lu]-PSMA-617 and other small molecule-based PSMA ligands have shown efficacy in reducing the tumor burden in mCRPC patients but irradiation to the salivary gland and kidneys is a concern and dose-limiting factor. Therefore, methods to reduce non-target organ toxicity are needed to safely treat patients and preserve their quality of life. Herein, we report that addition of cold PSMA ligand PSMA-11 can aid in reducing the uptake of [Lu]-PSMA-617 in the salivary glands and kidneys.

Methods: Groups of athymic nude mice (n = 4) bearing PC3-PIP (PSMA+) tumor xenografts were administered with [Lu]-PSMA-617 along with 0, 5, 100, 500, 1000, and 2000 pmoles of PSMA-11 and biodistribution studies were performed at 1 h.

Results: Biodistribution studies at 1 h post-administration revealed that [Lu]-PSMA-617 uptake in PC3-PIP tumors was 21.71 ± 6.13, 18.7 ± 2.03, 26.44 ± 2.94, 16.21 ± 3.5, 13.52 ± 3.68, and 12.03 ± 1.96 %ID/g when 0, 5, 100, 500, 1000, and 2000 pmoles of PSMA-11 were added, respectively. Corresponding uptake values in kidney were 123.14 ± 52.52, 132.31 ± 47.4, 84.29 ± 78.25, 2.12 ± 1.88, 1.16 ± 0.36, and 0.64 ± 0.23 %ID/g, respectively. Corresponding salivary gland uptake values were 0.48 ± 0.11, 0.45 ± 0.15, 0.38 ± 0.3, 0.08 ± 0.03, 0.09 ± 0.07, and 0.05 ± 0.02 % ID/g, respectively.

Conclusion: The uptake of [Lu]-PSMA-617 in the salivary gland and kidney can be substantially reduced without significantly impacting tumor uptake by adding cold PSMA-11.
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http://dx.doi.org/10.1007/s00259-020-05150-wDOI Listing
July 2021

PSA-Targeted Alpha-, Beta-, and Positron-Emitting Immunotheranostics in Murine Prostate Cancer Models and Nonhuman Primates.

Clin Cancer Res 2021 Apr 13;27(7):2050-2060. Epub 2021 Jan 13.

Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, California.

Purpose: Most patients with prostate cancer treated with androgen receptor (AR) signaling inhibitors develop therapeutic resistance due to restoration of AR functionality. Thus, there is a critical need for novel treatment approaches. Here we investigate the theranostic potential of hu5A10, a humanized mAb specifically targeting free PSA ().

Experimental Design: LNCaP-AR (LNCaP with overexpression of wildtype AR) xenografts (NSG mice) and _Hi- transgenic mice were imaged with Zr- or treated with Y- or Ac-labeled hu5A10; biodistribution and subcellular localization were analyzed by gamma counting, PET, autoradiography, and microscopy. Therapeutic efficacy of [Ac]hu5A10 and [Y]hu5A10 in LNCaP-AR tumors was assessed by tumor volume measurements, time to nadir (TTN), time to progression (TTP), and survival. Pharmacokinetics of [Zr]hu5A10 in nonhuman primates (NHP) were determined using PET.

Results: Biodistribution of radiolabeled hu5A10 constructs was comparable in different mouse models. Specific tumor uptake increased over time and correlated with PSA expression. Treatment with [Y]/[Ac]hu5A10 effectively reduced tumor burden and prolonged survival ( ≤ 0.0054). Effects of [Y]hu5A10 were more immediate than [Ac]hu5A10 (TTN, < 0.0001) but less sustained (TTP, < 0.0001). Complete responses were observed in 7 of 18 [Ac]hu5A10 and 1 of 9 mice [Y]hu5A10. Pharmacokinetics of [Zr]hu5A10 were consistent between NHPs and comparable with those in mice. [Zr]hu5A10-PET visualized the NHP-prostate over the 2-week observation period.

Conclusions: We present a complete preclinical evaluation of radiolabeled hu5A10 in mouse prostate cancer models and NHPs, and establish hu5A10 as a new theranostic agent that allows highly specific and effective downstream targeting of AR in PSA-expressing tissue. Our data support the clinical translation of radiolabeled hu5A10 for treating prostate cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278668PMC
April 2021

Gallagher's Principle of Metabolic Trapping.

Authors:
Steven M Larson

J Nucl Med 2020 12;61(Suppl 2):74S-76S

Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, and Molecular Pharmacology Program, Sloan Kettering Institute, New York, New York

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http://dx.doi.org/10.2967/jnumed.120.251942DOI Listing
December 2020

Alpha radioimmunotherapy using Ac-proteus-DOTA for solid tumors - safety at curative doses.

Theranostics 2020 14;10(25):11359-11375. Epub 2020 Sep 14.

Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY.

This is the initial report of an α-based pre-targeted radioimmunotherapy (PRIT) using Ac and its theranostic pair, In. We call our novel tumor-targeting DOTA-hapten PRIT system "proteus-DOTA" or "Pr." Herein we report the first results of radiochemistry development, radiopharmacology, and stoichiometry of tumor antigen binding, including the role of specific activity, anti-tumor efficacy, and normal tissue toxicity with the Pr-PRIT approach (as α-DOTA-PRIT). A series of α-DOTA-PRIT therapy studies were performed in three solid human cancer xenograft models of colorectal cancer (GPA33), breast cancer (HER2), and neuroblastoma (GD2), including evaluation of chronic toxicity at ~20 weeks of select survivors. Preliminary biodistribution experiments in SW1222 tumor-bearing mice revealed that Ac could not be efficiently pretargeted with current DOTA-Bn hapten utilized for Lu or Y, leading to poor tumor uptake . Therefore, we synthesized Pr consisting of an empty DOTA-chelate for Ac, tethered via a short polyethylene glycol linker to a lutetium-complexed DOTA for picomolar anti-DOTA chelate single-chain variable fragment (scFv) binding. Pr was radiolabeled with Ac and its imaging surrogate, In. studies verified anti-DOTA scFv recognition of [Ac]Pr, and biodistribution and clearance studies were performed to evaluate hapten suitability and targeting efficiency. Intravenously (i.v.) administered Ac- or In-radiolabeled Pr in mice showed rapid renal clearance and minimal normal tissue retention. pretargeting studies show high tumor accumulation of Pr (16.71 ± 5.11 %IA/g or 13.19 ± 3.88 %IA/g at 24 h p.i. for [Ac]Pr and [In]Pr, respectively) and relatively low uptake in normal tissues (all average ≤ 1.4 %IA/g at 24 h p.i.). Maximum tolerated dose (MTD) was not reached for either [Ac]Pr alone or pretargeted [Ac]Pr at administered activities up to 296 kBq/mouse. Single-cycle treatment consisting of α-DOTA-PRIT with either huA33-C825 bispecific anti-tumor/anti-DOTA-hapten antibody (BsAb), anti-HER2-C825 BsAb, or hu3F8-C825 BsAb for targeting GPA33, HER2, or GD2, respectively, was highly effective. In the GPA33 model, no complete responses (CRs) were observed but prolonged overall survival of treated animals was 42 d for α-DOTA-PRIT vs. 25 d for [Ac]Pr only ( < 0.0001); for GD2, CRs (7/7, 100%) and histologic cures (4/7, 57%); and for HER2, CRs (7/19, 37%) and histologic cures (10/19, 56%) with no acute or chronic toxicity. [Ac]Pr and its imaging biomarker [In]Pr demonstrate optimal radiopharmacologic behavior for theranostic applications of α-DOTA-PRIT. For this initial evaluation of efficacy and toxicity, single-cycle treatment regimens were performed in all three systems. Histologic toxicity was not observed, so MTD was not observed. Prolonged overall survival, CRs, and histologic cures were observed in treated animals. In comparison to RIT with anti-tumor IgG antibodies, [Ac]Pr has a much improved safety profile. Ultimately, these data will be used to guide clinical development of toxicity and efficacy studies of [Ac]Pr, with the goal of delivering massive lethal doses of radiation to achieve a high probability of cure without toxicity.
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http://dx.doi.org/10.7150/thno.48810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546012PMC
June 2021

IntraOmmaya compartmental radioimmunotherapy using I-omburtamab-pharmacokinetic modeling to optimize therapeutic index.

Eur J Nucl Med Mol Imaging 2021 04 13;48(4):1166-1177. Epub 2020 Oct 13.

Department of Pediatrics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.

Purpose: Radioimmunotherapy (RIT) delivered through the cerebrospinal fluid (CSF) has been shown to be a safe and promising treatment for leptomeningeal metastases. Pharmacokinetic models for intraOmmaya antiGD2 monoclonal antibody I-3F8 have been proposed to improve therapeutic effect while minimizing radiation toxicity. In this study, we now apply pharmacokinetic modeling to intraOmmaya I-omburtamab (8H9), an antiB7-H3 antibody which has shown promise in RIT of leptomeningeal metastases.

Methods: Serial CSF samples were collected and radioassayed from 61 patients undergoing a total of 177 intraOmmaya administrations of I-omburtamab for leptomeningeal malignancy. A two-compartment pharmacokinetic model with 12 differential equations was constructed and fitted to the radioactivity measurements of CSF samples collected from patients. The model was used to improve anti-tumor dose while reducing off-target toxicity. Mathematical endpoints were (a) the area under the concentration curve (AUC) of the tumor-bound antibody, AUC [C(t)], (b) the AUC of the unbound "harmful" antibody, AUC [C(t)], and (c) the therapeutic index, AUC [C(t)] ÷ AUC [C(t)].

Results: The model fit CSF radioactivity data well (mean R = 96.4%). The median immunoreactivity of I-omburtamab matched literature values at 69.1%. Off-target toxicity (AUC [C(t)]) was predicted to increase more quickly than AUC [C(t)] as a function of I-omburtamab dose, but the balance of therapeutic index and AUC [C(t)] remained favorable over a broad range of administered doses (0.48-1.40 mg or 881-2592 MBq). While antitumor dose and therapeutic index increased with antigen density, the optimal administered dose did not. Dose fractionization into two separate injections increased therapeutic index by 38%, and splitting into 5 injections by 82%. Increasing antibody immunoreactivity to 100% only increased therapeutic index by 17.5%.

Conclusion: The 2-compartmental pharmacokinetic model when applied to intraOmmaya I-omburtamab yielded both intuitive and nonintuitive therapeutic predictions. The potential advantage of further dose fractionization warrants clinical validation.

Clinical Trial Registration: ClinicalTrials.gov , NCT00089245.
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http://dx.doi.org/10.1007/s00259-020-05050-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279045PMC
April 2021

CAR Chase: Where Do Engineered Cells Go in Humans?

Front Oncol 2020 11;10:577773. Epub 2020 Sep 11.

Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, United States.

Chimeric antigen receptor (CAR) - and T-cell receptor (TCR) - modified T-cells are rapidly emerging as a viable treatment option for cancer patients. While initial clinical trials for these CAR T cells showed response rates of over 90% in some cases, retrospective studies have revealed a wide variability in patient responses as well as a significant proportion of patients relapsing after an initial response. In addition, patients often have severe adverse reactions to this therapy (e.g., cytokine release and neurologic syndromes). As a result, much research is still needed to be able to predict both therapeutic outcomes and possible toxicities. Furthermore, little success has been seen in treating solid tumors with engineered T cells and uncovering modes of failure is a topic of much research. Finally, little is known about the T cells' pharmacokinetics after infusion into the patient, as standard methods of tracking the cells analyze peripheral blood and tumor biopsies - both of which lack spatiotemporal information. Herein, we propose that reporter gene-based imaging of engineered T cells in humans would be tremendously valuable in elucidating the fate of the transplanted T cells and would greatly facilitate clinical translation of new CAR and TCR technologies. Currently, there are no FDA-approved reporter genes and few methods have advanced to human studies. Herein, we outline current reporter gene approaches to track engineered cells , analyze why current reporter genes have not progressed into the clinic, and propose "rules" for designing a widely applicable reporter gene for use in humans.
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http://dx.doi.org/10.3389/fonc.2020.577773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518311PMC
September 2020

Dickkopf-1 Can Lead to Immune Evasion in Metastatic Castration-Resistant Prostate Cancer.

JCO Precis Oncol 2020 29;4. Epub 2020 Sep 29.

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: Metastatic castration-resistant prostate cancer (mCRPC) with low androgen receptor (AR) and without neuroendocrine signaling, termed double-negative prostate cancer (DNPC), is increasingly prevalent in patients treated with AR signaling inhibitors and is in need of new biomarkers and therapeutic targets.

Methods: Candidate genes enriched in DNPC were determined using differential gene expression analysis of discovery and validation cohorts of mCRPC biopsies. Laboratory studies were carried out in human mCRPC organoid cultures, prostate cancer (PCa) cell lines, and mouse xenograft models. Epigenetic studies were carried out in a rapid autopsy cohort.

Results: Dickkopf-1 (DKK1) expression is increased in DNPC relative to prostate-specific antigen (PSA)-expressing mCRPC in the Stand Up to Cancer/Prostate Cancer Foundation discovery cohort (11.2 0.28 reads per kilobase per million mapped reads; < 0.05; n = 117) and in the University of Washington/Fred Hutchinson Cancer Research Center cohort (9.2 0.99 fragments per kilobase of transcript per million mapped reads; < .0001). DKK1 expression can be regulated by activated Wnt signaling in vitro and correlates with activating canonical Wnt signaling mutations and low PSA mRNA in mCRPC biopsies ( < .05). hypomethylation was associated with increased DKK1 mRNA expression (Pearson = -0.66; < .0001) in a rapid autopsy cohort (n = 7). DKK1-high mCRPC biopsies are infiltrated with significantly higher numbers of quiescent natural killer (NK) cells ( < .005) and lower numbers of activated NK cells ( < .0005). Growth inhibition of the human PCa model PC3 by the anti-DKK1 monoclonal antibody DKN-01 depends on the presence of NK cells in a severe combined immunodeficient xenograft mouse model.

Conclusion: These results support DKK1 as a contributor to the immunosuppressive tumor microenvironment of DNPC. These data have provided the rationale for a clinical trial targeting DKK1 in mCRPC (ClinicalTrials.gov identifier: NCT03837353).
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http://dx.doi.org/10.1200/PO.20.00097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529521PMC
September 2020

A Self-Assembling and Disassembling (SADA) Bispecific Antibody (BsAb) Platform for Curative Two-step Pretargeted Radioimmunotherapy.

Clin Cancer Res 2021 01 21;27(2):532-541. Epub 2020 Sep 21.

Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: Many cancer treatments suffer from dose-limiting toxicities to vital organs due to poor therapeutic indices. To overcome these challenges we developed a novel multimerization platform that rapidly removes tumor-targeting proteins from the blood to substantially improve therapeutic index.

Experimental Design: The platform was designed as a fusion of a self-assembling and disassembling (SADA) domain to a tandem single-chain bispecific antibody (BsAb, anti-ganglioside GD2 × anti-DOTA). SADA-BsAbs were assessed with multiple tumor models using two-step pretargeted radioimmunotherapy (PRIT) to evaluate tumor uptake, dosimetry, and antitumor responses.

Results: SADA-BsAbs self-assembled into stable tetramers (220 kDa), but could also disassemble into dimers or monomers (55 kDa) that rapidly cleared via renal filtration and substantially reduced immunogenicity in mice. When used with rapidly clearing DOTA-caged PET isotopes, SADA-BsAbs demonstrated accurate tumor localization, dosimetry, and improved imaging contrast by PET/CT. When combined with therapeutic isotopes, two-step SADA-PRIT safely delivered massive doses of alpha-emitting (Ac, 1.48 MBq/kg) or beta-emitting (Lu, 6,660 MBq/kg) S-2-(4-aminobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (DOTA) payloads to tumors, ablating them without any short-term or long-term toxicities to the bone marrow, kidneys, or liver.

Conclusions: The SADA-BsAb platform safely delivered large doses of radioisotopes to tumors and demonstrated no toxicities to the bone marrow, kidneys, or liver. Because of its modularity, SADA-BsAbs can be easily adapted to most tumor antigens, tumor types, or drug delivery approaches to improve therapeutic index and maximize the delivered dose..
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855367PMC
January 2021

Meeting report from the Prostate Cancer Foundation PSMA theranostics state of the science meeting.

Prostate 2020 11 31;80(15):1273-1296. Epub 2020 Aug 31.

Science Department, Prostate Cancer Foundation, Santa Monica, California.

Introduction: The Prostate Cancer Foundation (PCF) convened a PCF prostate-specific membrane antigen (PSMA) Theranostics State of the Science Meeting on 18 November 2019, at Weill Cornell Medicine, New York, NY.

Methods: The meeting was attended by 22 basic, translational, and clinical researchers from around the globe, with expertise in PSMA biology, development and use of PSMA theranostics agents, and clinical trials. The goal of this meeting was to discuss the current state of knowledge, the most important biological and clinical questions, and critical next steps for the clinical development of PSMA positron emission tomography (PET) imaging agents and PSMA-targeted radionuclide agents for patients with prostate cancer.

Results: Several major topic areas were discussed including the biology of PSMA, the role of PSMA-targeted PET imaging in prostate cancer, the physics and performance of different PSMA-targeted PET imaging agents, the current state of clinical development of PSMA-targeted radionuclide therapy (RNT) agents, the role of dosimetry in PSMA RNT treatment planning, barriers and challenges in PSMA RNT clinical development, optimization of patient selection for PSMA RNT trials, and promising combination treatment approaches with PSMA RNT.

Discussion: This article summarizes the presentations from the meeting for the purpose of globally disseminating this knowledge to advance the use of PSMA-targeted theranostic agents for imaging and treatment of patients with prostate cancer.
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http://dx.doi.org/10.1002/pros.24056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442561PMC
November 2020

γ-Tocotrienol-Loaded Liposomes for Radioprotection from Hematopoietic Side Effects Caused by Radiotherapeutic Drugs.

J Nucl Med 2021 04 21;62(4):584-590. Epub 2020 Aug 21.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York

With the successful development and increased use of targeted radionuclide therapy for treating cancer comes the increased risk of radiation injury to bone marrow-both direct suppression and stochastic effects, leading to neoplasia. Herein, we report a novel radioprotector drug, a liposomal formulation of γ-tocotrienol (GT3), or GT3-Nano for short, to mitigate bone marrow radiation damage during targeted radionuclide therapy. GT3 was loaded into liposomes using passive loading. Cu-GT3-Nano and H-GT3-Nano were synthesized to study the in vivo biodistribution profile of the liposome and GT3 individually. The radioprotection efficacy of GT3-Nano was assessed after acute Cs whole-body irradiation at a sublethal (4 Gy), a lethal (9 Gy), or a single high-dose administration of Sm-ethylenediamine--tetrakis(methylene phosphonic acid) (EDTMP). Flow cytometry and fluorescence microscopy were used to analyze hematopoietic cell population dynamics and the cellular site of GT3-Nano localization in the spleen and bone marrow, respectively. Bone marrow uptake and retention (percentage injected dose per gram of tissue) at 24 h was 6.98 ± 2.34 for Cu-GT3-Nano and 7.44 ± 2.52 for H-GT3-Nano. GT3-Nano administered 24 h before or after 4 Gy of total-body irradiation (TBI) promoted rapid and complete hematopoietic recovery, whereas recovery of controls stalled at 60%. GT3-Nano demonstrated dose-dependent radioprotection, achieving 90% survival at 50 mg/kg against lethal 9-Gy TBI. Flow cytometry of the bone marrow indicated that progenitor bone marrow cells MPP2 and CMP were upregulated in GT3-Nano-treated mice. Immunohistochemistry showed that GT3-Nano accumulates in CD105-positive sinusoid epithelial cells. GT3-Nano is highly effective in mitigating the marrow-suppressive effects of sublethal and lethal TBI in mice. GT3-Nano can facilitate rapid recovery of hematopoietic components in mice treated with the endoradiotherapeutic agent Sm-EDTMP.
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http://dx.doi.org/10.2967/jnumed.120.244681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049360PMC
April 2021

Genetic signature of prostate cancer mouse models resistant to optimized hK2 targeted α-particle therapy.

Proc Natl Acad Sci U S A 2020 06 12;117(26):15172-15181. Epub 2020 Jun 12.

Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095;

Hu11B6 is a monoclonal antibody that internalizes in cells expressing androgen receptor (AR)-regulated prostate-specific enzyme human kallikrein-related peptidase 2 (hK2; ). In multiple rodent models, Actinium-225-labeled hu11B6-IgG ([Ac]hu11B6-IgG) has shown promising treatment efficacy. In the present study, we investigated options to enhance and optimize [Ac]hu11B6 treatment. First, we evaluated the possibility of exploiting IgG, the IgG subclass with superior activation of complement and ability to mediate FC-γ-receptor binding, for immunotherapeutically enhanced hK2 targeted α-radioimmunotherapy. Second, we compared the therapeutic efficacy of a single high activity vs. fractionated activity. Finally, we used RNA sequencing to analyze the genomic signatures of prostate cancer that progressed after targeted α-therapy. [Ac]hu11B6-IgG was a functionally enhanced alternative to [Ac]hu11B6-IgG but offered no improvement of therapeutic efficacy. Progression-free survival was slightly increased with a single high activity compared to fractionated activity. Tumor-free animals succumbing after treatment revealed no evidence of treatment-associated toxicity. In addition to up-regulation of canonical aggressive prostate cancer genes, such as , , , and , we also noted a significant decrease in both (prostate-specific antigen ) and (prostate-specific membrane antigen) but not in and , demonstrating efficacy of sequential [Ac]hu11B6 in a mouse model.
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http://dx.doi.org/10.1073/pnas.1918744117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334567PMC
June 2020

Wil Borchers Nelp, MD (1930-2020).

Authors:
Steven M Larson

J Nucl Med 2020 Jun;61(6):19N-20N

Memorial Sloan Kettering Cancer Center New York, NY.

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June 2020

First-in-Human Trial of Epichaperome-Targeted PET in Patients with Cancer.

Clin Cancer Res 2020 10 4;26(19):5178-5187. Epub 2020 May 4.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: I-PU-H71 is an investigational first-in-class radiologic agent specific for imaging tumor epichaperome formations. The intracellular epichaperome forms under cellular stress and is a clinically validated oncotherapeutic target. We conducted a first-in-human study of microdose I-PU-H71 for PET to study biodistribution, pharmacokinetics, metabolism, and safety; and the feasibility of epichaperome-targeted tumor imaging.

Experimental Design: Adult patients with cancer ( = 30) received I-PU-H71 tracer (201±12 MBq, <25 μg) intravenous bolus followed by PET/CT scans and blood radioassays.

Results: I-PU-H71 PET detected tumors of different cancer types (breast, lymphoma, neuroblastoma, genitourinary, gynecologic, sarcoma, and pancreas). I-PU-H71 was retained by tumors for several days while it cleared rapidly from bones, healthy soft tissues, and blood. Radiation dosimetry is favorable and patients suffered no adverse effects.

Conclusions: Our first-in-human results demonstrate the safety and feasibility of noninvasive detection of tumor epichaperomes using I-PU-H71 PET, supporting clinical development of PU-H71 and other epichaperome-targeted therapeutics.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541604PMC
October 2020

First-in-Humans Trial of Dasatinib-Derivative Tracer for Tumor Kinase-Targeted PET.

J Nucl Med 2020 11 13;61(11):1580-1587. Epub 2020 Mar 13.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York

We developed a first-of-kind dasatinib-derivative imaging agent, F-SKI-249380 ( F-SKI), and validated its use for noninvasive in vivo tyrosine kinase-targeted tumor detection in preclinical models. In this study, we assessed the feasibility of using F-SKI for PET imaging in patients with malignancies. Five patients with a prior diagnosis of breast cancer, renal cell cancer, or leukemia underwent whole-body PET/CT imaging 90 min after injection of F-SKI (mean, 241.24 ± 116.36 MBq) as part of a prospective study. In addition, patients underwent either a 30-min dynamic scan of the upper abdomen including, at least partly, cardiac left ventricle, liver, spleen, and kidney ( = 2) or three 10-min whole-body PET/CT scans ( = 3) immediately after injection and blood-based radioactivity measurements to determine the time course of tracer distribution and facilitate radiation dose estimates. A subset of 3 patients had a delayed whole-body PET/CT scan at 180 min. Biodistribution, dosimetry, and tumor uptake were quantified. Absorbed doses were calculated using OLINDA/EXM 1.0. No adverse events occurred after injection of F-SKI. In total, 27 tumor lesions were analyzed, with a median SUV of 1.4 (range, 0.7-2.3) and tumor-to-blood ratios of 1.6 (range, 0.8-2.5) at 90 min after injection. The intratumoral drug concentrations calculated for 4 reference lesions ranged from 0.03 to 0.07 nM. In all reference lesions, constant tracer accumulation was observed between 30 and 90 min after injection. A blood radioassay indicated that radiotracer clearance from blood and plasma was initially rapid (blood half-time, 1.31 ± 0.81 min; plasma, 1.07 ± 0.66 min; = 4), followed variably by either a prolonged terminal phase (blood half-time, 285 ± 148.49 min; plasma, 240 ± 84.85 min; = 2) or a small rise to a plateau ( = 2). Like dasatinib, F-SKI underwent extensive metabolism after administration, as evidenced by metabolite analysis. Radioactivity was predominantly cleared via the hepatobiliary route. The highest absorbed dose estimates (mGy/MBq) in normal tissues were to the right colon (0.167 ± 0.04) and small intestine (0.153 ± 0.03). The effective dose was 0.0258 mSv/MBq (SD, 0.0034 mSv/MBq). F-SKI demonstrated significant tumor uptake, distinct image contrast despite low injected doses, and rapid clearance from blood.
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http://dx.doi.org/10.2967/jnumed.119.234864DOI Listing
November 2020

An -Acetylgalactosamino Dendron-Clearing Agent for High-Therapeutic-Index DOTA-Hapten Pretargeted Radioimmunotherapy.

Bioconjug Chem 2020 03 10;31(3):501-506. Epub 2020 Feb 10.

Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, United States.

Clearing agents (CAs) can rapidly remove nonlocalized targeting biomolecules from circulation for hepatic catabolism, thereby enhancing the therapeutic index (TI), especially for blood (marrow), of the subsequently administered radioisotope in any multistep pretargeting strategy. Herein we describe the synthesis and in vivo evaluation of a fully synthetic glycodendrimer-based CA for DOTA-based pretargeted radioimmunotherapy (DOTA-PRIT). The novel dendron-CA consists of a nonradioactive yttrium-DOTA-Bn molecule attached via a linker to a glycodendron displaying 16 terminal α-thio--acetylgalactosamine (α-SGalNAc) units (CCA α-16-DOTA-Y; molecular weight: 9059 Da). Pretargeting [Lu]LuDOTA-Bn with CCA α-16-DOTA-Y to GPA33-expressing SW1222 human colorectal xenografts was highly effective, leading to absorbed doses of [Lu]LuDOTA-Bn for blood, tumor, liver, spleen, and kidneys of 11.7, 468, 9.97, 5.49, and 13.3 cGy/MBq, respectively. Tumor-to-normal tissues absorbed-dose ratios (i.e., TIs) ranged from 40 (e.g., for blood and kidney) to about 550 for stomach.
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http://dx.doi.org/10.1021/acs.bioconjchem.9b00736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212493PMC
March 2020

Paradigms for Precision Medicine in Epichaperome Cancer Therapy.

Cancer Cell 2019 11 24;36(5):559-573.e7. Epub 2019 Oct 24.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Program in Molecular Pharmacology, Sloan Kettering Institute, New York, NY 10065, USA.

Alterations in protein-protein interaction networks are at the core of malignant transformation but have yet to be translated into appropriate diagnostic tools. We make use of the kinetic selectivity properties of an imaging probe to visualize and measure the epichaperome, a pathologic protein-protein interaction network. We are able to assay and image epichaperome networks in cancer and their engagement by inhibitor in patients' tumors at single-lesion resolution in real time, and demonstrate that quantitative evaluation at the level of individual tumors can be used to optimize dose and schedule selection. We thus provide preclinical and clinical evidence in the use of this theranostic platform for precision medicine targeting of the aberrant properties of protein networks.
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http://dx.doi.org/10.1016/j.ccell.2019.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996250PMC
November 2019

Do You Want an Inspirational Career? Choose Nuclear Medicine.

Authors:
Steven M Larson

J Nucl Med 2019 09;60(Suppl 2):25S-28S

All specialties of medicine require a continuous stream of skilled trainees in order to renew and grow. Over the 75 y of its existence, the field of nuclear medicine has rejuvenated itself repeatedly by welcoming waves of diverse trainees with adventuresome spirits who recognize the promise of the tracer principle for scientific discovery, clinical diagnosis, and targeted radionuclide therapy. Most recently, the rapid development of molecular imaging for precision medicine has made the field attractive to trainees seeking to combine expertise in nuclear medicine with high-level abilities in cross-sectional imaging. Also, substantial advances in therapeutic index achieved with modern targeted radionuclide therapy, combined with quantitative PET and SPECT imaging for dosimetry, have opened up exciting opportunities for radiotheranostics, ushering in a distinct group of trainees who want to combine nuclear medicine expertise with therapy including patient management. The training programs of the future will need to directly address the special needs of these diagnosticians and therapists. A subset of these groups will likely seek additional training in clinical or research fellowships to deepen their expertise in molecular imaging or targeted therapy. This enhanced training will increase the likelihood for an impactful career, whether in research, clinical care, or both. If we are truly going to attract the best and brightest students to nuclear medicine, leaders and mentors in the field must educate themselves in both aspects of nuclear medicine so we can fully capitalize on the opportunities to improve patient care with radionuclides.
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http://dx.doi.org/10.2967/jnumed.118.220574DOI Listing
September 2019

Biodistribution and Dosimetry of Intraventricularly Administered I-Omburtamab in Patients with Metastatic Leptomeningeal Tumors.

J Nucl Med 2019 12 12;60(12):1794-1801. Epub 2019 Aug 12.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.

Radiation dose estimations are key for optimizing therapies. We studied the role of I-omburtamab (8H9) given intraventricularly in assessing the distribution and radiation doses before I-omburtamab therapy in patients with metastatic leptomeningeal disease and compared it with the estimates from cerebrospinal fluid (CSF) sampling. Patients with histologically proven malignancy and metastatic disease to the central nervous system or leptomeninges who met eligibility criteria for I-omburtamab therapy underwent immuno-PET imaging with I-8H9 followed by I-8H9 antibody therapy. Patients were imaged with approximately 74 MBq of intraventricular I-omburtamab via an Ommaya reservoir. Whole-body PET images were acquired at approximately 4, 24, and 48 h after administration and analyzed for dosimetry calculations. Peripheral blood and CSF samples were obtained at multiple time points for dosimetry estimation. Forty-two patients with complete dosimetry and therapy data were analyzed. I-omburtamab PET-based radiation dosimetry estimations revealed mean (±SD) absorbed dose to the CSF for I-8H9 of 0.62 ± 0.40 cGy/MBq, compared with 2.22 ± 2.19 cGy/MBq based on I-omburtamab CSF samples and 1.53 ± 1.37 cGy/MBq based on I-omburtamab CSF samples. The mean absorbed dose to the blood was 0.051 ± 0.11 cGy/MBq for I-omburtamab samples and 0.07 ± 0.04 cGy/MBq for I-omburtamab samples. The effective whole-body radiation dose for I-omburtamab was 0.49 ± 0.27 mSv/MBq. The mean whole-body clearance half-time was 44.98 ± 16.29 h. PET imaging with I-omburtamab antibody administered intraventricularly allows for noninvasive estimation of dose to CSF and normal organs. High CSF-to-blood absorbed-dose ratios are noted, allowing for an improved therapeutic index to leptomeningeal disease and reduced systemic doses. PET imaging-based estimates were less variable and more reliable than CSF sample-based dosimetry.
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http://dx.doi.org/10.2967/jnumed.118.219576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894373PMC
December 2019

Thyroid Cancer Bone Metastasis: Survival and Genomic Characteristics of a Large Tertiary Care Cohort.

Clin Nucl Med 2019 08;44(8):e465-e471

Department of Radiology, Weill Medical College of Cornell University, New York, NY.

Bone metastasis (BM) in differentiated thyroid cancer (DTC) is the second most common site of metastasis after lung. Bone metastases are associated with worse prognosis in DTC. In this study, we examined risk factors for overall survival in patients with BM and for the first time explore the pattern of genomic alterations in DTC BM.

Patients And Methods: A Health Insurance Portability and Accountability Act (HIPAA) compliant, institutional review board-approved retrospective evaluation of the medical record was performed for all patients treated at a single institution for thyroid cancer over a 16-year period. Seventy-four patients met inclusion criteria. Multiple prognostic factors including age, sex, genes, radioactive iodine, and radiation or kinase inhibitor therapies were analyzed. Univariate and multivariate analyses were performed.

Results: Treatment with external beam radiation was found to significantly increase survival (P = 0.03). The 5-year survival rate was 59% and median survival was 92 months. Patients who developed bone metastasis earlier tend to live longer (P = 0.06). The presence of TERT and BRAF mutations did not significantly worsen the prognosis (P = 0.10).

Conclusion: Patients with DTC can benefit from early treatment with external beam radiation therapy, especially those who develop bone metastasis within 3 years of primary TC diagnosis. Kinase inhibitor treatment tended to prolong survival but not in a statistically significant manner. Sex, age, and TERT or BRAF genetic mutations did not significantly affect the prognosis.
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http://dx.doi.org/10.1097/RLU.0000000000002626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6621602PMC
August 2019

Imaging Sigma-1 Receptor (S1R) Expression Using Iodine-124-Labeled 1-(4-Iodophenyl)-3-(2-adamantyl)guanidine ([I]IPAG).

Mol Imaging Biol 2020 04;22(2):358-366

Department of Radiology, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA.

Purpose: Sigma-1 receptors (S1Rs) are overexpressed in almost all human cancers, especially in breast cancers. 1-(4-Iodophenyl)-3-(2-adamantyl)guanidine (IPAG) is a validated high-affinity S1R antagonist. The objective of the current study is to evaluate the potential of iodine-124-labeled IPAG ([I]IPAG) to image S1R-overexpressing tumors.

Procedures: [I]IPAG was synthesized from a tributyltin precursor dissolved in ethanol using chloramine-T as oxidant. Purity was analyzed using HPLC. In vitro and in vivo studies were performed using the breast cancer cell line MCF-7. Competitive inhibition studies were performed using haloperidol and cold IPAG. Tumors were established in athymic nude mice by injecting 10 cells subcutaneously. Mice were imaged on micro-positron emission tomography (PET) at 4, 24, 48, 72, and 144 h post i.v. injection. Biodistribution studies were performed at same time points. In vivo tracer dilution studies were performed using excess of IPAG and haloperidol. The efficacy of [I]IPAG to image tumors was evaluated in LNCaP tumor-bearing mice as well.

Results: [I]IPAG was synthesized in quantitative yield and in vitro studies indicated that [I]IPAG binding was specific to S1R. PET imaging studies in MCF7 tumor-bearing mice reveal that [I]IPAG accumulates in tumor and is preferentially retained while clearing from non-target organs. The tumor to background increases with time, and tumors could be clearly visualized starting from 24 h post administration. Similar results were obtained in mice bearing LNCaP tumors. In vivo tracer dilution studies showed that the uptake of [I]IPAG could be competitively inhibited by excess of IPAG and haloperidol.

Conclusions: [I]IPAG was synthesized successfully in high yields, and in vitro and in vivo studies demonstrate specificity of [I]IPAG. [I]IPAG shows specific accumulation in tumors with increasing tumor to background ratio at later time points and therefore has high potential for imaging S1R-overexpressing cancers.
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http://dx.doi.org/10.1007/s11307-019-01369-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893110PMC
April 2020

Pharmacokinetics and Biodistribution of a [Zr]Zr-DFO-MSTP2109A Anti-STEAP1 Antibody in Metastatic Castration-Resistant Prostate Cancer Patients.

Mol Pharm 2019 07 31;16(7):3083-3090. Epub 2019 May 31.

Department of Radiology , Joan and Sanford I. Weill Cornell Medical Center , New York , New York 10065 , United States.

A six-transmembrane epithelial antigen of prostate-1 (STEAP1) is a newly identified target in prostate cancer. The use of radio-labeled STEAP1-targeting antibodies with positron emission tomography (PET) may allow for detection of sites of metastatic prostate cancer and may refine patient selection for antigen-directed therapies. This was a prospective study in seven patients with metastatic castration-resistant prostate cancer who had at least one archival biopsy that was STEAP1-positive by immunohistochemistry. Patients received intravenous injections of ∼185 MBq and 10 mg of [Zr]Zr-DFO-MSTP2109A, a humanized IgG1 monoclonal antibody directed against STEAP1. PET/CT images, blood samples, and whole-body counts were monitored longitudinally in six patients. Here, we report on safety, biodistribution, pharmacokinetics, dose estimates to normal tissues, and initial tumor targeting for this group of patients. There was no significant acute or subacute toxicity. Favorable biodistribution and enhanced lesion uptake (in both bone and soft tissue) were observed on imaging using a mass of 10 mg of DFO-MSTP2109A. The best lesion discrimination was seen at the latest imaging time, a median of 6 days postadministration. Pharmacokinetics showed a median serum T β of 198 h, volume of central compartment of 3.54 L (similar to plasma volume), and clearance of 19.7 mL/h. The median biologic T for whole-body retention was 469 h. The highest mean absorbed doses to normal organs (mGy/MBq) were 1.18, 1.11, 0.78, 0.73, and 0.71 for liver, heart wall, lung, kidney, and spleen, respectively. Excellent targeting of metastatic prostate sites in both bone and soft tissue was observed, with an optimal imaging time of 6 days postadministration. The liver and heart were the normal organs that experienced the highest absorbed doses. The pharmacokinetics were similar to other antibodies without major cross-reactivity with normal tissues. A more detailed analysis of lesion targeting in a larger patient population with correlation to immunohistology and standard imaging modalities has been reported.
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http://dx.doi.org/10.1021/acs.molpharmaceut.9b00326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176438PMC
July 2019

Thyroid Cancer Brain Metastasis: Survival and Genomic Characteristics of a Large Tertiary Care Cohort.

Clin Nucl Med 2019 Jul;44(7):544-549

Department of Medicine, Memorial Sloan Kettering Cancer Center.

Purpose: Brain metastases (BMs) in patients with differentiated thyroid cancer (DTC) are rare but associated with poor prognosis. We examined risk factors for overall survival (OS) in this population and explored the pattern of genomic alterations.

Methods: Single-institution, retrospective review of all patients with DTC from January 2000 to November 2016 identified 79 patients for analysis. Multiple prognostic factors, including age, gender, distal metastasis (DM), diagnosis time, DM sites, BM diagnosis time, BM number and size, genomic sequencing data, craniectomy, external beam radiation therapy, and kinase inhibitor therapies, were evaluated. Univariate and multivariate analyses were performed.

Results: Median survival after BM was 18 months. One- and 3-year survival rates were 63% and 33%, respectively. Univariate analysis identified 4 covariates correlated with prolonged survival: time between DTC diagnosis and BM for less than 3 years (P = 0.01), time from initial DM diagnosis to BM for 22 months or less (P = 0.03), 3 BM sites or fewer (P = 0.002), and craniectomy (P = 0.05). Multivariate model revealed 3 variables associated with OS: DTC diagnosis to BM time of less than 3 years (P = 0.04), craniectomy (P = 0.06), and patients with fewer than 3 BM sites (P = 0.06). The majority of patients with BM had a telomerase reverse transcriptase promoter mutation, However, mutational status was not an independent predictor of survival.

Conclusions: For BM from DTC, time interval between DTC diagnosis and BM, number of BM sites, and craniectomy were independently associated with OS. Further studies are needed to define the role of genomic mutations in advanced cancer.
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http://dx.doi.org/10.1097/RLU.0000000000002618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546545PMC
July 2019

Imaging Patients with Metastatic Castration-Resistant Prostate Cancer Using Zr-DFO-MSTP2109A Anti-STEAP1 Antibody.

J Nucl Med 2019 11 3;60(11):1517-1523. Epub 2019 May 3.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Six-transmembrane epithelial antigen of prostate-1 (STEAP1) is a relatively newly identified target in prostate cancer. We evaluated the ability of PET/CT with Zr-DFO-MSTP2109A, an antibody that recognizes STEAP1, to detect lesions in patients with metastatic castration-resistant prostate cancer (mCRPC). Nineteen mCRPC patients were prospectively imaged using approximately 185 MBq/10 mg of Zr-DFO-MSTP2109A. Zr-DFO-MSTP2109A PET/CT images obtained 4-7 d after injection were compared with bone and CT scans. Uptake in lesions was measured. Fifteen patients were treated with an antibody-drug conjugate (ADC) based on MSTP2109A; ADC treatment-related data were correlated with tumor uptake by PET imaging. Bone or soft-tissue biopsy samples were evaluated. No significant toxicity occurred. Excellent uptake was observed in bone and soft-tissue disease. Median SUV was 20.6 in bone and 16.8 in soft tissue. Sixteen of 17 lesions biopsied were positive on Zr-DFO-MSTP2109A, and all sites were histologically positive (1 on repeat biopsy). Bayesian analysis resulted in a best estimate of 86% of histologically positive lesions being true-positive on imaging (95% confidence interval, 75%-100%). There was no correlation between SUV tumor uptake and STEAP1 immunohistochemistry, survival after ADC treatment, number of ADC treatment cycles, or change in prostate-specific antigen level. Zr-DFO-MSTP2109A is well tolerated and shows localization in mCRPC sites in bone and soft tissue. Given the high SUV in tumor and localization of a large number of lesions, this reagent warrants further exploration as a companion diagnostic in patients undergoing STEAP1-directed therapy.
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http://dx.doi.org/10.2967/jnumed.118.222844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836860PMC
November 2019

Measuring the unmeasurable: automated bone scan index as a quantitative endpoint in prostate cancer clinical trials.

Prostate Cancer Prostatic Dis 2019 12 29;22(4):522-530. Epub 2019 Apr 29.

Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

Background: Up to 90% of men with metastatic castration-resistant prostate cancer (mCRPC) will have a distribution of disease that includes bone metastases demonstrated on a Technetium-99m (Tc-MDP) bone scan. The Prostate Cancer Working Group 2 and 3 Consensus Criteria standardized the criteria for assessing progression based on the development of new lesions. These criteria have been recognized by regulatory authorities for drug approval. The bone scan index (BSI) is a method to quantitatively measure the burden of bony disease, and can assess both disease progression and regression. The automated BSI (aBSI) is a method of computer analysis to assess BSI, and is being qualified as a clinical trials endpoint.

Methods: Manual searching was used to identify the literature on BSI and aBSI. We summarize the most relevant aspects of the retrospective and prospective studies evaluating aBSI measurements, and provide a critical discussion on the potential advantages and caveats of aBSI.

Results: The development of neural artificial networks (EXINI boneBSI) to automatically determine the BSI reduces the turnaround time for assessing BSI with high reproducibility and accuracy. Several studies showed that the concordance between aBSI and BSI, as well as the interobserver concordance of aBSI, was >0.95. In a phase 3 assessment of aBSI, a doubling value increased the risk of death in 20%, pre-treatment aBSI values independently correlated with overall survival (OS) and time to symptomatic progression. Retrospective studies suggest that a decrease in aBSI after treatment may correlate with higher survival when compared with increasing aBSI.

Conclusions: aBSI provides a quantitative measurement that is feasible, reproducible, and in analyses to date correlates with OS and symptomatic progression. These findings support the aBSI to risk-stratify men with mCRPC for clinical trial enrollment. Future studies quantifying aBSI change over time as an intermediate endpoint for evaluating new systemic therapies are needed.
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http://dx.doi.org/10.1038/s41391-019-0151-4DOI Listing
December 2019

and Amplifications Determine Response to HER2 Inhibition in -Amplified Esophagogastric Cancer.

Cancer Discov 2019 02 21;9(2):199-209. Epub 2018 Nov 21.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.

The anti-HER2 antibody trastuzumab is standard care for advanced esophagogastric (EG) cancer with (HER2) amplification or overexpression, but intrinsic and acquired resistance are common. We conducted a phase II study of afatinib, an irreversible pan-HER kinase inhibitor, in trastuzumab-resistant EG cancer. We analyzed pretreatment tumor biopsies and, in select cases, performed comprehensive characterization of postmortem metastatic specimens following acquisition of drug resistance. Afatinib response was associated with coamplification of and . Heterogeneous Zr-trastuzumab PET uptake was associated with genomic heterogeneity and mixed clinical response to afatinib. Resistance to afatinib was associated with selection for tumor cells lacking amplification or with acquisition of amplification, which could be detected in plasma cell-free DNA. The combination of afatinib and a MET inhibitor induced complete tumor regression in and coamplified patient-derived xenograft models established from a metastatic lesion progressing on afatinib. Collectively, differential intrapatient and interpatient expression of HER2, EGFR, and MET may determine clinical response to HER kinase inhibitors in -amplified EG cancer. SIGNIFICANCE: Analysis of patients with -amplified, trastuzumab-resistant EG cancer who were treated with the HER kinase inhibitor afatinib revealed that sensitivity and resistance to therapy were associated with / coamplification and amplification, respectively. HER2-directed PET imaging and cell-free DNA sequencing could help guide strategies to overcome the emergence of resistant clones...
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http://dx.doi.org/10.1158/2159-8290.CD-18-0598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368868PMC
February 2019

Theranostic pretargeted radioimmunotherapy of internalizing solid tumor antigens in human tumor xenografts in mice: Curative treatment of HER2-positive breast carcinoma.

Theranostics 2018 6;8(18):5106-5125. Epub 2018 Oct 6.

Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

In recent reports, we have shown that optimized pretargeted radioimmunotherapy (PRIT) based on molecularly engineered antibody conjugates and Lu-DOTA chelate (DOTA-PRIT) can be used to cure mice bearing human solid tumor xenografts using antitumor antibodies to minimally internalizing membrane antigens, GPA33 (colon) and GD2 (neuroblastoma). However, many solid tumor membrane antigens are internalized after antibody binding and it is generally believed that internalizing tumor membrane antigens are not suitable targets for PRIT. In this study, we tested the hypothesis that DOTA-PRIT can be performed successfully to target HER2, an internalizing membrane antigen widely expressed in breast, ovarian, and gastroesophageal junction cancers. DOTA-PRIT was carried out in athymic nude mice bearing BT-474 xenografts, a HER2-expressing human breast cancer, using a three-step dosing regimen consisting of sequential intravenous administrations of: 1) a bispecific IgG-scFv (210 kD) format (BsAb) carrying the IgG sequence of the anti-HER2 antibody trastuzumab and the scFv "C825" with high-affinity, hapten-binding antibody for Bn-DOTA (metal) (BsAb: anti-HER2-C825), 2) a 500 kD dextran-based clearing agent, followed by 3) Lu-DOTA-Bn. At the time of treatment, athymic nude mice bearing established subcutaneous BT-474 tumors (medium- and smaller-sized tumors with tumor volumes of 209 ± 101 mm and ranging from palpable to 30 mm, respectively), were studied along with controls. We studied single- and multi-dose regimens. For groups receiving fractionated treatment, we verified quantitative tumor targeting during each treatment cycle using non-invasive imaging with single-photon emission computed tomography/computed tomography (SPECT/CT). We achieved high therapeutic indices (TI, the ratio of radiation-absorbed dose in tumor to radiation-absorbed dose to critical organs, such as bone marrow) for targeting in blood (TI = 28) and kidney (TI = 7), while delivering average radiation-absorbed doses of 39.9 cGy/MBq to tumor. Based on dosimetry estimates, we implemented a curative fractionated therapeutic regimen for medium-sized tumors that would deliver approximately 70 Gy to tumors, which required treatment with a total of 167 MBq Lu-DOTA-Bn/mouse (estimated absorbed tumor dose: 66 Gy). This regimen was well tolerated and achieved 100% complete responses (CRs; defined herein as tumor volume equal to or smaller than 4.2 mm), including 62.5% histologic cure (5/8) and 37.5% microscopic residual disease (3/8) at 85 days (d). Treatment controls showed tumor progression to 207 ± 201% of pre-treatment volume at 85 d and no CRs. Finally, we show that treatment with this curative Lu regimen leads to a very low incidence of histopathologic abnormalities in critical organs such as bone marrow and kidney among survivors compared with non-treated controls. Contrary to popular belief, we demonstrate that DOTA-PRIT can be successfully adapted to an internalizing antigen-antibody system such as HER2, with sufficient TIs and absorbed tumor doses to achieve a high probability of cures of established human breast cancer xenografts while sparing critical organs of significant radiotoxicity.
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http://dx.doi.org/10.7150/thno.26585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6217068PMC
September 2019

Quantification of bone flare on F-NaF PET/CT in metastatic castration-resistant prostate cancer.

Prostate Cancer Prostatic Dis 2019 05 9;22(2):324-330. Epub 2018 Nov 9.

Department of Medical Physics, University of Wisconsin, Madison, WI, USA.

Background: Bone flare has been observed on Tc-MDP bone scans of patients with metastatic castration-resistant prostate cancer (mCRPC). This exploratory study investigates bone flare in mCRPC patients receiving androgen receptor (AR) inhibitors using F-NaF PET/CT.

Methods: Twenty-nine mCRPC patients undergoing AR-inhibiting therapy (abiraterone, orteronel, enzalutamide) received NaF PET/CT scans at baseline, week 6, and week 12 of treatment. SUV metrics were extracted globally for each patient (SUV) and for each individual lesion (iSUV). Bone flare was defined as increasing SUV metrics or lesion number at week 6 followed by subsequent week 12 decrease. Differences in metrics across timepoints were compared using Wilcoxon tests. Cox proportional hazard regression was conducted between global metrics and progression-free survival (PFS).

Results: Total SUV was most sensitive for flare detection and was identified in 14/23 (61%) patients receiving CYP17A1-inhibitors (abiraterone, orteronel), and not identified in any of six patients receiving enzalutamide. The appearance of new lesions did not account for initial increases in SUV metrics. iSUV metrics followed patient-level trends: bone flare positive patients showed a median of 72% (range: 0-100%) of lesions with total iSUV flare. Increasing mean SUV at week 6 correlated with extended PFS (HR = 0.58, p = 0.02).

Conclusion: NaF PET bone flare was present on 61% of mCRPC patients in the first 6 weeks of treatment with CYP17A1-inhibitors. Characterization provided in this study suggests favorable PFS in patients showing bone flare. This characterization of NaF flare is important for guiding treatment assessment schedules to better distinguish between patients showing bone flare and those truly progressing, and should be performed for all emerging mCRPC treatments and imaging agents.
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http://dx.doi.org/10.1038/s41391-018-0110-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490782PMC
May 2019
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