PARP1-targeted alpha therapy enhances target expression.

Unlabelled: [Image: see text]

Supplementary Information: The online version contains supplementary material available at 10.1186/s13550-025-01256-0.

[F]FluorThanatrace PET imaging as a biomarker of response to PARP inhibitors in breast cancer.

Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) are approved for Breast Cancer gene (BRCA)-mutant HER2- breast cancer, and there is clinical interest in expanding indications to include homologous recombination deficient (HRD) breast cancers. Yet, response in these populations remains variable, suggesting clinical utility in developing a better biomarker to select patients for PARPi and predict response. Here, we evaluate a radiolabeled PARPi, [F]FluorThanatrace ([F]FTT), as a functional biomarker of PARPi response in breast cancer.

A biorthogonal chemistry approach for high-contrast antibody imaging of lymphoma at early time points.

Background: Monoclonal antibodies are highly specific for their targets making them effective for cancer therapy. However, their large molecular weight causes slow blood clearance, often requiring weeks to be removed from circulation. This limitation affects companion nuclear imaging and antibody-based diagnostics, necessitating delayed imaging.

MRS and Optical Imaging Studies of Therapeutic Response to Combination Therapy Targeting BRAF/MEK in Murine Melanomas.

Rationale And Objectives: Melanoma, an aggressive skin cancer, often harbors BRAFV600E mutations driving tumor progression via the mitogen-activated protein kinase (MAPK) pathway. While targeted therapies like BRAF (dabrafenib) and MEK (trametinib) inhibitors have improved outcomes, resistance linked to metabolic reprogramming remains a challenge. This study investigates metabolic changes induced by dual BRAF/MEK inhibition in a BRAFV600E-mutant murine melanoma model using magnetic resonance spectroscopy (MRS), optical redox imaging (ORI), and biochemical assays.

[F]Fluorthanatrace PET in Ovarian Cancer: Comparison with [F]FDG PET, Lesion Location, Tumor Grade, and Breast Cancer Gene Mutation Status.

Poly(adenosine diphosphate-ribose) polymerase-1 (PARP1) inhibitors have improved ovarian cancer treatment outcomes. However, clinical response remains heterogeneous. Existing biomarkers, mainly breast cancer susceptibility genes 1 and 2 (), are suboptimal.

Kinetic Analysis and Metabolism of Poly(Adenosine Diphosphate-Ribose) Polymerase-1-Targeted F-Fluorthanatrace PET in Breast Cancer.

The poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) have demonstrated efficacy in ovarian, breast, and prostate cancers, but current biomarkers do not consistently predict clinical benefit. F-fluorthanatrace (F-FTT) is an analog to rucaparib, a clinically approved PARPi, and is a candidate biomarker for PARPi response. This study intends to characterize F-FTT pharmacokinetics in breast cancer and optimize image timing for clinical trials.

Combination anti-PD-1 and anti-CTLA-4 therapy generates waves of clonal responses that include progenitor-exhausted CD8 T cells.

Combination checkpoint blockade with anti-PD-1 and anti-CTLA-4 antibodies has shown promising efficacy in melanoma. However, the underlying mechanism in humans remains unclear. Here, we perform paired single-cell RNA and T cell receptor (TCR) sequencing across time in 36 patients with stage IV melanoma treated with anti-PD-1, anti-CTLA-4, or combination therapy.

Artificial intelligence in immunotherapy PET/SPECT imaging.

Objective: Immunotherapy has dramatically altered the therapeutic landscape for oncology, but more research is needed to identify patients who are likely to achieve durable clinical benefit and those who may develop unacceptable side effects. We investigated the role of artificial intelligence in PET/SPECT-guided approaches for immunotherapy-treated patients.

Methods: We performed a scoping review of MEDLINE, CENTRAL, and Embase databases using key terms related to immunotherapy, PET/SPECT imaging, and AI/radiomics through October 12, 2022.

FDG PET/CT Imaging 1 Week after a Single Dose of Pembrolizumab Predicts Treatment Response in Patients with Advanced Melanoma.

Purpose: Immunologic response to anti-programmed cell death protein 1 (PD-1) therapy can occur rapidly with T-cell responses detectable in as little as one week. Given that activated immune cells are FDG avid, we hypothesized that an early FDG PET/CT obtained approximately 1 week after starting pembrolizumab could be used to visualize a metabolic flare (MF), with increased tumor FDG activity due to infiltration by activated immune cells, or a metabolic response (MR), due to tumor cell death, that would predict response.

Patients And Methods: Nineteen patients with advanced melanoma scheduled to receive pembrolizumab were prospectively enrolled.

68 Ga-DOTATATE PET to Characterize Lesions in the Neuroaxis.

Aim: The differentiation of paragangliomas, schwannomas, meningiomas, and other neuroaxis tumors in the head and neck remains difficult when conventional MRI is inconclusive. This study assesses the utility of 68 Ga-DOTATATE PET/CT as an adjunct to hone the diagnosis.

Patients And Methods: This retrospective study considered 70 neuroaxis lesions in 52 patients with 68 Ga-DOTATATE PET/CT examinations; 22 lesions (31%) had pathologic confirmation.

Harnessing imaging tools to guide immunotherapy trials: summary from the National Cancer Institute Cancer Imaging Steering Committee workshop.

As the immuno-oncology field continues the rapid growth witnessed over the past decade, optimising patient outcomes requires an evolution in the current response-assessment guidelines for phase 2 and 3 immunotherapy clinical trials and clinical care. Additionally, investigational tools-including image analysis of standard-of-care scans (such as CT, magnetic resonance, and PET) with analytics, such as radiomics, functional magnetic resonance agents, and novel molecular-imaging PET agents-offer promising advancements for assessment of immunotherapy. To document current challenges and opportunities and identify next steps in immunotherapy diagnostic imaging, the National Cancer Institute Clinical Imaging Steering Committee convened a meeting with diverse representation among imaging experts and oncologists to generate a comprehensive review of the state of the field.

Monitoring Therapeutic Response to Anti-FAP CAR T Cells Using [18F]AlF-FAPI-74.

Purpose: Despite the success of chimeric antigen receptor (CAR) T-cell therapy against hematologic malignancies, successful targeting of solid tumors with CAR T cells has been limited by a lack of durable responses and reports of toxicities. Our understanding of the limited therapeutic efficacy in solid tumors could be improved with quantitative tools that allow characterization of CAR T-targeted antigens in tumors and accurate monitoring of response.

Experimental Design: We used a radiolabeled FAP inhibitor (FAPI) [18F]AlF-FAPI-74 probe to complement ongoing efforts to develop and optimize FAP CAR T cells.

Using CD69 PET Imaging to Monitor Immunotherapy-Induced Immune Activation.

Immune checkpoint inhibitors (ICI) have been effective in treating a subset of refractory solid tumors, but only a small percentage of treated patients benefit from these therapies. Thus, there is a clinical need for reliable tools that allow for the early assessment of response to ICIs, as well as a preclinical need for imaging tools that aid in the future development and understanding of immunotherapies. Here we demonstrate that CD69, a canonical early-activation marker expressed on a variety of activated immune cells, including cytotoxic T cells and natural killer (NK) cells, is a promising biomarker for the early assessment of response to immunotherapies.

PSMA-targeting TGFβ-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: a phase 1 trial.

Chimeric antigen receptor (CAR) T cells have demonstrated promising efficacy, particularly in hematologic malignancies. One challenge regarding CAR T cells in solid tumors is the immunosuppressive tumor microenvironment (TME), characterized by high levels of multiple inhibitory factors, including transforming growth factor (TGF)-β. We report results from an in-human phase 1 trial of castration-resistant, prostate cancer-directed CAR T cells armored with a dominant-negative TGF-β receptor (NCT03089203).

CD8-Targeted PET Imaging of Tumor-Infiltrating T Cells in Patients with Cancer: A Phase I First-in-Humans Study of Zr-Df-IAB22M2C, a Radiolabeled Anti-CD8 Minibody.

There is a need for in vivo diagnostic imaging probes that can noninvasively measure tumor-infiltrating CD8+ leukocytes. Such imaging probes could be used to predict early response to cancer immunotherapy, help select effective single or combination immunotherapies, and facilitate the development of new immunotherapies or immunotherapy combinations. This study was designed to optimize conditions for performing CD8 PET imaging with Zr-Df-IAB22M2C and determine whether CD8 PET imaging could provide a safe and effective noninvasive method of visualizing the whole-body biodistribution of CD8+ leukocytes.

Immune PET Imaging.

Fluorodeoxyglucose (FDG) PET/CT is sensitive to metabolic, immune-related, and structural changes that can occur in tumors in cancer immunotherapy. Unique mechanisms of immune checkpoint inhibitors (ICIs) occasionally make response evaluation challenging, because tumors and inflammatory changes are both FDG avid. These response patterns and sequelae of ICI immunotherapy, such as immune-related adverse events, are discussed.

F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Following Chimeric Antigen Receptor T-cell Therapy in Large B-cell Lymphoma.

Purpose: F-Fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) is a well-established imaging modality to assess responses in patients with B-cell neoplasms. However, there is limited information about the utility of FDG PET/CT after chimeric antigen receptor T-cell (CART) therapies for large B-cell lymphomas. In this retrospective analysis, we aimed to evaluate how FDG PET/CT performs in patients receiving commercially available anti-CD19 CART therapies for relapsed/refractory (r/r) large B-cell lymphomas.

In vivo visualization of PARP inhibitor pharmacodynamics.

BACKGROUND[18F]FluorThanatrace ([18F]FTT) is a radiolabeled poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi) that enables noninvasive quantification of PARP with potential to serve as a biomarker for patient selection for PARPi therapy. Here we report for the first time to our knowledge noninvasive in vivo visualization of drug-target engagement during PARPi treatment.METHODSTwo single-arm, prospective, nonrandomized clinical trials were conducted at the University of Pennsylvania from May 2017 to March 2020.

Kinetic and Static Analysis of Poly-(Adenosine Diphosphate-Ribose) Polymerase-1-Targeted F-Fluorthanatrace PET Images of Ovarian Cancer.

The poly-(adenosine diphosphate-ribose) polymerase (PARP) family of proteins participates in numerous functions, most notably the DNA damage response. Cancer vulnerability to DNA damage has led to development of several PARP inhibitors (PARPi). This class of drugs has demonstrated therapeutic efficacy in ovarian, breast, and prostate cancers, but with variable response.

Positron Emission Tomography Imaging of Poly-(Adenosine Diphosphate-Ribose) Polymerase 1 Expression in Breast Cancer: A Nonrandomized Clinical Trial.

This nonrandomized clinical trial tested [F]FluorThanatrace as a method for measuring regional poly–(adenosine diphosphate–ribose) polymerase 1 expression in breast cancer and as a potential functional biomarker for breast cancer poly–(adenosine diphosphate–ribose) polymerase inhibitor response.

Breast Cancer F-ISO-1 Uptake as a Marker of Proliferation Status.

The σ receptor is a potential in vivo target for measuring proliferative status in cancer. The feasibility of using -(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1)-yl)butyl)-2-(2-F-fluoroethoxy)-5-methylbenzamide (F-ISO-1) to image solid tumors in lymphoma, breast cancer, and head and neck cancer has been previously established. Here, we report the results of the first dedicated clinical trial of F-ISO-1 in women with primary breast cancer.

Imaging CAR T Cell Trafficking with eDHFR as a PET Reporter Gene.

Cell-based therapeutics have considerable promise across diverse medical specialties; however, reliable human imaging of the distribution and trafficking of genetically engineered cells remains a challenge. We developed positron emission tomography (PET) probes based on the small-molecule antibiotic trimethoprim (TMP) that can be used to image the expression of the Escherichia coli dihydrofolate reductase enzyme (eDHFR) and tested the ability of [F]-TMP, a fluorine-18 probe, to image primary human chimeric antigen receptor (CAR) T cells expressing the PET reporter gene eDHFR, yellow fluorescent protein (YFP), and Renilla luciferase (rLuc). Engineered T cells showed an approximately 50-fold increased bioluminescent imaging signal and 10-fold increased [F]-TMP uptake compared to controls in vitro.

Prevalence and quantitative analysis of indium-111 pentetreotide (Octreoscan) uptake in the pancreatic head on SPECT/CT imaging: establishing a region of interest-based pathological uptake threshold.

Objective: Determine the prevalence of benign indium-111 (In) pentetreotide uptake in the pancreatic head and determine if a semi-quantitative method can be used to differentiate physiologic from pathologic uptake.

Patients And Methods: Institutional Review Board-approved, HIPAA-compliant retrospective review of 197 somatostatin receptor scintigraphy studies performed in 136 patients, from December 2012 to November 2013 at a large academic medical center. The pancreatic head uptake was visually graded and for all positive cases, two-dimensional and three-dimensional ratios of the pancreatic head to normal liver uptake were calculated.

A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma.

Immunologic responses to anti-PD-1 therapy in melanoma patients occur rapidly with pharmacodynamic T cell responses detectable in blood by 3 weeks. It is unclear, however, whether these early blood-based observations translate to the tumor microenvironment. We conducted a study of neoadjuvant/adjuvant anti-PD-1 therapy in stage III/IV melanoma.