Sally W. Schwarz

Future cancer research priorities in the USA: a Lancet Oncology Commission

We are in the midst of a technological revolution that is providing new insights into human biology and cancer. In this era of big data, we are amassing large amounts of information that is transforming how we approach cancer treatment and prevention. Enactment of the Cancer Moonshot within the 21st Century Cures Act in the USA arrived at a propitious moment in the advancement of knowledge, providing nearly US

Imaging myocardium enzymatic pathways with carbon-11 radiotracers.

2 billion of funding for cancer research and precision medicine. In 2016, the Blue Ribbon Panel (BRP) set out a roadmap of recommendations designed to exploit new advances in cancer diagnosis, prevention, and treatment. Those recommendations provided a high-level view of how to accelerate the conversion of new scientific discoveries into effective treatments and prevention for cancer. The US National Cancer Institute is already implementing some of those recommendations. As experts in the priority areas identified by the BRP, we bolster those recommendations to implement this important scientific roadmap. In this Commission, we examine the BRP recommendations in greater detail and expand the discussion to include additional priority areas, including surgical oncology, radiation oncology, imaging, health systems and health disparities, regulation and financing, population science, and oncopolicy. We prioritise areas of research in the USA that we believe would accelerate efforts to benefit patients with cancer. Finally, we hope the recommendations in this report will facilitate new international collaborations to further enhance global efforts in cancer control.

Optimization of the preparation of fluorine-18-labeled steroid receptor ligands 16alpha-[18F]fluoroestradiol (FES), [18F]fluoro furanyl norprogesterone (FFNP), and 16beta-[18F]fluoro-5alpha-dihydrotestosterone (FDHT) as radiopharmaceuticals

Publisher Summary This chapter elaborates the imaging of myocardium enzymatic pathways with carbon-11 radiotracers. Under normal conditions, the heart utilizes a variety of metabolic pathways, such as the oxidation of carbohydrates, fatty acids, lactate, and pyruvate, to meet the high-energy demands of contraction and maintenance of cellular function. Carbon-11 is produced by the 14 N(p, α) 11 C reaction using a gas target system of 0.5% oxygen in nitrogen with typical bombardments of 20 –40 min at 40 μA beam power. The product obtained from the target is [ 11 C]CO 2 , which is then trapped under vacuum in a specially designed stainless steel coil cooled to −196° with liquid nitrogen. It is found that as blood contains radiolabeled metabolites in addition to 1-[ 11 C]palmitate, the PET-derived 11 C blood activity must be corrected for the presence of 11 CO 2 in order to derive the true input function. It is found that data analyses require minimum manual data entry and, on average, are completed within 2 h from the time the myocardial positron emission tomography (PET) images are reconstructed, making these types of complex studies feasible to implement in a clinical PET environment.

[18F]FHBG PET/CT Imaging of CD34-TK75 Transduced Donor T Cells in Relapsed Allogeneic Stem Cell Transplant Patients: Safety and Feasibility

Fluorine-18-labeled steroid receptor tracers, 16α-[(18)F]fluoroestradiol (FES), [(18)F]fluoro furanyl norprogesterone (FFNP), and 16β-[(18)F]fluoro-5α-dihydrotestosterone (FDHT), are important imaging tools for studies of breast and prostate cancers using positron emission tomography (PET). The automated production of these ligands with high specific activity (SA) as radiopharmaceuticals requires modification and optimization of the currently reported methods. [(18)F]FES with high SA was synthesized in over 60% radiochemical yield (RCY) at the end of synthesis (EOS) using a small amount of precursor (1) (as low as 0.3 mg) and 1 M H2SO4 for deprotection of the intermediate (2). [(18)F]FFNP was synthesized in up to 77% RCY at EOS using the triflate precursor (4) at room temperature or in 25% RCY using the mesylate precursor (6) at 65°C. Both methods are highly reproducible and afford high SA. [(18)F]FDHT was synthesized by radiofluoride incorporation at room temperature, reduction with NaBH4 , and deprotection with HCl/acetone, giving [(18)F]FDHT in up to 75% yield (RCY). All of these methods can be easily translated to automated production. The information provided here will aid in the development of automated production of these steroid receptor tracers with high or improved yields, optimal SA, and ease of processing for research and clinical use.

Regulatory Requirements for PET Drug Production

Described herein is a first-in-man attempt to both genetically modify T cells with an imagable suicide gene and track these transduced donor T cells in allogeneic stem cell transplantation recipients using noninvasive positron emission tomography/computerized tomography (PET/CT) imaging. A suicide gene encoding a human CD34-Herpes Simplex Virus-1-thymidine kinase (CD34-TK75) fusion enabled enrichment of retrovirally transduced T cells (TdT), control of graft-versus-host disease and imaging of TdT migration and expansion in vivo in mice and man. Analysis confirmed that CD34-TK75-enriched TdT contained no replication competent γ-retrovirus, were sensitive to ganciclovir, and displayed characteristic retroviral insertion sites (by targeted sequencing). Affinity-purified CD34-TK75+-selected donor T cells (1.0-13 × 105)/kg were infused into eight patients who relapsed after allogeneic stem cell transplantation. Six patients also were administered 9-[4-(18F)fluoro-3-hydroxymethyl-butyl]guanine ([18F]FHBG) to specifically track the genetically modified donor T cells by PET/CT at several time points after infusion. All patients were assessed for graft-versus-host disease, response to ganciclovir, circulating TdT cells (using both quantitative polymerase chain reaction and [18F]FHBG PET/CT imaging), TdT cell clonal expansion, and immune response to the TdT. This phase 1 trial demonstrated that genetically modified T cells and [18F]FHBG can be safely infused in patients with relapsed hematologic malignancies after allogeneic stem cell transplantation.Described herein is a first-in-man attempt to both genetically modify T cells with an imagable suicide gene and track these transduced donor T cells in allogeneic stem cell transplantation recipients using noninvasive positron emission tomography/computerized tomography (PET/CT) imaging. A suicide gene encoding a human CD34-Herpes Simplex Virus-1-thymidine kinase (CD34-TK75) fusion enabled enrichment of retrovirally transduced T cells (TdT), control of graft-versus-host disease and imaging of TdT migration and expansion in vivo in mice and man. Analysis confirmed that CD34-TK75-enriched TdT contained no replication competent γ-retrovirus, were sensitive to ganciclovir, and displayed characteristic retroviral insertion sites (by targeted sequencing). Affinity-purified CD34-TK75(+)-selected donor T cells (1.0-13 × 10(5))/kg were infused into eight patients who relapsed after allogeneic stem cell transplantation. Six patients also were administered 9-[4-((18)F)fluoro-3-hydroxymethyl-butyl]guanine ([(18)F]FHBG) to specifically track the genetically modified donor T cells by PET/CT at several time points after infusion. All patients were assessed for graft-versus-host disease, response to ganciclovir, circulating TdT cells (using both quantitative polymerase chain reaction and [(18)F]FHBG PET/CT imaging), TdT cell clonal expansion, and immune response to the TdT. This phase 1 trial demonstrated that genetically modified T cells and [(18)F]FHBG can be safely infused in patients with relapsed hematologic malignancies after allogeneic stem cell transplantation.

Challenges for Developing PET Tracers: Isotopes, Chemistry, and Regulatory Aspects

The Food and Drug Administration (FDA) issued the final rule for title 21 of Code of Federal Regulations part 212 regarding the regulations on current good manufacturing practice for PET drugs. The regulations are intended to ensure that PET drugs meet the safety and quality assurance requirements of the Federal Food, Drug, and Cosmetic Act. The new regulation became effective December 12, 2011, but the FDA used regulatory discretion to allow new drug applications and abbreviated new drug applications to be filed until June 12, 2012, without interruption of the existing PET drug production for human use. The production of PET drugs for both clinical use and clinical research use are outlined in this continuing education module, including an overview of specific requirements for compliance. Additionally, FDA preapproval inspections and postapproval reporting requirements are reviewed.

Diversification in the Supply Chain of 99 Mo Ensures a Future for 99m Tc

The primary limitation on the development of new radiotracers for use with positron emission tomography (PET) is the time constraints created by working with radionuclides with the short half-lives inherent to carbon 11 and fluorine 18, the main radionuclides used in PET radiotracer development. In the past decade there have been several developments in the radiosynthetic methods used in PET chemistry, advances that are expected to lead to an increase in the number of radiotracers making the transition from clinical research studies to clinical PET studies. This article reviews developments in PET radiochemistry that will facilitate this process and discusses the application of these basic principles of PET radiotracer development in central nervous system research. Current status of regulatory requirements for the development of new PET radiotracers for imaging studies in humans is reviewed.

Immunoscintigraphy with a new indium-111-labeled monoclonal antibody (MAb 1A3) in patients with colorectal cancer

The uncertain availability of 99mTc has become a concern for nuclear medicine departments across the globe. An issue for the United States is that currently it is dependent on a supply of 99mTc (from 99Mo) that is derived solely by production outside the United States. Since the United States uses half the world’s 99Mo production, the U.S. 99Mo supply chain would be greatly enhanced if a producer were located within the United States. The fragility of the old 99Mo supply chain is being addressed as new facilities are constructed and new processes are developed to produce 99Mo without highly enriched uranium. The conversion to low-enriched uranium is necessary to minimize the potential misuse of highly enriched uranium in the world for nonpeaceful means. New production facilities, new methods for the production of 99Mo, and a new generator elution system for the supply of 99mTc are currently being pursued. The progress made in all these areas will be discussed, as they all highlight the need to embrace diversity to ensure that we have a robust and reliable supply of 99mTc in the future.

Radiopharmacy: regulations and legislations in relation to human applications

PURPOSE: This study was designed to evaluate a new anticolorectal carcinoma monoclonal antibody (1A3), conjugated with the bifunctional chelating agentN,N′-bis(2-hydroxybenzyl) 1 (4-bromoacetamidobenzyl) 1,2-ethylenediamine-N,N′-diacetic acid and labeled with indium-111, in a Phase I/II study involving 38 patients with localized or advanced colorectal cancer. METHODS: Patients were injected with indium-111-N,N′-bis(2-hydroxybenzyl) 1 (4-bromoacetamidobenzyl) 1,2-ethylenediamine-N, N′-diacetic acid-monoclonal antibody 1A3 (1–50 mg, 1–5 mCi) and imaged at two or three sessions one to five days later. Scintigraphic findings were compared with radiologic, pathologic, surgical, and other clinical findings to assess the accuracy of radioimmunoscintigraphy. RESULTS: At least one known tumor site was clearly defined by planar scintigraphy in 29 (76 percent) patients. Increased radioactivity was seen in 40 of 63 known tumor sites (37/43 abdominal-pelvic, 3/15 hepatic, and 0/5 pulmonary sites) without any apparent dose-related effects. Nineteen previously undetected sites were considered positive by imaging, and, of these, six were biopsy-proven tumor sites, four were probable tumor sites, three were definitely false positive sites, and six were probable false positive sites. Radioimmunoscintigraphy detected proven tumor in 15 of 16 patients with negative or equivocal computed tomography results. Of the 28 patients with rectosigmoid cancer, 25 (89 percent) had positive studies with 34 of 47 tumor sites showing definite uptake on the scintigrams. This included 3 of 9 hepatic metastases. The only adverse reaction occurred in one patient who developed transient hives. Human anti-mouse antibody responses occurred in approximately one-half of the patients injected with doses of 10 or 50 mg. CONCLUSION: This study shows that radioimmunoscintigraphy with this indium-111-labeled monoclonal antibody is safe, it can detect most nonhepatic abdominalpelvic tumors with a positive predictive value of 83 (44/ 53) percent, and it should prove to be useful, particularly in the diagnosis of recurrent rectal carcinoma.

The Future of USP Monographs for PET Drugs

Radiopharmaceuticals (RPs) have attracted tremendous interest as molecular imaging tracers in diagnostic applications and as biomarkers in drug development, in particular using Positron Emission Tomography (PET). This article summarizes important legal documents and guidelines in relation to human application of PET-RPs that pose a major challenge in implementing the full potential of this technology, thereby differentiating the US from the European situation. Regulations are reviewed with respect to licensing, conducting clinical trials and RP production - including Good Manufacturing Practice (GMP) for radioactive compounds. Professional requirements, including education, are discussed, with an outlook on future developments.: