Considerations on Integrating Prostate-Specific Membrane Antigen Positron Emission Tomography Imaging Into Clinical Prostate Cancer Trials by National Clinical Trials Network Cooperative Groups.

PURPOSE: As prostate-specific membrane antigen (PSMA) positron emission tomography (PET) becomes increasingly available in the United States, the greater sensitivity of the technology in comparison to conventional imaging poses challenges for clinical trials. The NCI Clinical Imaging Steering Committee (CISC) PSMA PET Working Group was convened to coordinate the identification of these challenges in various clinical scenarios and to develop consensus recommendations on how best to integrate PSMA PET into ongoing and upcoming National Clinical Trials Network (NCTN) trials. METHODS: NCI CISC and NCI Genitourinary Steering Committee members and leadership nominated clinicians, biostatisticians, patient advocates, and other imaging experts for inclusion in the PSMA PET Working Group. From April to July 2021, the working group met independently and in conjunction with the CISC to frame challenges, including stage migration, response assessment, trial logistics, and statistical challenges, and to discuss proposed solutions. An anonymous, open-ended survey was distributed to members to collect feedback on challenges faced. Representatives from each NCTN group were invited to present an overview of affected trials. From these discussions, the consensus document was developed and circulated for the inclusion of multiple rounds of feedback from both the Working Group and CISC. RESULTS: The current consensus document outlines the key challenges for clinical prostate cancer trials resulting from the increasing availability of PSMA PET. We discuss implications for patient selection and definition of end points and provide guidance and potential solutions for different clinical scenarios, particularly with regard to best practices in defining eligibility criteria and outcome measures. RECOMMENDATIONS: This article provides guidance regarding clinical trial design and conduct, and the interpretation of trial results.

The Role of Lineage Plasticity in Prostate Cancer Therapy Resistance.

Lineage plasticity has emerged as an important mechanism of treatment resistance in prostate cancer. Treatment-refractory prostate cancers are increasingly associated with loss of luminal prostate markers, and in many cases induction of developmental programs, stem cell-like phenotypes, and neuroendocrine/neuronal features. Clinically, lineage plasticity may manifest as low PSA progression, resistance to androgen receptor (AR) pathway inhibitors, and sometimes small cell/neuroendocrine pathologic features observed on metastatic biopsy. This mechanism is not restricted to prostate cancer as other malignancies also demonstrate lineage plasticity during resistance to targeted therapies. At present, there is no established therapeutic approach for patients with advanced prostate cancer developing lineage plasticity or small cell neuroendocrine prostate cancer (NEPC) due to knowledge gaps in the underlying biology. Few clinical trials address questions in this space, and the outlook for patients remains poor. To move forward, urgently needed are: (i) a fundamental understanding of how lineage plasticity occurs and how it can best be defined; (ii) the temporal contribution and cooperation of emerging drivers; (iii) preclinical models that recapitulate biology of the disease and the recognized phenotypes; (iv) identification of therapeutic targets; and (v) novel trial designs dedicated to the entity as it is defined. This Perspective represents a consensus arising from the NCI Workshop on Lineage Plasticity and Androgen Receptor-Independent Prostate Cancer. We focus on the critical questions underlying lineage plasticity and AR-independent prostate cancer, outline knowledge and resource gaps, and identify strategies to facilitate future collaborative clinical translational and basic studies in this space.

Brain Malignancy Steering Committee clinical trials planning workshop: report from the Targeted Therapies Working Group.

Glioblastoma is the most common primary brain malignancy and is associated with poor prognosis despite aggressive local and systemic therapy, which is related to a paucity of viable treatment options in both the newly diagnosed and recurrent settings. Even so, the rapidly increasing number of targeted therapies being evaluated in oncology clinical trials offers hope for the future. Given the broad range of possibilities for future trials, the Brain Malignancy Steering Committee convened a clinical trials planning meeting that was held at the Udvar-Hazy Center in Chantilly, Virginia, on September 19 and 20, 2013. This manuscript reports the deliberations leading up to the event from the Targeted Therapies Working Group and the results of the meeting.

IL-15 ex vivo overcomes CD4+ T cell deficiency for the induction of human antigen-specific CD8+ T cell responses.

CD4(+) Th cells are important for the induction and maintenance of antigen-specific CD8(+) T cell function, so their loss or dysfunction in HIV-infected or cancer patients could reduce the patients' ability to control viral infection. Previous work in murine systems indicated that IL-15 codelivered with vaccines could overcome CD4(+) Th cell deficiency for induction of functionally efficient CD8(+) T cells and maintenance of viral-specific CTLs, but its efficacy in helping primary human CD8(+) T cell responses is unknown. In the present study, a peptide-pulsed, DC-based human coculture ex vivo system was used to study the role of IL-15 in overcoming CD4(+) Th deficiency to elicit CD8(+) T cell responses in CD4-depleted PBMCs from healthy individuals and PBMCs from HIV-1-infected patients. We found that IL-15 could overcome CD4(+) Th deficiency to induce primary and recall memory CD8(+) T cell responses in healthy individuals. Moreover, in CD4-deficient, HIV-1-infected patients with diminished CD8(+) T cell responses, IL-15 greatly enhanced CD8(+) T cell responses to alloantigen. These results suggest that IL-15 may be useful in the development of therapeutic and preventive vaccines against cancers and viral infections in patients defective in CD4(+) Th cell.

Pilot analysis of cytokines levels in stored granulocyte-colony-stimulating factor-mobilized peripheral blood stem cell concentrates.

BACKGROUND: The transfusion of peripheral blood stem cell (PBSC) concentrates is sometimes associated with febrile transfusion reactions. PBSC concentrates contain large numbers of white blood cells, and during storage the levels of soluble cytokines that could cause transfusion reactions may increase. STUDY DESIGN AND METHODS: Aliquots of granulocyte-colony-stimulating factor (CSF)-mobilized PBSC concentrates from nine healthy subjects were stored in bags at 2 to 8°C for 48 hours. The levels of 19 growth factors and biologic response modifiers were measured in the plasma of PBSC concentrates at 0, 24, and 48 hours of storage using a nested enzyme-linked immunosorbent assay. The same 19 factor levels were also measured in blood plasma from six healthy subjects. RESULTS: There were no significant differences in the PBSC and plasma levels of soluble interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α, which can cause febrile reactions. The levels of TGF-ß1, matrix metalloproteinase-8, CCL5/(reduced on activation normal T expressed and secreted), and platelet (PLT)-derived growth factor-AB were significantly greater in PBSCs than in plasma and the level of CCL2/MCP-1 was significantly less in PBSCs. Duration of PBSC storage had no effect on the levels of these five factors. There was a trend for reduced levels of IL-1ß, IL-2, IL-7, IL-8, IL-12p70, IL-15, interferon-γ, CD40L, and granulocyte-macrophage-CSF and increased levels of TNF-α and IL-10 levels in PBSC concentrates, but the differences were not significant. CONCLUSIONS: There was no increase in stored PBSC concentrates of cytokines that have been associated with febrile transfusion reactions; however, the levels of other factors that were likely released by PLTs and granulocytes during the collection process were elevated.