Constitutively active MyD88/CD40 costimulation enhances expansion and efficacy of chimeric antigen receptor T cells targeting hematological malignancies.

Successful adoptive chimeric antigen receptor (CAR) T-cell therapies against hematological malignancies require CAR-T expansion and durable persistence following infusion. Balancing increased CAR-T potency with safety, including severe cytokine-release syndrome (sCRS) and neurotoxicity, warrants inclusion of safety mechanisms to control in vivo CAR-T activity. Here, we describe a novel CAR-T cell platform that utilizes expression of the toll-like receptor (TLR) adaptor molecule, MyD88, and tumor-necrosis factor family member, CD40 (MC), tethered to the CAR molecule through an intentionally inefficient 2A linker system, providing a constitutive signal that drives CAR-T survival, proliferation, and antitumor activity against CD19 and CD123 hematological cancers.

Two-Dimensional Regulation of CAR-T Cell Therapy with Orthogonal Switches.

Use of chimeric antigen receptors (CARs) as the basis of targeted adoptive T cell therapies has enabled dramatic efficacy against multiple hematopoietic malignancies, but potency against bulky and solid tumors has lagged, potentially due to insufficient CAR-T cell expansion and persistence. To improve CAR-T cell efficacy, we utilized a potent activation switch based on rimiducid-inducible MyD88 and CD40 (iMC)-signaling elements. To offset potential toxicity risks by this enhanced CAR, an orthogonally regulated, rapamycin-induced, caspase-9-based safety switch (iRC9) was developed to allow elimination of CAR-T cells.

A Randomized, Double-Blind, Placebo-Controlled Trial to Assess the Utility of Tacrolimus (FK506) for the Prevention of Erectile Dysfunction Following Bilateral Nerve-Sparing Radical Prostatectomy.

Introduction: Radical prostatectomy (RP) is associated with erectile dysfunction, largely mediated through cavernous nerve injury. There are robust pre-clinical data supporting a potential role for neuromodulatory agents in this patient population. This study assessed tacrolimus in improving erectile function recovery rates after RP (ClinicalTrials.

Regulated Expansion and Survival of Chimeric Antigen Receptor-Modified T Cells Using Small Molecule-Dependent Inducible MyD88/CD40.

Anti-tumor efficacy of T cells engineered to express chimeric antigen receptors (CARs) is dependent on their specificity, survival, and in vivo expansion following adoptive transfer. Toll-like receptor (TLR) and CD40 signaling in T cells can improve persistence and drive proliferation of antigen-specific CD4 and CD8 T cells following pathogen challenge or in graft-versus-host disease (GvHD) settings, suggesting that these costimulatory pathways may be co-opted to improve CAR-T cell persistence and function. Here, we present a novel strategy to activate TLR and CD40 signaling in human T cells using inducible MyD88/CD40 (iMC), which can be triggered in vivo via the synthetic dimerizing ligand, rimiducid, to provide potent costimulation to CAR-modified T cells.

Phase I trial of antigen-targeted autologous dendritic cell-based vaccine with in vivo activation of inducible CD40 for advanced prostate cancer.

This phase I trial reports the safety and activity of BPX101, a second-generation antigen-targeted autologous antigen presenting cell (APC) vaccine in men with metastatic castration-resistant prostate cancer (mCRPC). To manufacture BPX101, APCs collected in a single leukapheresis were transduced with adenoviral vector Ad5f35 encoding inducible human (ih)-CD40, followed by incubation with protein PA001, which contains the extracellular domain of human prostate-specific membrane antigen. The ih-CD40 represents a modified chimeric version of the dendritic cell (DC) co-stimulatory molecule, CD40, which responds to a bioinert membrane-permeable activating dimerizer drug, rimiducid (AP1903), permitting temporally controlled, lymphoid-localized, DC-specific activation.

Phase 2 Study of Tc-Trofolastat SPECT/CT to Identify and Localize Prostate Cancer in Intermediate- and High-Risk Patients Undergoing Radical Prostatectomy and Extended Pelvic LN Dissection.

Tc-trofolastat (Tc-MIP-1404), a small-molecule inhibitor of prostate-specific membrane antigen, shows high potential to detect prostate cancer (PCa) noninvasively using SPECT. We therefore wanted to assess the performance of Tc-trofolastat SPECT/CT in a phase 2 multicenter, multireader prospective study in patients with intermediate- and high-grade PCa, before radical prostatectomy and extended pelvic lymph node (LN) dissection, with histopathology as the gold standard. PCa patients ( = 105) with an increased risk of LN involvement (LNI) underwent pelvic Tc-trofolastat SPECT/CT before radical prostatectomy with extended pelvic LN dissection.

Prostate Health Index improves multivariable risk prediction of aggressive prostate cancer.

Objective: To examine the use of the Prostate Health Index (PHI) as a continuous variable in multivariable risk assessment for aggressive prostate cancer in a large multicentre US study.

Materials And Methods: The study population included 728 men, with prostate-specific antigen (PSA) levels of 2-10 ng/mL and a negative digital rectal examination, enrolled in a prospective, multi-site early detection trial. The primary endpoint was aggressive prostate cancer, defined as biopsy Gleason score ≥7.

MyD88/CD40 Genetic Adjuvant Function in Cutaneous Atypical Antigen-Presenting Cells Contributes to DNA Vaccine Immunogenicity.

Therapeutic DNA-based vaccines aim to prime an adaptive host immune response against tumor-associated antigens, eliminating cancer cells primarily through CD8+ cytotoxic T cell-mediated destruction. To be optimally effective, immunological adjuvants are required for the activation of tumor-specific CD8+ T cells responses by DNA vaccination. Here, we describe enhanced anti-tumor efficacy of an in vivo electroporation-delivered DNA vaccine by inclusion of a genetically encoded chimeric MyD88/CD40 (MC) adjuvant, which integrates both innate and adaptive immune signaling pathways.

Intratesticular epidermoid cyst masquerading as testicular torsion.

Epidermoid cysts are benign tumors that comprise approximately 1% of all testicular masses. They usually present as painless masses that can be identified on scrotal ultrasound as well-demarcated intratesticular lesions with mixed echogenicity. This case report describes a rare presentation of an extremely large intratesticular epidermoid cyst with clinical and radiologic findings more consistent with testicular torsion.

The prostate health index selectively identifies clinically significant prostate cancer.

Purpose: The Prostate Health Index (phi) is a new test combining total, free and [-2]proPSA into a single score. It was recently approved by the FDA and is now commercially available in the U.S.

Prospective multicenter evaluation of the Beckman Coulter Prostate Health Index using WHO calibration.

Purpose: Reported prostate specific antigen values may differ substantially among assays using Hybritech® or WHO standardization. The Beckman Coulter® Prostate Health Index and [-2]proPSA are newly approved serum markers associated with prostate cancer risk and aggressiveness. We studied the influence of assay standardization on these markers.

A multicenter study of [-2]pro-prostate specific antigen combined with prostate specific antigen and free prostate specific antigen for prostate cancer detection in the 2.0 to 10.0 ng/ml prostate specific antigen range.

Purpose: Prostate specific antigen and free prostate specific antigen have limited specificity to detect clinically significant, curable prostate cancer, leading to unnecessary biopsy, and detection and treatment of some indolent tumors. Specificity to detect clinically significant prostate cancer may be improved by [-2]pro-prostate specific antigen. We evaluated [-2]pro-prostate specific antigen, free prostate specific antigen and prostate specific antigen using the formula, ([-2]pro-prostate specific antigen/free prostate specific antigen × prostate specific antigen(1/2)) to enhance specificity to detect overall and high grade prostate cancer.

A composite MyD88/CD40 switch synergistically activates mouse and human dendritic cells for enhanced antitumor efficacy.

The in vivo therapeutic efficacy of DC-based cancer vaccines is limited by suboptimal DC maturation protocols. Although delivery of TLR adjuvants systemically boosts DC-based cancer vaccine efficacy, it could also increase toxicity. Here, we have engineered a drug-inducible, composite activation receptor for DCs (referred to herein as DC-CAR) comprising the TLR adaptor MyD88, the CD40 cytoplasmic region, and 2 ligand-binding FKBP12 domains.

The phosphatase SRC homology region 2 domain-containing phosphatase-1 is an intrinsic central regulator of dendritic cell function.

Dendritic cells (DCs) initiate proinflammatory or regulatory T cell responses, depending on their activation state. Despite extensive knowledge of DC-activating signals, the understanding of DC inhibitory signals is relatively limited. We show that Src homology region 2 domain-containing phosphatase-1 (SHP-1) is an important inhibitor of DC signaling, targeting multiple activation pathways.

Emerging vaccine therapy approaches for prostate cancer.

Prostate cancer vaccines attempt to induce clinically relevant, cancer-specific systemic immune responses in patients with prostate cancer and represent a new class of targeted, nontoxic therapies. With a growing array of vaccine technologies in preclinical or clinical development, autologous antigen-presenting cell vaccines loaded with the antigen, prostate acid phosphatase, and poxvirus vaccines targeting prostate-specific antigen have recently demonstrated a significant survival benefit in randomized trials of patients with metastatic castration-resistant prostate cancer, whereas others have failed to demonstrate any benefit. The combination of vaccines with chemotherapy, radiotherapy, and other biologic agents is also being evaluated.

Pre-treatment biomarker levels improve the accuracy of post-prostatectomy nomogram for prediction of biochemical recurrence.

Purpose: We tested the ability of several pre-operative blood-based biomarkers to enhance the accuracy of standard post-operative features for the prediction of biochemical recurrence (BCR) after radical prostatectomy (RP).

Methods: Pre-operative plasma levels of Endoglin, interleukin-6 (IL-6), interleukin-6 soluble receptor (IL-6sR), transforming growth factor-beta1 (TGF-beta1), urokinase plasminogen activator (uPA), urokinase plasminogen inhibitor-1 (PAI-1), urokinase plasminogen receptor (uPAR), vascular cell adhesion molecule-1 (VCAM1), and vascular endothelial growth factor (VEGF) were measured using commercially available enzyme immunoassays in 423 consecutive patients treated with RP for clinically localized prostate cancer. Standard post-operative features consisted of surgical margin status, extracapsular extension, seminal vesicle invasion, lymph node involvement, and pathologic Gleason sum.

A multi-institutional matched-control analysis of adjuvant and salvage postoperative radiation therapy for pT3-4N0 prostate cancer.

Objectives: It is unclear whether postoperative salvage radiation therapy (SRT) and early adjuvant radiotherapy (ART) after radical prostatectomy lead to equivalent long-term tumor control. We studied a group of patients undergoing ART by comparing them with a matched control group undergoing SRT after biochemical failure.

Methods: Using a multi-institutional database of 2299 patients, 449 patients with pT3-4N0 disease were eligible for inclusion, including 211 patients receiving ART and 238 patients receiving SRT.

Testosterone therapy in hypogonadal men and potential prostate cancer risk: a systematic review.

This paper provides a systematic review of the literature about prostate cancer risk associated with testosterone therapy for hypogonadism. A comprehensive search of MEDLINE, EMBASE and other resources was conducted to identify articles that highlight occurrences of prostate cancer in men receiving testosterone therapy for hypogonadism treatment. Articles that met study inclusion criteria were assessed for causality between testosterone treatment and prostate cancer, increased prostate-specific antigen or abnormal digital rectal examination findings.

Improved prediction of disease relapse after radical prostatectomy through a panel of preoperative blood-based biomarkers.

Purpose: The preoperative blood levels of biomarkers may allow accurate identification of patients who are likely to fail radical prostatectomy as a first-line therapy for localized prostate cancer, thereby allowing more efficient delivery of neoadjuvant and adjuvant therapy. The aim of this study was to determine the added value of biomarkers relative to established predictors of biochemical recurrence, such as clinical stage, biopsy Gleason sum, and preoperative prostate-specific antigen.

Experimental Design: The preoperative plasma levels of transforming growth factor-beta1 (TGF-beta1), interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), vascular endothelial growth factor (VEGF), vascular cell adhesion molecule-1 (VCAM-1), endoglin, urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor-1, and uPA receptor were measured with the use of commercially available enzyme immunoassays in 423 consecutive patients treated with radical prostatectomy and bilateral lymphadenectomy for clinically localized prostate cancer.

Preoperative plasma endoglin levels predict biochemical progression after radical prostatectomy.

Purpose: Endoglin (CD105) is a transmembrane glycoprotein expressed by human vascular endothelial cells thought to play a pivotal role in endothelial cell proliferation. The aim of this study was to evaluate the association of preoperative plasma endoglin levels with established clinical and pathologic features of prostate cancer and disease progression after radical prostatectomy.

Experimental Design: Preoperative plasma endoglin levels were measured in 425 patients who underwent radical prostatectomy for clinically localized prostate cancer using a commercially available ELISA assay.

Prostate-specific antigen and prostate-specific antigen derivatives as predictors of benign prostatic hyperplasia progression.

Benign prostatic hyperplasia (BPH) is the most common urologic affliction in aging men, leading to adverse clinical outcomes in a significant proportion of the population. Serum prostate-specific antigen (PSA) has been established as a marker for prostate cancer for the past two decades but more recently has been recognized as an equally important marker of BPH presence and progression. Over this time, the discovery and study of multiple isoforms of PSA have led to even more sensitive and specific methods to differentiate BPH from prostate cancer.

Do margins matter? The prognostic significance of positive surgical margins in radical prostatectomy specimens.

Purpose: The prognostic significance of positive surgical margins (PSM) in radical prostatectomy (RP) specimens remains unclear. While most studies have concluded that a PSM is an independent adverse prognostic factor, others report that surgical margin status has no effect on prognosis. One reason for these discordant conclusions is the variable number of patients with a PSM who receive adjuvant therapy and the differing statistical methods used to account for the effects of the time course of adjuvant treatment on recurrence.

Use of preoperative plasma endoglin for prediction of lymph node metastasis in patients with clinically localized prostate cancer.

Purpose: Current predictive tools and imaging modalities are not accurate enough to preoperatively diagnose lymph node metastases in patients with prostate cancer. The aim of the study was to evaluate whether preoperative plasma endoglin improves the prediction of lymph node metastases in patients with clinically localized prostate cancer.

Experimental Design: Endoglin levels were measured using a commercially available ELISA assay in banked plasma from 425 patients treated with radical prostatectomy and bilateral lymphadenectomy for clinically localized prostatic adenocarcinoma at two university hospitals between July 1994 and November 1997.