PSMA-targeting TGFß-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)-ß. 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-ß receptor (NCT03089203). Primary endpoints were safety and feasibility, while secondary objectives included assessment of CAR T cell distribution, bioactivity and disease response. All prespecified endpoints were met. Eighteen patients enrolled, and 13 subjects received therapy across four dose levels. Five of the 13 patients developed grade ≥2 cytokine release syndrome (CRS), including one patient who experienced a marked clonal CAR T cell expansion, >98% reduction in prostate-specific antigen (PSA) and death following grade 4 CRS with concurrent sepsis. Acute increases in inflammatory cytokines correlated with manageable high-grade CRS events. Three additional patients achieved a PSA reduction of ≥30%, with CAR T cell failure accompanied by upregulation of multiple TME-localized inhibitory molecules following adoptive cell transfer. CAR T cell kinetics revealed expansion in blood and tumor trafficking. Thus, clinical application of TGF-ß-resistant CAR T cells is feasible and generally safe. Future studies should use superior multipronged approaches against the TME to improve outcomes.

TNF blockade uncouples toxicity from antitumor efficacy induced with CD40 chemoimmunotherapy.

Agonist CD40 antibodies are under clinical development in combination with chemotherapy as an approach to prime for antitumor T cell immunity. However, treatment with anti-CD40 is commonly accompanied by both systemic cytokine release and liver transaminase elevations, which together account for the most common dose-limiting toxicities. Moreover, anti-CD40 treatment increases the potential for chemotherapy-induced hepatotoxicity. Here, we report a mechanistic link between cytokine release and hepatotoxicity induced by anti-CD40 when combined with chemotherapy and show that toxicity can be suppressed without impairing therapeutic efficacy. We demonstrate in mice and humans that anti-CD40 triggers transient hepatotoxicity marked by increased serum transaminase levels. In doing so, anti-CD40 sensitizes the liver to drug-induced toxicity. Unexpectedly, this biology is not blocked by the depletion of multiple myeloid cell subsets, including macrophages, inflammatory monocytes, and granulocytes. Transcriptional profiling of the liver after anti-CD40 revealed activation of multiple cytokine pathways including TNF and IL-6. Neutralization of TNF, but not IL-6, prevented sensitization of the liver to hepatotoxicity induced with anti-CD40 in combination with chemotherapy without impacting antitumor efficacy. Our findings reveal a clinically feasible approach to mitigate toxicity without impairing efficacy in the use of agonist CD40 antibodies for cancer immunotherapy.

Combining radiomic phenotypes of non-small cell lung cancer with liquid biopsy data may improve prediction of response to EGFR inhibitors.

Among non-small cell lung cancer (NSCLC) patients with therapeutically targetable tumor mutations in epidermal growth factor receptor (EGFR), not all patients respond to targeted therapy. Combining circulating-tumor DNA (ctDNA), clinical variables, and radiomic phenotypes may improve prediction of EGFR-targeted therapy outcomes for NSCLC. This single-center retrospective study included 40 EGFR-mutant advanced NSCLC patients treated with EGFR-targeted therapy. ctDNA data included number of mutations and detection of EGFR T790M. Clinical data included age, smoking status, and ECOG performance status. Baseline chest CT scans were analyzed to extract 429 radiomic features from each primary tumor. Unsupervised hierarchical clustering was used to group tumors into phenotypes. Kaplan-Meier (K-M) curves and Cox proportional hazards regression were modeled for progression-free survival (PFS) and overall survival (OS). Likelihood ratio test (LRT) was used to compare fit between models. Among 40 patients (73% women, median age 62 years), consensus clustering identified two radiomic phenotypes. For PFS, the model combining radiomic phenotypes with ctDNA and clinical variables had c-statistic of 0.77 and a better fit (LRT p = 0.01) than the model with clinical and ctDNA variables alone with a c-statistic of 0.73. For OS, adding radiomic phenotypes resulted in c-statistic of 0.83 versus 0.80 when using clinical and ctDNA variables (LRT p = 0.08). Both models showed separation of K-M curves dichotomized by median prognostic score (p < 0.005). Combining radiomic phenotypes, ctDNA, and clinical variables may enhance precision oncology approaches to managing advanced non-small cell lung cancer with EGFR mutations.

Blood-based gene expression signature associated with metastatic castrate-resistant prostate cancer patient response to abiraterone plus prednisone or enzalutamide.

BACKGROUND: Precision medicine approaches for managing patients with metastatic castrate-resistant prostate cancer (mCRPC) are lacking. Non-invasive approaches for molecular monitoring of disease are urgently needed, especially for patients suffering from bone metastases for whom tissue biopsy is challenging. Here we utilized baseline blood samples to identify mCRPC patients most likely to benefit from abiraterone plus prednisone (AAP) or enzalutamide. METHODS: Baseline blood samples were collected for circulating tumor cell (CTC) enumeration and qPCR-based gene expression analysis from 51 men with mCRPC beginning treatment with abiraterone or enzalutamide. RESULTS: Of 51 patients (median age 68 years [51-82]), 22 received AAP (abiraterone 1000 mg/day plus prednisone 10 mg/day) and 29 received enzalutamide (160 mg/day). The cohort was randomly divided into training (n = 37) and test (n = 14) sets. Baseline clinical variables (Gleason score, PSA, testosterone, and hemoglobin), CTC count, and qPCR-based gene expression data for 141 genes/isoforms in CTC-enriched blood were analyzed with respect to overall survival (OS). Genes with expression most associated with OS included MSLN, ARG2, FGF8, KLK3, ESRP2, NPR3, CCND1, and WNT5A. Using a Cox-elastic net model for our test set, the 8-gene expression signature had a c-index of 0.87 (95% CI [0.80, 0.94]) and was more strongly associated with OS than clinical variables or CTC count alone, or a combination of the three variables. For patients with a low-risk vs. high-risk gene expression signature, median OS was not reached vs. 18 months, respectively (HR 5.32 [1.91-14.80], p = 0.001). For the subset of 41 patients for whom progression-free survival (PFS) data was available, the median PFS for patients with a low-risk vs high-risk gene expression signature was 20 vs. 5 months, respectively (HR 2.95 [1.46-5.98], p = 0.003). CONCLUSIONS: If validated in a larger prospective study, this test may predict patients most likely to benefit from second-generation antiandrogen therapy.

Septal atrial pacing for the prevention of atrial fibrillation.

AIMS: Atrial fibrillation (AF) produces significant morbidity and mortality. The current method of permanent pacing of the right atrium (RA) may cause delayed interatrial conduction and predispose to AF. We hypothesized that atrial septal pacing would reduce AF compared with high RA pacing. METHODS AND RESULTS: The patients were randomized into two groups. After randomization, patients received a dual-chamber rate-responsive device capable of mode-switching with advanced telemetry features. Devices were programmed in a standardized manner. To be eligible, the patients were required to have a conventional indication for a permanent pacemaker and recurrent paroxysmal AF. Group 1 was paced from high RA and Group 2 was paced from the atrial septum. Analysis of 43 patients who have completed 6 months of follow-up and 22 patients who completed 12 months of follow-up showed no significant differences in the number of mode-switching episodes or in AF burden between groups (P = NS by Mann-Whitney) although there was a trend for less AF with septal pacing. There were no differences in thresholds, sensing, or lead impedance. Lead parameters remained stable over time and there were no displacements of the electrodes after implantation. No patient experienced lead-related complications. A significant variability in AF burden was noted in this patient population. CONCLUSIONS: Implantation of an atrial-active fixation lead on the atrial septum is safe and feasible. However, this study showed no significant difference between septal pacing and high atrial pacing, using the endpoints of AF duration and number of AF episodes.

Anticoagulants for atrial fibrillation: why is the treatment rate so low?

The incidence of atrial fibrillation (AF) is increasing in many countries along with aging demographics. Atrial fibrillation is clearly associated with an increased rate of stroke. Numerous large clinical trials have shown that dose-adjusted warfarin can reduce the stroke rate in these patients, particularly in the elderly, and clear guidelines for the use of anticoagulants in such patients have been published. However, many studies show that treatment rates remain disappointingly low (< or = 50%). Numerous barriers to the use of dose-adjusted warfarin exist, including practical, patient-, physician-, and healthcare system-related barriers. These include the complex pharmacokinetics of warfarin, the need for continuous prothrombin time monitoring and dose adjustments, bleeding events, noncompliance, drug interactions, and increased costs of monitoring and therapy. Possible solutions to this problem are discussed and include improved patient and physician education, the use of anticoagulation clinics, new approaches to AF, and potential treatment improvements through use of newer anticoagulants.

Is right ventricular outflow tract pacing an alternative to left ventricular/biventricular pacing?

The right ventricular apex has been used as the traditional pacing site since the development of transvenous pacing in 1959. Some studies suggest that pacing the right ventricular apex may cause remodeling and is harmful. In the past decade, there have been a multitude of studies of the hemodynamic, electrophysiological, electrocardiographic, and clinical effects of ventricular pacing at other sites. Pacing of the left ventricle singly or with biventricular pacing has emerged as an effective and safe therapy for moderate to severe congestive heart failure in patients with prolonged QRS complexes. Studies of alternate right ventricular sites, like the right ventricular outflow tract, have given mixed results. Not all patients can be treated with left ventricular pacing, which is a time-consuming and difficult procedure. Right ventricular pacing is easier and less expensive than left ventricular pacing and further study of additional right ventricular sites seems warranted.

Determination of repetitive slow pathway conduction for evaluation of the efficacy of radiofrequency ablation in AVNRT.

AIMS: To determine whether the loss of repetitive slow pathway conduction identifies a successful radiofrequency ablation of atrioventricular nodal reentry tachycardia (AVNRT). METHODS AND RESULTS: Thirty nine consecutive patients undergoing ablation of AVNRT using the slow pathway approach were included. At baseline and after each radiofrequency application with an episode of junctional rhythm, repetitive slow pathway conduction was assessed as follows: Effective refractory period of the fast pathway was determined. The coupling interval of the first atrial extrastimulus (A2) was set at 30 ms below the effective refractory period of the fast pathway to ensure its conduction via the slow pathway. The second atrial extrastimulus (A3) was introduced at progressively longer coupling intervals starting from 200 ms until: (1) it propagated to the His bundle or (2) an anterogradely blocked AV nodal echo of A2 appeared before a conducted A3 depolarized the atrium in the His bundle electrogram. The response was termed repetitive slow pathway conduction if A3 was conducted with an AH > 200 ms. Application was considered successful if no AVNRT could be induced. Repetitive slow pathway conduction was present after 1 of 39 successful and after 34 of 40 ineffective applications (P < 0.0001). Repetitive slow pathway conduction identified a successful application with 97% sensitivity, 86% specificity, 86% positive predictive value, and 97% negative predictive value. CONCLUSION: The presence of repetitive slow pathway conduction identifies an unsuccessful application with a clinically meaningful negative predictive value.