Acute exercise induces distinct quantitative and phenotypical T cell profiles in men with prostate cancer.

Background: Reduced testosterone levels can influence immune system function, particularly T cells. Exercise during cancer reduces treatment-related side effects and provide a stimulus to mobilize and redistribute immune cells. However, it is unclear how conventional and unconventional T cells (UTC) respond to acute exercise in prostate cancer survivors compared to healthy controls. Methods: Age-matched prostate cancer survivors on androgen deprivation therapy (ADT) and those without ADT (PCa) along with non-cancer controls (CON) completed ∼45 min of intermittent cycling with 3 min at 60% of peak power interspersed by 1.5 min of rest. Fresh, unstimulated immune cell populations and intracellular perforin were assessed before (baseline), immediately following (0 h), 2 h, and 24 h post-exercise. Results: At 0 h, conventional T cell counts increased by 45%-64% with no differences between groups. T cell frequency decreased by -3.5% for CD3+ and -4.5% for CD4+ cells relative to base at 0 h with CD8+ cells experiencing a delayed decrease of -4.5% at 2 h with no group differences. Compared to CON, the frequency of CD8+CD57+ cells was -18.1% lower in ADT. Despite a potential decrease in maturity, ADT increased CD8+perforin+ GMFI. CD3+Vα7.2+CD161+ counts, but not frequencies, increased by 69% post-exercise while CD3+CD56+ cell counts increased by 127% and were preferentially mobilized (+1.7%) immediately following the acute cycling bout. There were no UTC group differences. Cell counts and frequencies returned to baseline by 24 h. Conclusion: Following acute exercise, prostate cancer survivors demonstrate normal T cell and UTC responses that were comparable to CON. Independent of exercise, ADT is associated with lower CD8+ cell maturity (CD57) and perforin frequency that suggests a less mature phenotype. However, higher perforin GMFI may attenuate these changes, with the functional implications of this yet to be determined.

[177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial.

BACKGROUND: Lutetium-177 [177Lu]Lu-PSMA-617 is a radiolabelled small molecule that delivers ß radiation to cells expressing prostate-specific membrane antigen (PSMA), with activity and safety in patients with metastatic castration-resistant prostate cancer. We aimed to compare [177Lu]Lu-PSMA-617 with cabazitaxel in patients with metastatic castration-resistant prostate cancer. METHODS: We did this multicentre, unblinded, randomised phase 2 trial at 11 centres in Australia. We recruited men with metastatic castration-resistant prostate cancer for whom cabazitaxel was considered the next appropriate standard treatment. Participants were required to have adequate renal, haematological, and liver function, and an Eastern Cooperative Oncology Group performance status of 0-2. Previous treatment with androgen receptor-directed therapy was allowed. Men underwent gallium-68 [68Ga]Ga-PSMA-11 and 2-flourine-18[18F]fluoro-2-deoxy-D-glucose (FDG) PET-CT scans. PET eligibility criteria for the trial were PSMA-positive disease, and no sites of metastatic disease with discordant FDG-positive and PSMA-negative findings. Men were randomly assigned (1:1) to [177Lu]Lu-PSMA-617 (6·0-8·5 GBq intravenously every 6 weeks for up to six cycles) or cabazitaxel (20 mg/m2 intravenously every 3 weeks for up to ten cycles). The primary endpoint was prostate-specific antigen (PSA) response defined by a reduction of at least 50% from baseline. This trial is registered with ClinicalTrials.gov, NCT03392428. FINDINGS: Between Feb 6, 2018, and Sept 3, 2019, we screened 291 men, of whom 200 were eligible on PET imaging. Study treatment was received by 98 (99%) of 99 men randomly assigned to [177Lu]Lu-PSMA-617 versus 85 (84%) of 101 randomly assigned to cabazitaxel. PSA responses were more frequent among men in the [177Lu]Lu-PSMA-617 group than in the cabazitaxel group (65 vs 37 PSA responses; 66% vs 37% by intention to treat; difference 29% (95% CI 16-42; p<0·0001; and 66% vs 44% by treatment received; difference 23% [9-37]; p=0·0016). Grade 3-4 adverse events occurred in 32 (33%) of 98 men in the [177Lu]Lu-PSMA-617 group versus 45 (53%) of 85 men in the cabazitaxel group. No deaths were attributed to [177Lu]Lu-PSMA-617. INTERPRETATION: [177Lu]Lu-PSMA-617 compared with cabazitaxel in men with metastatic castration-resistant prostate cancer led to a higher PSA response and fewer grade 3 or 4 adverse events. [177Lu]Lu-PSMA-617 is a new effective class of therapy and a potential alternative to cabazitaxel. FUNDING: Prostate Cancer Foundation of Australia, Endocyte (a Novartis company), Australian Nuclear Science and Technology Organization, Movember, The Distinguished Gentleman's Ride, It's a Bloke Thing, and CAN4CANCER.

Natural killer cell mobilization and egress following acute exercise in men with prostate cancer.

NEW FINDINGS: What is the central question of this study? What are the characteristics of the NK cell response following acute moderate-intensity aerobic exercise in prostate cancer survivors and is there a relationship between stress hormones and NK cell mobilization? What is the main finding and its importance? NK cell numbers and proportions changed similarly between prostate cancer survivors and controls following acute exercise. Consecutive training sessions can likely be used without adverse effects on the immune system during prostate cancer treatment. ABSTRACT: Prostate cancer treatment affects multiple physiological systems, although the immune response during exercise has been minimally investigated. The objective was to characterize the natural killer (NK) cell response following acute exercise in prostate cancer survivors. Prostate cancer survivors on androgen deprivation therapy (ADT) and those without (PCa) along with non-cancer controls (CON) completed a moderate intensity cycling bout. NK cells were phenotyped before and 0, 2 and 24 h after acute exercise using flow cytometry. CD56 total NK cell frequency increased by 6.2% at 0 h (P < 0.001) and decreased by 2.5% at 2 h (P < 0.01) with similar findings in CD56dim cells. NK cell counts also exhibited a biphasic response. Independent of exercise, ADT had intracellular interferon γ (IFNγ) expression that was nearly twofold higher than CON (P < 0.01). PCa perforin expression was reduced by 11.4% (P < 0.05), suggesting these cells may be more prone to degranulation. CD57- NK cells demonstrated increased perforin and IFNγ frequencies after exercise with no change within the CD57+ populations. All NK and leukocyte populations returned to baseline by 24 h. NK cell mobilization and egress with acute exercise appear normal, as cell counts and frequencies in prostate cancer survivors change similarly to CON. However, lower perforin proportions (PCa) and higher IFNγ expression (ADT) may alter NK cytotoxicity and require further investigation. The return of NK cell proportions to resting levels overnight suggests that consecutive training sessions can be used without adverse effects on the immune system during prostate cancer treatment.

Effect of androgen deprivation therapy on the contractile properties of type I and type II skeletal muscle fibres in men with non-metastatic prostate cancer.

The contractile properties of vastus lateralis muscle fibres were examined in prostate cancer (PrCa) patients undergoing androgen deprivation therapy (ADT) and in age- and activity-matched healthy male subjects (Control). Mechanically-skinned muscle fibres were exposed to a sequence of heavily Ca2+ -buffered solutions at progressively higher free [Ca2+ ] to determine their force-Ca2+ relationship. Ca2+ -sensitivity was decreased in both type I and type II muscle fibres of ADT subjects relative to Controls (by -0.05 and -0.04 pCa units, respectively, P < .02), and specific force was around 13% lower in type I fibres of ADT subjects than in Controls (P = .02), whereas there was no significant difference in type II fibres. Treatment with the reducing agent dithiothreitol slightly increased specific force in type I and type II fibres of ADT subjects (by ~2%-3%, P < .05) but not in Controls. Pure type IIx fibres were found frequently in muscle from ADT subjects but not in Controls, and the overall percentage of myosin heavy chain IIx in muscle samples was 2.5 times higher in ADT subjects (P < .01). The findings suggest that testosterone suppression can negatively impact the contractile properties by (i) reducing Ca2+ -sensitivity in both type I and type II fibres and (ii) reducing maximum specific force in type I fibres.

Attenuation of Resting but Not Load-Mediated Protein Synthesis in Prostate Cancer Patients on Androgen Deprivation.

CONTEXT: Androgen deprivation therapy (ADT) is a common prostate cancer (PCa) treatment but results in muscular atrophy. Periodic increases in muscle protein synthesis (MPS) that occur after resistance exercise or protein intake may ameliorate this muscle loss, but the impact of these anabolic stimuli during ADT is unclear. OBJECTIVE: To determine the acute MPS response to whey protein supplementation with and without resistance exercise during ADT. DESIGN: Acute response in PCa patients vs age-matched controls (CON). SETTING: Academic laboratory setting. PARTICIPANTS: PCa patients on ADT (N = 8) and CON (N = 10). INTERVENTION: A standardized diet was consumed for 2 days prior to performing unilateral knee extension resistance exercise followed by ingestion of 40 g of whey protein. MAIN OUTCOME MEASURES: Bilateral biopsies and stable isotope infusions were used to determine MPS rates at rest after protein ingestion with and without resistance exercise. RESULTS: Baseline MPS during ADT was suppressed relative to CON (P = 0.01). Protein consumption stimulated MPS in both groups (approximate twofold increase, both P < 0.001), but to a greater extent in CON (P = 0.003). Protein plus resistance exercise increased MPS (∼3.4-fold increase, both P < 0.001) to a greater extent than did protein alone (P < 0.001), but with no difference between groups (P = 0.380). CONCLUSIONS: ADT reduces basal and protein feeding-induced rises in MPS; however, combined protein ingestion with resistance exercise stimulated MPS to a similar degree as CON. Testosterone appears to play a role in maintaining muscle mass but is not necessary to initiate a robust response in MPS following resistance exercise when combined with protein ingestion.

Triple targeting of Auger emitters using octreotate conjugated to a DNA-binding ligand and a nuclear localizing signal.

PURPOSE: We investigated the effect of incorporation of a nuclear localization signal (NLS) into a conjugate comprising the DNA binding ligand para-iodoHoechst (PIH) and octreotate on its DNA binding and affinity to the somatostatin receptor (SSTR). Confirmation of these properties would support development of similar conjugates labelled with Auger emitters for their potential in Auger endoradiotherapy. MATERIALS AND METHODS: We synthesized conjugates of PIH and octreotate (PO) or PIH and NLS (PN) and a conjugate comprising PIH, NLS and octreotate (PNO). DNA-binding characteristics of PIH and conjugates were assessed using synthetic DNA oligonucleotides employing spectrophotometric titration of ligand solutions with DNA. We used membranes from the type 2 SSTR (SSTR2) overexpressing human non-small cell lung cancer cell line A427-7 to investigate the binding affinity of PNO. RESULTS: We demonstrated PN and PNO retain specific high affinity DNA-binding properties observed for PIH, and acquire an additional non-specific binding capacity. No DNA binding was observed for PO. PNO retains its binding affinity for SSTR. CONCLUSIONS: The DNA-binding properties of PNO and its affinity for SSTR suggests that it could potentially be used for tumour-specific delivery of PIH labelled with an Auger emitter in SSTR expressing tumours.

A phase I trial of radioimmunotherapy with 131I-A5B7 anti-CEA antibody in combination with combretastatin-A4-phosphate in advanced gastrointestinal carcinomas.

PURPOSE: In preclinical models, radioimmunotherapy with (131)I-A5B7 anti-carcinoembryonic antigen (CEA) antibody ((131)I-A5B7) combined with the vascular disruptive agent combretastatin-A4-phosphate (CA4P) produced cures unlike either agent alone. We conducted a phase I trial determining the dose-limiting toxicity (DLT), maximum tolerated dose, efficacy, and mechanism of this combination in patients with gastrointestinal adenocarcinomas. EXPERIMENTAL DESIGN: Patients had CEA of 10 to 1,000 microg/L, QTc < or =450 ms, no cardiac arrhythmia/ischaemia, and adequate hematology/biochemistry. Tumor was suitable for blood flow analysis by dynamic contrast enhanced-magnetic resonance imaging (MRI). The starting dose was 1,800 MBq/m(2) of (131)I-A5B7 on day 1 and 45 mg/m(2) CA4P given 48 and 72 hours post-(131)I-A5B7, then weekly for up to seven weeks. RESULTS: Twelve patients were treated, with mean age of 63 years (range, 32-77). Two of six patients at the first dose level had DLTs (grade 4 neutropenia). The dose was reduced to 1,600 MBq/m(2), and CA4P escalated to 54 mg/m(2). Again, two of six patients had DLTs (neutropenia). Of ten assessable patients, three had stable disease and seven had progressive disease. Single-photon emission computed tomography confirmed tumor antibody uptake in all 10 patients. DCE-MRI confirmed falls in kinetic parameters (K(trans)/IAUGC(60)) in 9 of 12 patients. The change of both pharmacokinetic parameters reached a level expected to produce efficacy in one patient who had a minor response on computed tomography and a reduced serum tumor marker level. CONCLUSIONS: This is believed to be the first trial reporting the combination of radioimmunotherapy and vascular disruptive agent; each component was shown to function, and myelosuppression was dose-limiting. Optimal dose and timing of CA4P, and moderate improvements in the performance of radioimmunotherapy seem necessary for efficacy.