L-Selectin Is Dispensable for T Regulatory Cell Function Postallogeneic Bone Marrow Transplantation: CD62L−/− Tregs Inhibit Acute GvHD

In murine models, the adoptive transfer of CD4+/CD25+ regulatory T cells (Tregs) inhibited graft-versus-host disease (GvHD). Previous work has indicated a critical role for the adhesion molecule L-selectin (CD62L) in the function of Tregs in preventing GvHD. Here we examined the capacity of naive wild-type (WT), CD62L−/− and ex vivo expanded CD62LLo Tregs to inhibit acute GvHD. Surprisingly, we found that CD62L−/− Tregs were potent suppressors of GvHD, whereas CD62LLo Tregs were unable to inhibit disease despite being functionally competent to suppress allo T cell responses in vitro. Concomitant with improved outcomes, WT and CD62L−/− Tregs significantly reduced liver pathology and systemic pro-inflammatory cytokine production, although CD62L−/− Tregs were less effective in reducing lung pathology. While accumulation of CD62L−/− Tregs in GvHD target organs was equivalent to WT Tregs, CD62L−/− Tregs did not migrate as well as WT Tregs to peripheral lymph nodes (PLNs) over the first 2 weeks posttransplantation. This work demonstrated that CD62L was dispensable for Treg-mediated protection from GvHD

Subsequent therapy following pembrolizumab + axitinib or sunitinib treatment for advanced renal cell carcinoma (RCC) in the phase III KEYNOTE-426 study

Background: In the phase III KEYNOTE-426 study, pembrolizumab + axitinib showed significant improvement in OS, PFS, and ORR vs sunitinib in patients with RCC. This analysis assessed subsequent treatment in patients enrolled in KEYNOTE-426. Methods: Treatment-naive patients with clear cell RCC, KPS score �70%, and measurable disease (RECIST v1.1) were randomly assigned 1:1 to receive pembrolizumab 200 mg IV every 3 weeks for up to 35 doses + axitinib 5 mg orally twice daily or sunitinib 50 mg once daily (4 weeks on/2 weeks off) until progression, toxicity, or withdrawal. Type of and time to subsequent therapy were assessed. Results: Of patients in the pembrolizumab + axitinib arm and in the sunitinib arm, 81.4% (349/432) and 90.6% of patients (385/429), respectively, discontinued treatment; radiologic or clinical PD was the most common reason for discontinuation in both (pembrolizumab + axitinib: 65.0% [227/349]; sunitinib: 68.1% [262/385]). Of patients who discontinued, 58.5% of patients (204/349) in the pembrolizumab + axitinib arm and 73.0% (281/385) in the sunitinib arm received subsequent therapy (Table). Although a similar proportion of patients in both arms received subsequent therapy with a VEGF/VEGFR inhibitor (pembrolizumab + axitinib: 88.2% [180/204]; sunitinib: 68.7% [193/281]), a greater proportion of patients in the sunitinib arm (74.4% [209/281]) received subsequent PD-1/PD-L1 inhibitor therapy than in the pembrolizumab + axitinib arm (21.6% [44/204]). Of patients in the pembrolizumab + axitinib arm and the sunitinib arm, 32.4% (66/204) and 22.8% (64/281), respectively, received other therapies

Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer.

Background We previously reported that olaparib led to significantly longer imaging-based progression-free survival than the physician's choice of enzalutamide or abiraterone among men with metastatic castration-resistant prostate cancer who had qualifying alterations in homologous recombination repair genes and whose disease had progressed during previous treatment with a next-generation hormonal agent. The results of the final analysis of overall survival have not yet been reported.Methods In an open-label, phase 3 trial, we randomly assigned patients in a 2:1 ratio to receive olaparib (256 patients) or the physician's choice of enzalutamide or abiraterone plus prednisone as the control therapy (131 patients). Cohort A included 245 patients with at least one alteration in BRCA1, BRCA2, or ATM, and cohort B included 142 patients with at least one alteration in any of the other 12 prespecified genes. Crossover to olaparib was allowed after imaging-based disease progression for patients who met certain criteria. Overall survival in cohort A, a key secondary end point, was analyzed with the use of an alpha-controlled, stratified log-rank test at a data maturity of approximately 60%. The primary and other key secondary end points were reported previously.Results The median duration of overall survival in cohort A was 19.1 months with olaparib and 14.7 months with control therapy (hazard ratio for death, 0.69; 95% confidence interval [CI], 0.50 to 0.97; P = 0.02). In cohort B, the median duration of overall survival was 14.1 months with olaparib and 11.5 months with control therapy. In the overall population (cohorts A and B), the corresponding durations were 17.3 months and 14.0 months. Overall, 86 of 131 patients (66%) in the control group crossed over to receive olaparib (56 of 83 patients [67%] in cohort A). A sensitivity analysis that adjusted for crossover to olaparib showed hazard ratios for death of 0.42 (95% CI, 0.19 to 0.91) in cohort A, 0.83 (95% CI, 0.11 to 5.98) in cohort B, and 0.55 (95% CI, 0.29 to 1.06) in the overall population.Conclusions Among men with metastatic castration-resistant prostate cancer who had tumors with at least one alteration in BRCA1, BRCA2, or ATM and whose disease had progressed during previous treatment with a next-generation hormonal agent, those who were initially assigned to receive olaparib had a significantly longer duration of overall survival than those who were assigned to receive enzalutamide or abiraterone plus prednisone as the control therapy, despite substantial crossover from control therapy to olaparib. (Funded by AstraZeneca and Merck Sharp and Dohme; PROfound ClinicalTrials.gov number, NCT02987543.)

Olaparib for Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND:Multiple loss-of-function alterations in genes that are involved in DNA repair, including homologous recombination repair, are associated with response to poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition in patients with prostate and other cancers. METHODS:We conducted a randomized, open-label, phase 3 trial evaluating the PARP inhibitor olaparib in men with metastatic castration-resistant prostate cancer who had disease progression while receiving a new hormonal agent (e.g., enzalutamide or abiraterone). All the men had a qualifying alteration in prespecified genes with a direct or indirect role in homologous recombination repair. Cohort A (245 patients) had at least one alteration in BRCA1, BRCA2, or ATM; cohort B (142 patients) had alterations in any of 12 other prespecified genes, prospectively and centrally determined from tumor tissue. Patients were randomly assigned (in a 2:1 ratio) to receive olaparib or the physician's choice of enzalutamide or abiraterone (control). The primary end point was imaging-based progression-free survival in cohort A according to blinded independent central review. RESULTS:In cohort A, imaging-based progression-free survival was significantly longer in the olaparib group than in the control group (median, 7.4 months vs. 3.6 months; hazard ratio for progression or death, 0.34; 95% confidence interval, 0.25 to 0.47; P<0.001); a significant benefit was also observed with respect to the confirmed objective response rate and the time to pain progression. The median overall survival in cohort A was 18.5 months in the olaparib group and 15.1 months in the control group; 81% of the patients in the control group who had progression crossed over to receive olaparib. A significant benefit for olaparib was also seen for imaging-based progression-free survival in the overall population (cohorts A and B). Anemia and nausea were the main toxic effects in patients who received olaparib. CONCLUSIONS:In men with metastatic castration-resistant prostate cancer who had disease progression while receiving enzalutamide or abiraterone and who had alterations in genes with a role in homologous recombination repair, olaparib was associated with longer progression-free survival and better measures of response and patient-reported end points than either enzalutamide or abiraterone. (Funded by AstraZeneca and Merck Sharp & Dohme; PROfound ClinicalTrials.gov number, NCT02987543.)

Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: We previously reported that olaparib led to significantly longer imaging-based progression-free survival than the physician\u27s choice of enzalutamide or abiraterone among men with metastatic castration-resistant prostate cancer who had qualifying alterations in homologous recombination repair genes and whose disease had progressed during previous treatment with a next-generation hormonal agent. The results of the final analysis of overall survival have not yet been reported. METHODS: In an open-label, phase 3 trial, we randomly assigned patients in a 2:1 ratio to receive olaparib (256 patients) or the physician\u27s choice of enzalutamide or abiraterone plus prednisone as the control therapy (131 patients). Cohort A included 245 patients with at least one alteration in RESULTS: The median duration of overall survival in cohort A was 19.1 months with olaparib and 14.7 months with control therapy (hazard ratio for death, 0.69; 95% confidence interval [CI], 0.50 to 0.97; P = 0.02). In cohort B, the median duration of overall survival was 14.1 months with olaparib and 11.5 months with control therapy. In the overall population (cohorts A and B), the corresponding durations were 17.3 months and 14.0 months. Overall, 86 of 131 patients (66%) in the control group crossed over to receive olaparib (56 of 83 patients [67%] in cohort A). A sensitivity analysis that adjusted for crossover to olaparib showed hazard ratios for death of 0.42 (95% CI, 0.19 to 0.91) in cohort A, 0.83 (95% CI, 0.11 to 5.98) in cohort B, and 0.55 (95% CI, 0.29 to 1.06) in the overall population. CONCLUSIONS: Among men with metastatic castration-resistant prostate cancer who had tumors with at least one alteration i

Single-cell protein diet of a novel recombinant vitellogenin yeast enhances growth and survival of first-feeding tilapia (Oreochromis mossambicus) larvae

Journal of Nutrition1353513-518JONU