The ectonucleotidase CD39 identifies tumor-reactive CD8+ T cells predictive of immune checkpoint blockade efficacy in human lung cancer.

Improved identification of anti-tumor T cells is needed to advance cancer immunotherapies. CD39 expression is a promising surrogate of tumor-reactive CD8+ T cells. Here, we comprehensively profiled CD39 expression in human lung cancer. CD39 expression enriched for CD8+ T cells with features of exhaustion, tumor reactivity, and clonal expansion. Flow cytometry of 440 lung cancer biospecimens revealed weak association between CD39+ CD8+ T cells and tumoral features, such as programmed death-ligand 1 (PD-L1), tumor mutation burden, and driver mutations. Immune checkpoint blockade (ICB), but not cytotoxic chemotherapy, increased intratumoral CD39+ CD8+ T cells. Higher baseline frequency of CD39+ CD8+ T cells conferred improved clinical outcomes from ICB therapy. Furthermore, a gene signature of CD39+ CD8+ T cells predicted benefit from ICB, but not chemotherapy, in a phase III clinical trial of non-small cell lung cancer. These findings highlight CD39 as a proxy of tumor-reactive CD8+ T cells in human lung cancer.

A Modified Net Reclassification Improvement Statistic.

The continuous net reclassification improvement (NRI) statistic is a popular model change measure that was developed to assess the incremental value of new factors in a risk prediction model. Two prominent statistical issues identified in the literature call the utility of this measure into question: (1) it is not a proper scoring function and (2) it has a high false positive rate when testing whether new factors contribute to the risk model. For binary response regression models, these subjects are interrogated and a modification of the continuous NRI, guided by the likelihood-based score residual, is proposed to address these issues. Within a nested model framework, the modified NRI may be viewed as a distance measure between two risk models. An application of the modified NRI is illustrated using prostate cancer data.

Immune biomarkers and response to checkpoint inhibition of BRAFV600 and BRAF non-V600 altered lung cancers.

BACKGROUND: While 2-4% of lung cancers possess alterations in BRAF, little is known about the immune responsiveness of these tumours. METHODS: Clinical and genomic data were collected from 5945 patients with lung cancers whose tumours underwent next-generation sequencing between 2015 and 2018. Patients were followed through 2020. RESULTS: In total, 127 patients with metastatic BRAF-altered lung cancers were identified: 29 tumours had Class I mutations, 59 had Class II/III alterations, and 39 had variants of unknown significance (VUS). Tumour mutation burden was higher in Class II/III than Class I-altered tumours (8.8 mutations/Mb versus 4.9, P < 0.001), but this difference was diminished when stratified by smoking status. The overall response rate to immune checkpoint inhibitors (ICI) was 9% in Class I-altered tumours and 26% in Class II/III (P = 0.25), with median time on treatment of 1.9 months in both groups. Among patients with Class I-III-altered tumours, 36-month HR for death in those who ever versus never received ICI was 1.82 (1.17-6.11). Nine patients were on ICI for >2 years (two with Class I mutations, two with Class II/III alterations, and five with VUS). CONCLUSIONS: A subset of patients with BRAF-altered lung cancers achieved durable disease control on ICI. However, collectively no significant clinical benefit was seen.

Genomic correlates of clinical outcome in advanced prostate cancer.

Heterogeneity in the genomic landscape of metastatic prostate cancer has become apparent through several comprehensive profiling efforts, but little is known about the impact of this heterogeneity on clinical outcome. Here, we report comprehensive genomic and transcriptomic analysis of 429 patients with metastatic castration-resistant prostate cancer (mCRPC) linked with longitudinal clinical outcomes, integrating findings from whole-exome, transcriptome, and histologic analysis. For 128 patients treated with a first-line next-generation androgen receptor signaling inhibitor (ARSI; abiraterone or enzalutamide), we examined the association of 18 recurrent DNA- and RNA-based genomic alterations, including androgen receptor (AR) variant expression, AR transcriptional output, and neuroendocrine expression signatures, with clinical outcomes. Of these, only RB1 alteration was significantly associated with poor survival, whereas alterations in RB1, AR, and TP53 were associated with shorter time on treatment with an ARSI. This large analysis integrating mCRPC genomics with histology and clinical outcomes identifies RB1 genomic alteration as a potent predictor of poor outcome, and is a community resource for further interrogation of clinical and molecular associations.

Baseline Testosterone Levels in Men with Clinically Localized High-Risk Prostate Cancer Treated with Radical Prostatectomy with or without Neoadjuvant Chemohormonal Therapy (Alliance).

PURPOSE: Men with low serum testosterone at the time of prostate cancer diagnosis are frequently considered to have more aggressive disease. We examined treatment outcomes in men with clinically localized high-risk cancer to determine if baseline testosterone level identified men at higher risk for cancer progression after treatment. MATERIALS AND METHODS: Alliance/CALGB 90203 randomized men with clinically localized high-risk prostate cancer to radical prostatectomy alone or neoadjuvant chemohormonal therapy and radical prostatectomy. Men with available baseline testosterone levels who had not received androgen deprivation prior to study enrollment were studied (656). Testosterone level was examined as a continuous variable, as quartiles, and separately in men with an absolute testosterone level above/below 150 ng/dl. Outcomes evaluated were overall survival and event-free survival with events defined by biochemical recurrence, secondary treatment, prostate cancer metastasis, and death. RESULTS: We were unable to demonstrate a difference between baseline serum testosterone level measured as a continuous variable, as quartiles, or as a dichotomous variable (above/below 150 ng/dl) with the outcomes measured. This finding was observed in both arms of the study. CONCLUSIONS: Baseline serum testosterone level did not predict outcomes in men with clinically localized high-risk prostate cancer treated with radical prostatectomy alone or neoadjuvant chemohormonal therapy and radical prostatectomy.

Toxicity and response after CD19-specific CAR T-cell therapy in pediatric/young adult relapsed/refractory B-ALL.

Chimeric antigen receptor (CAR) T cells have demonstrated clinical benefit in patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We undertook a multicenter clinical trial to determine toxicity, feasibility, and response for this therapy. A total of 25 pediatric/young adult patients (age, 1-22.5 years) with R/R B-ALL were treated with 19-28z CAR T cells. Conditioning chemotherapy included high-dose (3 g/m2) cyclophosphamide (HD-Cy) for 17 patients and low-dose (≤1.5 g/m2) cyclophosphamide (LD-Cy) for 8 patients. Fifteen patients had pretreatment minimal residual disease (MRD; <5% blasts in bone marrow), and 10 patients had pretreatment morphologic evidence of disease (≥5% blasts in bone marrow). All toxicities were reversible, including severe cytokine release syndrome in 16% (4 of 25) and severe neurotoxicity in 28% (7 of 25) of patients. Treated patients were assessed for response, and, among the evaluable patients (n = 24), response and peak CAR T-cell expansion were superior in the HD-Cy/MRD cohorts, as compared with the LD-Cy/morphologic cohorts without an increase in toxicity. Our data support the safety of CD19-specific CAR T-cell therapy for R/R B-ALL. Our data also suggest that dose intensity of conditioning chemotherapy and minimal pretreatment disease burden have a positive impact on response without a negative effect on toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01860937.

The added value of new covariates to the brier score in cox survival models.

Calibration is an important measure of the predictive accuracy for a prognostic risk model. A widely used measure of calibration when the outcome is survival time is the expected Brier score. In this paper, methodology is developed to accurately estimate the difference in expected Brier scores derived from nested survival models and to compute an accompanying variance estimate of this difference. The methodology is applicable to time invariant and time-varying coefficient Cox survival models. The nested survival model approach is often applied to the scenario where the full model consists of conventional and new covariates and the subset model contains the conventional covariates alone. A complicating factor in the methodologic development is that the Cox model specification cannot, in general, be simultaneously satisfied for nested models. The problem has been resolved by projecting the properly specified full survival model onto the lower dimensional space of conventional markers alone. Simulations are performed to examine the method's finite sample properties and a prostate cancer data set is used to illustrate its application.

Measuring the temporal prognostic utility of a baseline risk score.

In the time-to-event setting, the concordance probability assesses the relative level of agreement between a model-based risk score and the survival time of a patient. While it provides a measure of discrimination over the entire follow-up period of a study, the probability does not provide information on the longitudinal durability of a baseline risk score. It is possible that a baseline risk model is able to segregate short-term from long-term survivors but unable to maintain its discriminatory strength later in the follow-up period. As a consequence, this would motivate clinicians to re-evaluate the risk score longitudinally. This longitudinal re-evaluation may not, however, be feasible in many scenarios since a single baseline evaluation may be the only data collectible due to treatment or other clinical or ethical reasons. In these scenarios, an attenuation of the discriminatory power of the patient risk score over time would indicate decreased clinical utility and call into question whether this score should remain a prognostic tool at later time points. Working within the concordance probability paradigm, we propose a method to address this clinical scenario and evaluate the discriminatory power of a baseline derived risk score over time. The methodology is illustrated with two examples: a baseline risk score in colorectal cancer defined at the time of tumor resection, and for circulating tumor cells in metastatic prostate cancer.

Inference for the difference in the area under the ROC curve derived from nested binary regression models.

The area under the curve (AUC) statistic is a common measure of model performance in a binary regression model. Nested models are used to ascertain whether the AUC statistic increases when new factors enter the model. The regression coefficient estimates used in the AUC statistics are computed using the maximum rank correlation methodology. Typically, inference for the difference in AUC statistics from nested models is derived under asymptotic normality. In this work, it is demonstrated that the asymptotic normality is true only when at least one of the new factors is associated with the binary outcome. When none of the new factors are associated with the binary outcome, the asymptotic distribution for the difference in AUC statistics is a linear combination of chi-square random variables. Further, when at least one new factor is associated with the outcome and the population difference is small, a variance stabilizing reparameterization improves the asymptotic normality of the AUC difference statistic. A confidence interval using this reparameterization is developed and simulations are generated to determine their coverage properties. The derived confidence interval provides information on the magnitude of the added value of new factors and enables investigators to weigh the size of the improvement against potential costs associated with the new factors. A pancreatic cancer data example is used to illustrate this approach.

Safe mobilization of CD34+ cells in adults with ß-thalassemia and validation of effective globin gene transfer for clinical investigation.

We conducted a pilot trial to investigate the safety and effectiveness of mobilizing CD34(+) hematopoietic progenitor cells (HPCs) in adults with ß-thalassemia major. We further assessed whether thalassemia patient CD34(+) HPCs could be transduced with a globin lentiviral vector under clinical conditions at levels sufficient for therapeutic implementation. All patients tolerated granulocyte colony-stimulating factor well with minimal side effects. All cell collections exceeded 8 × 10(6) CD34(+) cells/kg. Using clinical grade TNS9.3.55 vector, we demonstrated globin gene transfer averaging 0.53 in 3 validation runs performed under current good manufacturing practice conditions. Normalized to vector copy, the vector-encoded ß-chain was expressed at a level approximating normal hemizygous protein output. Importantly, stable vector copy number (0.2-0.6) and undiminished vector expression were obtained in NSG mice 6 months posttransplant. Thus, we validated a safe and effective procedure for ß-globin gene transfer in thalassemia patient CD34(+) HPCs, which we will implement in the first US trial in patients with severe inherited globin disorders. This trial is registered at www.clinicaltrials.gov as #NCT01639690.

Estimating the concordance probability in a survival analysis with a discrete number of risk groups.

A clinical risk classification system is an important component of a treatment decision algorithm. A measure used to assess the strength of a risk classification system is discrimination, and when the outcome is survival time, the most commonly applied global measure of discrimination is the concordance probability. The concordance probability represents the pairwise probability of lower patient risk given longer survival time. The c-index and the concordance probability estimate have been used to estimate the concordance probability when patient-specific risk scores are continuous. In the current paper, the concordance probability estimate and an inverse probability censoring weighted c-index are modified to account for discrete risk scores. Simulations are generated to assess the finite sample properties of the concordance probability estimate and the weighted c-index. An application of these measures of discriminatory power to a metastatic prostate cancer risk classification system is examined.

Everolimus combined with gefitinib in patients with metastatic castration-resistant prostate cancer: Phase 1/2 results and signaling pathway implications.

BACKGROUND: The effects of mammalian target of rapamycin (mTOR) inhibition are limited by feedback reactivation of receptor tyrosine kinase signaling in phosphatase and tensin homolog-null tumors. Thus, this study tested the combination of mTOR inhibition (everolimus) and epidermal growth factor receptor inhibition (gefitinib) in castration-resistant prostate cancer (CRPC). METHODS: In phase 1, 12 patients (10 with CRPC and 2 with glioblastoma) received daily gefitinib (250 mg) with weekly everolimus (30, 50, or 70 mg). In phase 2, 27 CRPC patients received gefitinib with everolimus (70 mg). RESULTS: Phase 1 revealed no pharmacokinetic interactions and no dose-limiting toxicities. In phase 2, 18 of 27 patients (67%) discontinued treatment before the 12-week evaluation because of progression as evidenced by prostate-specific antigen (PSA) levels (n = 6) or imaging (n = 5) or because of a grade 2 or higher toxicity (n = 7). Thirteen of the 37 CRPC patients (35%) exhibited a rapidly rising PSA level after they had begun treatment, and this declined upon discontinuation. Fluorodeoxyglucose positron emission tomography 24 to 72 hours after the initiation of treatment showed a decrease in the standardized uptake value consistent with mTOR inhibition in 27 of the 33 evaluable patients (82%); there was a corresponding rise in PSA in 20 of these 27 patients (74%). CONCLUSIONS: The combination of gefitinib and everolimus did not result in significant antitumor activity. The induction of PSA in tumors treated with mTOR inhibitors was consistent with preclinical data showing that phosphoinositide 3-kinase (PI3K) pathway signaling feedback inhibits the androgen receptor (AR). This clinical evidence of relief of feedback inhibition promoting enhanced AR activity supports future studies combining PI3K pathway inhibitors and second-generation AR inhibitors in CRPC.

Human Langerhans cells use an IL-15R-α/IL-15/pSTAT5-dependent mechanism to break T-cell tolerance against the self-differentiation tumor antigen WT1.

Human CD34(+) progenitor-derived Langerhans-type dendritic cells (LCs) are more potent stimulators of T-cell immunity against tumor and viral antigens in vitro than are monocyte-derived DCs (moDCs). The exact mechanisms have remained elusive until now, however. LCs synthesize the highest amounts of IL-15R-α mRNA and protein, which binds IL-15 for presentation to responder lymphocytes, thereby signaling the phosphorylation of signal transducer and activator of transcription 5 (pSTAT5). LCs electroporated with Wilms tumor 1 (WT1) mRNA achieve sufficiently sustained presentation of antigenic peptides, which together with IL-15R-α/IL-15, break tolerance against WT1 by stimulating robust autologous, WT1-specific cytolytic T-lymphocytes (CTLs). These CTLs develop from healthy persons after only 7 days' stimulation without exogenous cytokines and lyse MHC-restricted tumor targets, which include primary WT1(+) leukemic blasts. In contrast, moDCs require exogenous rhuIL-15 to phosphorylate STAT5 and attain stimulatory capacity comparable to LCs. LCs therefore provide a more potent costimulatory cytokine milieu for T-cell activation than do moDCs, thus accounting for their superior stimulation of MHC-restricted Ag-specific CTLs without need for exogenous cytokines. These data support the use of mRNA-electroporated LCs, or moDCs supplemented with exogenous rhuIL-15, as vaccines for cancer immunotherapy to break tolerance against self-differentiation antigens shared by tumors.

Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+ lymphomas after allogeneic hematopoietic cell transplantation.

We evaluated HLA-compatible donor leukocyte infusions (DLIs) and HLA-compatible or HLA-disparate EBV-specific T cells (EBV-CTLs) in 49 hematopoietic cell transplantation recipients with biopsy-proven EBV-lymphoproliferative disease (EBV-LPD). DLIs and EBV-CTLs each induced durable complete or partial remissions in 73% and 68% of treated patients including 74% and 72% of patients surviving ≥ 8 days after infusion, respectively. Reversible acute GVHD occurred in recipients of DLIs (17%) but not EBV-CTLs. The probability of complete response was significantly lower among patients with multiorgan involvement. In responders, DLIs and EBV-CTLs regularly induced exponential increases in EBV-specific CTL precursor (EBV-CTLp) frequencies within 7-14 days, with subsequent clearance of EBV viremia and resolution of disease. In nonresponders, EBV-CTLps did not increase and EBV viremia persisted. Treatment failures were correlated with impaired T-cell recognition of tumor targets. Either donor-derived EBV-CTLs that had been sensitized with autologous BLCLs transformed by EBV strain B95.8 could not lyse spontaneous donor-derived EBV-transformed BLCLs expanded from the patient's blood or biopsied tumor or they failed to lyse their targets because they were selectively restricted by HLA alleles not shared by the EBV-LPD. Therefore, either unselected DLIs or EBV-specific CTLs can eradicate both untreated and Rituxan-resistant lymphomatous EBV-LPD, with failures ascribable to impaired T-cell recognition of tumor-associated viral antigens or their presenting HLA alleles.

A phase I/II study of valemetostat (DS-3201b), an EZH1/2 inhibitor, in combination with irinotecan in patients with recurrent small cell lung cancer.

PURPOSE: Recurrent small cell lung cancer (SCLC) has few effective treatments. The EZH2-SLFN11 pathway is a driver of acquired chemoresistance that may be targeted. PATIENTS AND METHODS: This phase I/II trial investigated valemetostat, an EZH1/2 inhibitor, with fixed-dose irinotecan in patients with recurrent SCLC. Phase I primary objectives were to assess safety and a recommended phase II dose (RP2D). The phase II primary objective was to determine overall response rate (ORR), with secondary objectives of duration of response (DoR), progression-free survival (PFS) and overall survival (OS). Immunohistochemistry of pre- and on-treatment tumor biopsies and pharmacokinetics analysis were performed. RESULTS: Twenty-two patients enrolled (phase I, n=12; phase II n=10); one withdrew consent prior to treatment. Three dose-limiting toxicities (DLTs) in dose-escalation resulted in valemetostat 100 mg orally daily selected as RP2D. Among 21 toxicity-evaluable patients, the most frequent (≥20%) treatment-related adverse events were diarrhea, fatigue, nausea, and rash; 3 patients discontinued treatment for toxicity. In phase II, 3/10 patients experienced DLTs triggering a stopping rule. The ORR was 4/19 (21%, 95% CI 6 to 46%). The median DoR, PFS and OS were 4.6 mo, 2.2 mo (95% CI 1.3 to 7.6 mo) and 6.6 mo (95% CI 4.3 to not reached). SLFN11, EZH2 and SCLC subtyping markers did not correlate with response. MHC-I protein expression increased in 4/4 patients with paired biopsies, including 3/3 responders; two responders demonstrated subtype switching on treatment. CONCLUSIONS: Valemetostat and irinotecan was not tolerated but demonstrated efficacy in recurrent SCLC. Valemetostat may warrant further investigation in SCLC.

PRESTO: A Phase III, Open-Label Study of Intensification of Androgen Blockade in Patients With High-Risk Biochemically Relapsed Castration-Sensitive Prostate Cancer (AFT-19).

PURPOSE: Patients with biochemically recurrent prostate cancer (BRPC) after radical prostatectomy and a short PSA doubling time are at risk for distant metastases. Apalutamide, an androgen receptor antagonist, and abiraterone acetate plus prednisone (AAP) prolong survival in the metastatic setting. We evaluated whether intensification of androgen-deprivation therapy (ADT) improves outcomes in BRPC. PATIENTS AND METHODS: PRESTO is a randomized phase III, open-label trial in patients with BRPC and PSA doubling time ≤9 months (ClinicalTrials.gov identifier: NCT03009981). Patients were randomly assigned 1:1:1 to receive a finite 52-week treatment course with ADT control, ADT + apalutamide, or ADT + apalutamide + AAP. The primary end point was PSA progression-free survival (PSA-PFS), defined as serum PSA >0.2 ng/mL after treatment completion. RESULTS: Five hundred three patients were enrolled. The median PSA was 1.8 ng/mL (IQR, 1.0-3.6). At the first planned interim analysis, both experimental arms significantly prolonged PSA-PFS compared with the control arm (median, 24.9 months for ADT + apalutamide v 20.3 months for ADT; hazard ratio [HR], 0.52 [95% CI, 0.35 to 0.77]; P = .00047; median, 26.0 months for ADT + apalutamide + AAP v 20.0 months for ADT; HR, 0.48 [95% CI, 0.32 to 0.71]; P = .00008). Median time to testosterone recovery did not differ across treatment arms. The most common grade ≥3 adverse event was hypertension (7.5%, 7.4%, and 18% in ADT, ADT + apalutamide, and ADT + apalutamide + AAP arms, respectively). CONCLUSION: Intensified AR blockade for a finite duration prolongs PSA-PFS with a manageable safety profile, without adversely affecting time to testosterone recovery. The addition of apalutamide to ADT should be considered in patients with high-risk BRPC.

T cell-depleted stem cell transplantation for adults with high-risk acute lymphoblastic leukemia: long-term survival for patients in first complete remission with a decreased risk of graft-versus-host disease.

Consolidation with allogeneic hematopoietic stem cell transplantation (allo-HSCT) provides a survival benefit to patients with acute lymphoblastic leukemia (ALL). We have previously reported comparable survival and relapse rates after T cell-depleted (TCD) allo-HSCT compared with unmodified transplantations for acute myelogenous leukemia, myelodysplastic syndrome, and non-Hodgkin lymphoma with significantly decreased graft-versus-host disease (GVHD). We performed a 56-patient retrospective study to evaluate TCD allo-HSCT for the treatment of ALL after myeloablative total body irradiation-based therapy. The 2-year and 5-year overall survival rates for patients with ALL after TCD allo-HSCT were 0.39 (95% confidence interval [CI], 0.26-0.52) and 0.32 (95% CI, 0.19-0.44), respectively, and the 2-year and 5-year disease-free survival rates were 0.38 (95% CI, 0.25-0.50) and 0.32 (95% CI, 0.20-0.44). There was a trend toward improved survival of patients who underwent TCD allo-HSCT in first complete remission compared with those who did so in other remission states. The cumulative incidence of grade II-IV acute GVHD at 1 year was 0.20 (95% CI, 0.10-0.31), and no patients developed grade IV acute GVHD. The cumulative incidence of chronic GVHD in 41 evaluable patients at 2 and 5 years was 0.15 (95% CI, 0.04-0.26), and that of extensive chronic GVHD at 2 and 5 years was 0.05 (95% CI, 0-11.6). We demonstrate OS and DFS rates that compare favorably to unmodified allo-HSCT with lower rates of GVHD.

Repetitively dosed docetaxel and ¹5³samarium-EDTMP as an antitumor strategy for metastatic castration-resistant prostate cancer.

BACKGROUND: ß-emitting bone-seeking radiopharmaceuticals have historically been administered for pain palliation whereas docetaxel prolongs life in patients with metastatic castration-resistant prostate cancer (mCRPC). In combination, these agents simultaneously target the bone stroma and cancer cell to optimize antitumor effects. The toxicity and efficacy when each agent is combined at full, recommended doses, in a repetitive fashion is not well established. METHODS: Patients with progressive mCRPC and ≥ 3 bone lesions received (153) Sm-EDTMP (samarium-153 ethylene diamine tetramethylene phosphonate) at a dose of 1.0 mCi/kg every 9 weeks and docetaxel at a dose of 75 mg/m(2) every 3 weeks. In the absence of unacceptable toxicity, patients were allowed to continue additional cycles, defined by 9 weeks of treatment, until intolerance or biochemical/radiographic disease progression. RESULTS: Of the 30 patients treated, approximately 50% were considered to be taxane-naive, 36.7% were taxane-refractory, and 13.3% had previously been exposed to taxanes but were not considered refractory. Patients received on average 2.5 cycles of treatment (6.5 doses of docetaxel and 2.5 doses of (153) Sm-EDTMP). Twelve patients (40%) demonstrated a decline in their prostate-specific antigen level of ≥ 50%. The median progression-free survival (biochemical or radiographic) was 7.0 months and the overall survival was 14.3 months. Nine patients (30%) did not recover platelet counts >100 K/mm(3) after a median of 3 cycles to allow for additional treatment, with 4 patients experiencing prolonged thrombocytopenia. The most common reasons for trial discontinuation were progressive disease and hematologic toxicity. CONCLUSIONS: The results of the current study indicate that (153) Sm-EDTMP can be safely combined with docetaxel at full doses on an ongoing basis in patients with mCRPC. Although thrombocytopenia limited therapy for some patients, preliminary efficacy supports the strategy of combining a radiopharmaceutical with chemotherapy, which is an appealing strategy given the anticipated availability of α emitters that can prolong survival.

A measure of explained risk in the proportional hazards model.

A measure of explained risk is developed for application with the proportional hazards model. The statistic, which is called the estimated explained relative risk, has a simple analytical form and is unaffected by censoring that is independent of survival time conditional on the covariates. An asymptotic confidence interval for the limiting value of the estimated explained relative risk is derived, and the role of individual factors in the computation of its estimate is established. Simulations are performed to compare the results of the estimated explained relative risk to other known explained risk measures with censored data. Prostate cancer data are used to demonstrate an analysis incorporating the proposed approach.

Janus kinase-2 inhibition induces durable tolerance to alloantigen by human dendritic cell-stimulated T cells yet preserves immunity to recall antigen.

Janus kinase-2 (JAK2) conveys receptor-binding signals by several inflammatory cytokines, including IL-6, via phosphorylation of signal transducer and activator of transcription 3 (STAT3). We demonstrate that selective JAK2 inhibition by TG101348 during initial encounters between human T cells and allogeneic monocyte-derived dendritic cells induces durable, profound, and specific T-cell tolerance upon reexposure to the same alloantigens. Subsequent responses by nonalloreactive T cells to stimulation de novo by a pathogenic nominal antigen remain intact. TG101348 also suppresses primed T-cell responses when present only during alloantigen restimulation. TG101348 ablates IL-6/JAK2-mediated phosphorylation of STAT3, but has no off-target effects on IL-2 or IL-15/JAK3/pSTAT5-dependent signaling, which sustain the responses of regulatory T cells (Tregs) and other effector T cells. JAK2 inhibition preserves Treg numbers and thereby enhances the ratio of CD4(+) Tregs to CD8(+)CD25(+) effector T cells in favor of Tregs. JAK2 inhibition also reduces the production of IL-6 and TNF-α in allogeneic MLRs, impairing the activation of central and effector memory T cells as well as the expansion of responder Th1 and Th17 cells. While we have reported the limitations of isolated IL-6R-α inhibition on dendritic cell-stimulated alloreactivity, we demonstrate here that JAK2 represents a relevant biologic target for controlling GVHD or allograft rejection without broader immune impairment.