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Immunotherapy is an innovative treatment approach that harnesses a patient's immune system to treat cancer. It has provided an alternative and complementary treatment modality to conventional chemotherapy. Combining immunotherapy with cytotoxic chemotherapy agent has become the leading trend and the most active research field in oncology. To accommodate this growing trend, we propose a Bayesian phase I/II dose‐finding design to identify the optimal biological dose combination (OBDC), defined as the dose combination with the highest desirability in the risk‐benefit trade‐off. We propose new statistical models to describe the relationship between the doses and treatment outcomes, including immune response, toxicity and progression‐free survival (PFS). During the trial, based on accrued data, we continuously update model estimates and adaptively assign patients to dose combinations with high desirability. The simulation study shows that our design has desirable operating characteristics. [ABSTRACT FROM AUTHOR]

Traditionally, drug development has evaluated dose, safety, activity, and comparative benefit in a sequence of phases using trial designs and endpoints specifically devised for each phase. Innovations in drug development seek to consolidate the phases and rapidly expand accrual with "seamless" trial designs. Although consolidation and rapid accrual may yield efficiencies, widespread use of seamless first-in-human (FiH) trials without careful consideration of objectives, statistical analysis plans, or trial oversight raises concerns. A working group formed by the National Cancer Institute convened to consider and discuss opportunities and challenges for such trials as well as encourage responsible use of these designs. We reviewed all abstracts presented at American Society of Clinical Oncology annual meetings from 2010 to 2017 for FiH trials enrolling at least 100 patients. We identified 1786 early-phase trials enrolling 57 559 adult patients. Fifty-one of the trials (2.9%) investigated 50 investigational new drugs, were seamless, and accounted for 14.6% of the total patients. The seamless trials included a median of 3 (range = 1-13) expansion cohorts. The overall risk of clinically significant treatment-related adverse events (grade 3-4) was 49.1% (range = 0.0-100%), and seven studies reported at least one toxic death. Rapid expansion of FiH trials may lead to earlier drug approval and corresponding widespread patient access to active therapeutics. Nevertheless, seamless designs must adhere to established ethical, scientific, and statistical standards. Protocols should include prospectively planned analyses of efficacy in disease- or biomarker-defined cohorts of sufficient rigor to support accelerated approval. [ABSTRACT FROM AUTHOR]

Introduction: Evidence-based cessation methods including nicotine replacement therapy (NRT), non-NRT medications, quitlines, and behavioral treatments are underutilized by smokers attempting to quit. Although a number of studies have demonstrated a relationship between state-level tobacco policies (eg, taxation, appropriations) and cessation, whether such state-level factors influence likelihood of using an evidence-based treatment is unclear. Accordingly, the aims of the present study were: (1) to describe evidence-based cessation method utilization by state and (2) to examine the effect of state-level factors on cessation method utilization above and beyond individual-level predictors.Methods: Data were utilized from the 2010-2011 Tobacco Use Supplement to the Current Population Survey (TUS-CPS). Participants included 9232 smokers who reported a past-year quit attempt. Data on 11 state-level predictors were collated from national datasets. Analyses were based on: (1) descriptive characterization of quit method usage, (2) logistic regression models to determine state-level factors as predictors of quit method utilization, controlling for individual-level predictors, (3) cluster analyses grouping states with similar state-level factors, and (4) examination of cluster as a predictor of cessation method.Results: Tobacco control appropriations significantly predicted NRT, quitline, and behavioral treatment utilization. Additional state-level factors that demonstrated significant relationships included Medicaid coverage of non-NRT medications and behavioral treatment, tobacco tax rate, smoking prevalence, and percentage of population uninsured. State clustering significantly predicted quit method across all four methods.Conclusions: State-level factors influence the likelihood of residents utilizing evidence-based quit methods. Results are discussed in terms of implications for tobacco policy at the state level.Implications: Results from the present study highlight state tobacco control appropriations as a robust predictor of evidence-based cessation method utilization. Other significant state-level predictors of evidence-based cessation method utilization included Medicaid coverage of non-NRT medications and behavioral treatment, tobacco tax rate, smoking prevalence, and percentage of population uninsured. Moreover, state-level predictors clustered together to significantly predict evidence-based cessation method utilization. Thus, increasing tobacco control appropriations, extending health insurance coverage, maximizing revenue from tobacco taxation and tobacco settlements, and ultimately decreasing smoking prevalence are important targets for individual states to promote utilization of evidence-based cessation methods. [ABSTRACT FROM AUTHOR]

Abstract: T cell receptor (TCR) gene‐modified T cells are a promising immunotherapy but require refinement to improve clinical responses and limit off‐target toxicities. A variety of TCR and gene‐delivery vector modifications have been developed to enhance introduced TCR expression and limit introduced/endogenous TCR chain mispairing, improving target antigen recognition and minimizing mispairing‐induced cross‐reactivity. Using our well‐characterized HCV1406 TCR, we previously compared the impact of various chain pairing enhancing modifications on TCR expression and cognate antigen recognition. HCV1406 TCR is also natively cross‐reactive against naturally occurring altered peptide ligands (APLs), which was shown to be dependent on high TCR surface density. In this report, we observed in a Jurkat model that absent TCR chain pairing competition alleviated CD8‐dependent APL recognition and induced novel cross‐reactivity of HCV1406 TCR. We then compared chain pairing enhancing modifications’ effects on TCR cross‐reactivity in Jurkat and T cells, showing C‐terminal leucine zippers and constant region murinization alleviated CD8 dependence and induced novel APL recognition. While modifications enhancing TCR chain pairing intend to avoid cross‐reactivity by limiting mispairing with the endogenous TCR, these data suggest they may also enhance natural cross‐reactivity and reduce dependence on CD8. These observations have significant implications on the design/implementation of TCR gene‐modified T cells. [ABSTRACT FROM AUTHOR]

Introduction: The majority of smokers do not intend to quit in the near term, making unmotivated smokers a key group to target in public health efforts. Although it is often assumed that continuing smokers will have stable rates of smoking over time, limited research has addressed this issue, particularly among smokers not seeking treatment. In the current study, the aims were to (1) characterize the trajectory of naturalistic smoking among unmotivated smokers and (2) examine relationships between naturalistic smoking trajectories and other smoking-related variables.Methods: The study sample comprised 579 control-group (ie, untreated) smokers within a parent clinical trial, who completed a total of nine assessments over 1 year.Results: Trajectory modeling identified four smoking trajectory groups: stable (72%), shallow decreasers (20%), steep decreasers (5%), and increasers (3%). Membership in the decreasing groups was associated with higher motivation to quit, greater history of quit attempts, and higher cigarettes per day. Females were more likely to be in the increasing versus stable group.Conclusions: Findings provide needed information on stability and change in cigarette consumption over the course of 1 year among an untreated sample of smokers and identified baseline sociodemographic and smoking-related predictors of smoking trajectory group. Refining understanding of these groups is critical in updating population-based tobacco policy modeling efforts and informing cessation induction efforts that capitalize on naturalistic changes in smoking rate over time.Implications: In the current study, we found that approximately 25% of smokers who endorsed low quit motivation at baseline reduced their cigarette consumption over the course of a year, while 3% increased their cigarette consumption and the majority of smokers (72%) maintained a stable pattern. Refining understanding of smoking trajectories is critical in updating population-based tobacco policy modeling efforts and informing cessation induction efforts that capitalize on naturalistic changes in smoking rate over time. [ABSTRACT FROM AUTHOR]

Introduction: Snus uptake is nominal among US smokers. This longitudinal study examines (1) perceptions of snus among US smokers given free snus for 6 weeks and (2) a method for assessment of an alternative tobacco product at the population level.Methods: Adult smokers (n = 543; 69.2% female; Mage = 49.3 years), uninterested in quitting, received free snus for ad libitum use. Based on their snus use during a 6-week sampling period, participants included: (1) never users (18.4%, n = 100); (2) experimenters; that is, used ≥ once, but not during the last week of sampling (33.1%; n = 180); and (3) persistent users; that is, used ≥ once during the final week, and ≥ once during any other week of the sampling period. (48.4%; n = 263).Results: Following the sampling period, those who became persistent users were more likely than experimenters to report that switching to alternative tobacco products would lower their risk for health problems (66.5% vs. 50.0%; p = .006). Persistent users also reported greater negative affect relief and craving reduction (ps < .001) than experimenters. Finally, persistent users were more likely than experimenters to describe snus in favorable terms with respect to ease of use, satisfaction, and liking (ps < .05).Conclusions: Subjective experiences with snus, rather than nicotine dependence, explained experimentation versus persistent use. Even among smokers who became persistent snus users, snus was perceived as a poor substitute for cigarettes. This study design (randomized, yet naturalistic) could be extended to other novel tobacco products, including e-cigarettes, to help understand the role new products may have in the tobacco landscape.Implications: This is the first large scale, US-based naturalistic assessment of smokers' reactions to snus during an extended sampling period. This study is directly in line with FDA goals to better understand predictors of initiation, uptake, and use of other tobacco products such as snus, and serves as model for assessment methods of alternative tobacco products at the population level. Most smokers tried the provided sample of snus (approximately 82%). Subjective experiences with snus, rather than nicotine dependence, explained experimentation versus persistent use. Even among smokers who became persistent snus users, snus was perceived as a poor substitute for cigarettes. [ABSTRACT FROM AUTHOR]

Background: As most smokers initiate smoking during adolescence, assessment of smoking motives that underlie trajectories of dependence is critical for both prevention and cessation efforts. In the current study, we expected participants with higher nicotine dependence would smoke (a) less for positive reinforcement (PR) and (b) more for negative reinforcement (NR) motives. We secondarily assessed the relative contribution of PR to NR motives across levels of dependence. Methods: Data were drawn from a study on cue-elicited craving among occasional versus daily adolescent smokers aged 16–20 years (N = 111). Smoking motives were assessed in relation to 3 commonly used measures of nicotine dependence: (a) Fagerström Test for Nicotine Dependence (FTND), (b) Autonomy over Smoking Scale (AUTOS), and (c) Nicotine Dependence Syndrome Scale (NDSS). Results: Compared to occasional smokers, daily smokers had significantly higher scores on each dependence measure and endorsed more prominent NR smoking motives. Each measure of nicotine dependence was strongly associated with NR motives for smoking, although measures differed in their association with PR motives. As expected, the FTND, AUTOS, and NDSS each significantly predicted smoking motive difference score (PR − NR), such that higher dependence was associated with more prominent NR motives for smoking. Conclusions: Results are consistent with our understanding of dependence and provide further support for 3 common measures of nicotine dependence among early stage smokers. [ABSTRACT FROM PUBLISHER]

Introduction: Use of pharmacotherapy for smoking cessation improves quit rates, but these treatments are underutilized, particularly among Black smokers. Attitudes toward pharmacotherapy may differ between racial/ethnic minorities and Caucasian smokers. It was hypothesized that Black and non-Hispanic White smokers would differ in their attitudes toward pharmacotherapy and that the association between attitudes toward and actual use of pharmacotherapy would differ by race. Methods: The study consisted of a single, cross-sectional telephone-based survey of current smokers (N = 697), which examined the relationship between race, attitudes toward pharmacotherapy, and pharmacotherapy usage in a representative bi-racial sample (39% Black). Results: Black smokers were significantly less likely to report ever use of pharmacotherapy (23%) than Caucasians (39%; odds ratio [OR] = 0.46; 95% CI: 0.33–0.66). Compared with Caucasians, Blacks had significantly less favorable attitudes toward pharmacotherapy, including disbelief about efficacy (p = .03), addiction concerns (p = .03), harmfulness of pharmacotherapy (p = .008), and need for treatment of any kind to quit smoking (p = .004). In a multiple logistic regression, racial group (Caucasian is referent: OR = 0.55, p = .003), addiction concerns (OR = 0.80, p < .01), and need for treatment of any kind to quit smoking (OR = 1.52, p < .001) were predictive of pharmacotherapy use. Conclusions: These findings replicate and build upon previous research demonstrating underutilization of pharmacotherapy and enduring misconceptions about pharmacotherapy, particularly among Black smokers. Regardless of racial group, misconceptions about pharmacotherapy are related to lower rates of use. Efforts to improve understanding about the efficacy and safety of these products are needed to boost utilization and impact cessation rates. [ABSTRACT FROM PUBLISHER]

Introduction:: Favorable views of cigarette use may be a potentiating factor that influences the progression of nicotine dependence among adolescents. [ABSTRACT FROM PUBLISHER]

Investigations of transcript levels on a genomic scale using hybridization-based arrays have led to formidable advances in our understanding of the biology of many human illnesses. At the same time, these investigations have generated controversy because of the probabilistic nature of the conclusions and the surfacing of noticeable discrepancies between the results of studies addressing the same biological question. In this article, we present simple and effective data analysis and visualization tools for gauging the degree to which the findings of one study are reproduced by others and for integrating multiple studies in a single analysis. We describe these approaches in the context of studies of breast cancer and illustrate that it is possible to identify a substantial biologically relevant subset of the human genome within which hybridization results are reliable. The subset generally varies with the platforms used, the tissues studied, and the populations being sampled. Despite important differences, it is also possible to develop simple expression measures that allow comparison across platforms, studies, laboratories and populations. Important biological signals are often preserved or enhanced. Cross-study validation and combination of microarray results requires careful, but not overly complex, statistical thinking and can become a routine component of genomic analysis. [ABSTRACT FROM AUTHOR]

We designed, implemented and evaluated an educational intervention to increase fruit and vegetable consumption among urban African- American women. Women aged 20-50 years (n = 212) from 11 public housing communities participated in seven 90-min classes with a professional nutritionist. Our prospective pre- and post-test design, with 4-month follow-up, assessed the relationship between attendance and dietary change, using three 24-hour recalls per time point. Mean change in average dally dietary values for fruits and vegetables, calories and percent calories from fat (post-test versus pre-test, follow-up versus pre-test) was compared by class attendance, to evaluate the impact of class attendance on dietary change. Attendance varied from zero (35%) to five to seven classes (42%). Baseline dietary recalls showed average daily consumption of 3.05 servings of fruits and vegetables, 2416 calories and 35.8% calories from fat. No improvements in fruit and vegetable consumption, but statistically significant decreases in total calories and percent calories from fat, were seen at both endpoints. Women attending five to seven classes had the greatest dietary improvements, averaging, at post-test and follow-up, respectively, 246.2 and 324.5 fewer calories and 3.08 and 2.97% fewer calories from fat. Results suggest that, for some residents of low-resource communities, small group interventions are popular, effective vehicles for nutrition education. [ABSTRACT FROM AUTHOR]

Background Most men will develop prostatic abnormalities, such as benign prostatic hyperplasia (BPH) or prostate cancer, as they age. Prostate-specific antigen (PSA) is a serine protease that is secreted at high levels by the normal and diseased prostate. Therapies that are activated by PSA may prove effective in treating prostatic malignancies. Methods We modified proaerolysin (PA), the inactive precursor of a bacterial cytolytic pore-forming protein, to produce a PSA-activated protoxin (PRX302). The viability of the prostate adenocarcinoma cell lines LNCaP, PC-3, CWR22H, and DU145 and the bladder cancer cell line TSU after treatment with PA or PRX302 in the presence or absence of purified PSA was assayed. Mice carrying xenograft tumors derived from LNCaP, CWR22H, or TSU cells were treated with intratumoral injection of PA or PRX302, and tumor size was monitored. To test the safety of PRX302, we administered it into the PSA-secreting prostate glands of cynomolgus monkeys. All statistical tests were two-sided. Results Native PA was highly toxic in vitro but had no tumor-specific effects in vitro or in vivo. Picomolar concentrations of PRX302 led to PSA-dependent decreases in cell viability in vitro (PRX302 versus PRX302 + PSA: DU145 cells, mean viability = 78.7% versus mean = 1.6%, difference = 77.1%, 95% confidence interval [CI] = 70.6% to 86.1%; P<.001; TSU cells, mean = 100.2% versus mean = 1.4%, difference = 98.8%, 95% CI = 96.4% to 104.0%; P<.001). Single intratumoral injections of PRX302 produced substantial and often complete regression of PSA-secreting human prostate cancer xenografts (5 pg dose, complete regression in 6 of 26 mice bearing LNCaP or CWR22H xenografts [23%]; 10 pg dose, complete regression in 10 of 26 mice [38.5%]) but not PSA-null bladder cancer xenografts. The prostates of cynomolgus monkeys injected with a single dose of PRX302 displayed extensive but organ-confined damage, with no toxicity to neighboring organs or general morbidity. Conclusions Our observations demonstrate the potential safe and effective intraprostatic application of this engineered protoxin. [ABSTRACT FROM AUTHOR]

Clostridium novyi-NT (C. novyi-NT) spores have been shown to be potent therapeutic agents in experimental tumors of mice and rabbits. In the present study, pharmacologic and toxicologic studies were performed to better understand the factors influencing the efficacy and toxicity of this form of therapy. We found that spores were rapidly cleared from the circulation by the reticuloendothelial system. Even after large doses were administered, no clinical toxicity was observed in healthy mice or rabbits. The spores were also not toxic in mice harboring poorly vascularized non-neoplastic lesions, including myocardial infarcts. In tumor-bearing mice, toxicity appeared related to tumor size and spore dose, as expected with any bacterial infection. However, there was no laboratory or histopathologic evidence of sepsis, and the toxicity could be effectively controlled by simple hydration. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Adaptive Therapy for Androgen-Independent Prostate Cancer: A Randomized Selection Trial of Four Regimens," by P. F. Thall, C. Logothetis, and L. C. Pagliaro in the previous issue of the periodical.