BMI, irAE, and gene expression signatures associate with resistance to immune-checkpoint inhibition and outcomes in renal cell carcinoma.

BACKGROUND: Clinical variables may correlate with lack of response to treatment (primary resistance) or clinical benefit in patients with clear cell renal cell carcinoma (ccRCC) treated with anti-programmed death 1/ligand one antibodies. METHODS: In this multi-institutional collaboration, clinical characteristics of patients with primary resistance (defined as progression on initial computed tomography scan) were compared to patients with clinical benefit using Two sample t-test and Chi-square test (or Fisher's Exact test). The Kaplan-Meier method was used to estimate the distribution of progression-free survival (PFS) and overall survival (OS) in all patients and the subsets of patients with clinical benefit or primary resistance. Cox's regression model was used to evaluate the correlation between survival endpoints and variables of interest. To explore clinical factors in a larger, independent patient sample, The Cancer Genome Atlas (TCGA) was analyzed. RNAseq gene expression data as well as demographic and clinical information were downloaded for primary tumors of 517 patients included within TCGA-ccRCC. RESULTS: Of 90 patients, 38 (42.2%) had primary resistance and 52 (57.8%) had clinical benefit. Compared with the cohort of patients with initial benefit, primary resistance was more likely to occur in patients with worse ECOG performance status (p = 0.03), earlier stage at diagnosis (p = 0.04), had no prior nephrectomy (p = 0.04) and no immune-related adverse events (irAE) (p = 0.02). In patients with primary resistance, improved OS was significantly correlated with lower International Metastatic RCC Database Consortium risk score (p = 0.02) and lower neutrophil:lymphocyte ratio (p = 0.04). In patients with clinical benefit, improved PFS was significantly associated with increased BMI (p = 0.007) and irAE occurrence (p = 0.02) while improved OS was significantly correlated with overweight BMI (BMI 25-30; p = 0.03) and no brain metastasis (p = 0.005). The cohort TCGA-ccRCC was examined for the correlations between gene expression patterns, clinical factors, and survival outcomes observing associations of T-cell inflammation and angiogenesis signatures with histologic grade, pathologic stage and OS. CONCLUSIONS: Clinical characteristics including performance status, BMI and occurrence of an irAE associate with outcomes in patients with ccRCC treated with immunotherapy. The inverse association of angiogenesis gene signature with ccRCC histologic grade highlight opportunities for adjuvant combination VEGFR2 tyrosine kinase inhibitor and immune-checkpoint inhibition.

Use of Hospital-Based Food Pantries Among Low-Income Urban Cancer Patients.

To examine uptake of a novel emergency food system at five cancer clinics in New York City, hospital-based food pantries, and predictors of use, among low-income urban cancer patients. This is a nested cohort study of 351 patients who first visited the food pantries between October 3, 2011 and January 1, 2013. The main outcome was continued uptake of this food pantry intervention. Generalized estimating equation (GEE) statistical analysis was conducted to model predictors of pantry visit frequency. The median number of return visits in the 4 month period after a patient's initial visit was 2 and the mean was 3.25 (SD 3.07). The GEE model showed that younger patients used the pantry less, immigrant patients used the pantry more (than US-born), and prostate cancer and Stage IV cancer patients used the pantry more. Future long-term larger scale studies are needed to further assess the utilization, as well as the impact of food assistance programs such as the this one, on nutritional outcomes, cancer outcomes, comorbidities, and quality of life. Cancer patients most at risk should be taken into particular consideration.

Food insecurity: limitations of emergency food resources for our patients.

Rates of food insecurity are high among medically underserved patients. We analyzed food pantry responsiveness to the needs of medically ill cancer patients in New York City with the intent ofidentifying barriers to available food resources. Our data, collected from 60 pantries, suggest that the emergency food system is currently unable to accommodate patient needs. Accessibility issues include restricted service hours and documentation requirements. Food services were limited in quantity of food provided and the number of nutritious, palatable options. Additional emergency food resources and long-term approaches that provide ongoing food support to patients throughout their treatment period are needed.

Pembrolizumab in the treatment of locally advanced or metastatic urothelial carcinoma: clinical trial evidence and experience.

The treatment of advanced urothelial carcinoma (UC) has dramatically changed with the advent of immune checkpoint inhibitors that disrupt the T-cell inhibitory interaction between the programmed cell death (PD)-1 receptor and its ligand (PD-L1). Pembrolizumab, a highly specific, monoclonal antibody directed against PD-1, has demonstrated clinical efficacy as well as a favorable toxicity profile, and has emerged as a new standard of care in the treatment of advanced UC. This review will summarize clinical efficacy from recent trials that led to the approval of pembrolizumab in treating platinum-refractory advanced UC as well as treating patients who are ineligible for first-line cisplatin-containing chemotherapy. While immune checkpoint inhibition has reinvigorated the treatment landscape of advanced UC and generated a great deal of optimism, only a minority of patients benefit. Combination strategies with the goal of increasing response rates are desperately needed as are biomarkers predictive of response.

Growth factor engineering by degenerate homoduplex gene family recombination.

There is great interest in engineering human growth factors as potential therapeutic agonists and antagonists. We approached this goal with a synthetic DNA recombination method. We aligned a pool of "top-strand" oligonucleotides incorporating polymorphisms from mammalian genes encoding epidermal growth factor (EGF) using multiple polymorphic "scaffold" oligonucleotides. Top strands were then linked by gap filling and ligation. This approach avoided heteroduplex annealing in the linkage of highly degenerate oligonucleotides and thus achieved completely random recombination. Cloned genes from a human-mouse chimeric library captured every possible permutation of the parental polymorphisms, creating an apparently complete recombined gene-family library, which has not been previously described. This library yielded a chimeric protein whose agonist activity was enhanced 123-fold. A second library from five mammalian EGF homologs possessed the highest reported recombination density (1 crossover per 12.4 bp). The five-homolog library yielded the strongest-binding hEGF variant yet reported. In addition, it contained strongly binding EGF variants with antagonist properties. Our less biased approach to DNA shuffling should be useful for the engineering of a wide variety of proteins.

Atezolizumab in invasive and metastatic urothelial carcinoma.

INTRODUCTION: Until recently, there has been little advancement in the management of invasive and metastatic urothelial cancer in over 30 years, and outcomes with cisplatin-based chemotherapy remain unchanged. Inhibitors targeting PD-1 signaling on cytotoxic T-cells have revolutionized bladder cancer therapy leading to durable responses. Atezolizumab is an engineered humanized anti-PD-L1 monoclonal antibody that inhibits PD-L1 binding to PD-1 and B7.1, enhancing immune-mediated tumor killing and is currently approved as second-line treatment after failure of platinum-based chemotherapy as well as first-line in cisplatin-ineligible patients. Areas covered: This article summarizes all reported phase I, II and III clinical trials that assessed the safety and efficacy of atezolizumab in the treatment of locally advanced and metastatic urothelial carcinoma. Expert commentary: Treatment with atezolizumab showed durable response and a toxicity profile that appears favorable to cytotoxic chemotherapy historically in the treatment of metastatic urothelial cancer among individuals who had progressed after prior platinum-based therapy and among those ineligible for treatment with first-line cisplatin. PD-L1 expression and tumor mutation load associate with response, however further research is needed to identify additional markers to improve prediction of response to atezolizumab.

Do our patients have enough to eat?: Food insecurity among urban low-income cancer patients.

This study assessed the prevalence and predictors of food insecurity among a cohort of underserved oncology patients at New York City cancer clinics. A demographic survey and the U.S. Household Food Security Survey Module were administered. A multivariate General Linear Model Analysis of Covariance was used to evaluate predictors of food insecurity. Four hundred and four (404) completed the surveys. Nearly one-fifth (18%) had very low, 38% low, 17% marginal, and 27% high food security. The Analysis of Covariance was statistically significant (F[7, 370] = 19.08; p < .0001; R-Square = 0.26). Younger age, Spanish language, poor health care access, and having less money for food since beginning cancer treatment were significantly associated with greater food insecurity. This cohort of underserved cancer patients had rates of food insecurity nearly five times those of the state average. More research is needed to understand better the causes and impact of food insecurity among cancer and chronic disease patients.