Sukeshi R. Patel

Genetic Variations in the Receptor-Ligand Pair CCR5 and CCL3L1 Are Important Determinants of Susceptibility to Kawasaki Disease

Kawasaki disease (KD) is an enigmatic, self-limited vasculitis of childhood that is complicated by development of coronary-artery aneurysms. The high incidence of KD in Asian versus European populations prompted a search for genetic polymorphisms that are differentially distributed among these populations and that influence KD susceptibility. Here, we demonstrate a striking, inverse relationship between the worldwide distribution of CCR5- Delta 32 allele and the incidence of KD. In 164 KD patient-parent trios, 4 CCR5 haplotypes including the CCR5- Delta 32 allele were differentially transmitted from heterozygous parents to affected children. However, the magnitude of the reduced risk of KD associated with the CCR5- Delta 32 allele and certain CCR5 haplotypes was significantly greater in individuals who also possessed a high copy number of the gene encoding CCL3L1, the most potent CCR5 ligand. These findings, derived from the largest genetic study of any systemic vasculitis, suggest a central role of CCR5-CCL3L1 gene-gene interactions in KD susceptibility and the importance of gene modifiers in infectious diseases.

Review: Oncolytic virotherapy, updates and future directions

Oncolytic viruses (OVs) are viral strains that can infect and kill malignant cells while spare their normal counterparts. OVs can access cells through binding to receptors on their surface or through fusion with the plasma membrane and establish a lytic cycle in tumors, while leaving normal tissue essentially unharmed. Multiple viruses have been investigated in humans for the past century. IMLYGIC™ (T-VEC/Talimogene Laherparepvec), a genetically engineered Herpes Simplex Virus, is the first OV approved for use in the United States and the European Union for patients with locally advanced or non-resectable melanoma.Although OVs have a favorable toxicity profile and are impressively active anticancer agents in vitro and in vivo the majority of OVs have limited clinical efficacy as a single agent. While a virus-induced antitumor immune response can enhance oncolysis, when OVs are used systemically, the antiviral immune response can prevent the virus reaching the tumor tissue and having a therapeutic effect. Intratumoral administration can provide direct access to tumor tissue and be beneficial in reducing side effects.Immune checkpoint stimulation in tumor tissue has been noted after OV therapy and can be a natural response to viral-induced oncolysis. Also for immune checkpoint inhibition to be effective in treating cancer, an immune response to tumor neoantigens and an inflamed tumor microenvironment are required, both of which treatment with an OV may provide. Therefore, direct and indirect mechanisms of tumor killing provide rationale for clinical trials investigating the combination of OVs other forms of cancer therapy, including immune checkpoint inhibition.Oncolytic viruses (OVs) are viral strains that can infect and kill malignant cells while spare their normal counterparts. OVs can access cells through binding to receptors on their surface or through fusion with the plasma membrane and establish a lytic cycle in tumors, while leaving normal tissue essentially unharmed. Multiple viruses have been investigated in humans for the past century. IMLYGIC™ (T-VEC/Talimogene Laherparepvec), a genetically engineered Herpes Simplex Virus, is the first OV approved for use in the United States and the European Union for patients with locally advanced or non-resectable melanoma. Although OVs have a favorable toxicity profile and are impressively active anticancer agents in vitro and in vivo the majority of OVs have limited clinical efficacy as a single agent. While a virus-induced antitumor immune response can enhance oncolysis, when OVs are used systemically, the antiviral immune response can prevent the virus reaching the tumor tissue and having a therapeutic effect. Intratumoral administration can provide direct access to tumor tissue and be beneficial in reducing side effects. Immune checkpoint stimulation in tumor tissue has been noted after OV therapy and can be a natural response to viral-induced oncolysis. Also for immune checkpoint inhibition to be effective in treating cancer, an immune response to tumor neoantigens and an inflamed tumor microenvironment are required, both of which treatment with an OV may provide. Therefore, direct and indirect mechanisms of tumor killing provide rationale for clinical trials investigating the combination of OVs other forms of cancer therapy, including immune checkpoint inhibition.

Comparative dosing and efficacy of sorafenib in hepatocellular cancer patients with varying liver dysfunction

BACKGROUND Sorafenib is the only FDA-approved systemic therapy for advanced hepatocellular carcinoma (HCC). In clinical practice, dose reductions are often required, although there are limited efficacy data related to dose modifications. Given the prevalence of HCC in South Texas, we assessed the efficacy and safety of sorafenib therapy in relation to dose and Child Pugh (CP) score. METHODS A retrospective analysis was done of advanced HCC patients, starting sorafenib at 400 mg twice daily, or at physician discretion at 400 mg daily, with the goal of titrating to twice daily. Overall survival (OS) and progression-free survival (PFS) were assessed. RESULTS Among 107 patients, median OS (mOS) was 10.2 months; median PFS (mPFS) was 5.2 months. mOS for sorafenib 400 mg/day was 6.6 vs. 800 mg/day was 12.8 months [hazard ratio (HR), 0.59; P=0.04]; mPFS was 3.5 vs. 5.9 months, respectively (HR, 0.66; P=0.07). For Child Pugh A class (CP-A) patients, mOS was 15.8 months for 400 mg/day vs. 12.8 months for 800 mg/day (HR, 1.48; P=0.35); mPFS was 9.0 vs. 5.9 months, respectively (HR, 1.23; P=0.56). For Child Pugh B class (CP-B) patients, mOS was 5.0 months for 400 mg/day vs. 11.2 months for 800 mg/day (HR, 0.33; P=0.002); mPFS was 2.1 vs. 5.6 months, respectively (HR, 0.41; P=0.006). No differences in adverse events (AEs) were observed in CP-A vs. CP-B. CONCLUSIONS Patients with CP-A or CP-B advanced HCC should be offered sorafenib at 400 mg twice daily with optimal management of AEs in order to improve survival.

Vorinostat and hydroxychloroquine improve immunity and inhibit autophagy in metastatic colorectal cancer

Hydroxychloroquine (HCQ) enhances the anti-cancer activity of the histone deacetylase inhibitor, vorinostat (VOR), in pre-clinical models and early phase clinical studies of metastatic colorectal cancer (mCRC). Mechanisms could include autophagy inhibition, accumulation of ubiquitinated proteins, and subsequent tumor cell apoptosis. There is growing evidence that autophagy inhibition could lead to improved anti-cancer immunity. To date, effects of autophagy on immunity have not been reported in cancer patients. To address this, we expanded an ongoing clinical study to include patients with advanced, refractory mCRC to evaluate further the clinical efficacy and immune effects of VOR plus HCQ. Refractory mCRC patients received VOR 400 milligrams orally with HCQ 600 milligrams orally daily, in a 3-week cycle. The primary endpoint was median progression-free survival (mPFS). Secondary endpoints include median overall survival (mOS), adverse events (AE), pharmacodynamic of inhibition of autophagy in primary tumors, immune cell analyses, and cytokine levels. Twenty patients were enrolled (19 evaluable for survival) with a mPFS of 2.8 months and mOS of 6.7 months. Treatment-related grade 3–4 AEs occurred in 8 patients (40%), with fatigue, nausea/vomiting, and anemia being the most common. Treatment significantly reduced CD4+CD25hiFoxp3+ regulatory and PD-1+ (exhausted) CD4+ and CD8+ T cells and decreased CD45RO-CD62L+ (naive) T cells, consistent with improved anti-tumor immunity. On-study tumor biopsies showed increases in lysosomal protease cathepsin D and p62 accumulation, consistent with autophagy inhibition. Taken together, VOR plus HCQ is active, safe and well tolerated in refractory CRC patients, resulting in potentially improved anti-tumor immunity and inhibition of autophagy.

An evaluation of elderly patients (≥ 70 years old) enrolled in Phase I clinical trials at University of Texas Health Science Center at San Antonio-Cancer Therapy Research Center from 2009 to 2011

OBJECTIVE Elderly patients with cancer are under-represented in clinical trials, and there is especially scant data on their participation in early-phase trials. In an effort to provide more data, we reviewed our Phase I experience. METHODS We conducted a retrospective analysis of 461 patients enrolled in Phase I clinical trials at the Cancer Therapy Research Center (CTRC) from 2009 to 2011 to determine the rate of completion of at least 12 weeks of treatment, incidence of adverse events, prevalence of co-morbidities, functional status, and survival. Elderly (E) was defined as ≥70 years; non-elderly (NE) was defined as ≤69 years. RESULTS The elderly represented 15% (69/461) of enrolled patients. The most common malignancies were colon (20%), hematologic (18%), lung (15%), and breast (8%). The median age of E was 72 years (range 70-85, SD 3.15), and 49% of the E was female. Co-morbidities (E vs. NE) include diabetes (28% vs. 23%), hypertension (65% vs. 44%), and chronic kidney disease (91% vs. 48%). Thirty-two percent of E vs. 37% of NE completed at least 12 weeks of treatment. Reasons for not completing in E vs. NE respectively were progression of disease (43% vs. 61%), toxicity (28% vs. 9%), and self-withdrawal (11% vs. 7%). Reasons for not completing the protocol was significantly associated with being elderly (p = 0.005). There were non-significant differences in toxicity in E vs. NE CONCLUSION Elderly patients have a higher likelihood of not completing trials for reasons including toxicity. This highlights the need for better Phase I trial-designs incorporating ideal geriatric assessment tools.

A comparison of races and leukemia subtypes among patients in different cancer survivorship phases.

BACKGROUND The three phases of cancer survivorship include the acute survival phase (ASP), the extended survival phase (ESP), and the permanent survival phase (PSP). This Institutional Review Board-approved retrospective pilot project compared races and leukemia subtypes among patients in the ASP, ESP, and PSP. METHODS Fifty-five adult patients from our National Cancer Institute-designated cancer center were individually interviewed. Subjects were asked about multiple areas of survivorship including their social support system, distress level, and quality of life. RESULTS Demographics of the 55 patients are acute lymphocytic leukemia (ALL), 10; acute myelocytic leukemia (AML), 9; chronic lymphocytic leukemia (CLL), 23; and chronic myelocytic leukemia (CML), 13. There were 23 females and 32 males, 30 Hispanics, 20 Caucasians, and 5 African-Americans. Twenty-two patients were in the ASP, 21 in the ESP, and 12 in the PSP. AML patients experienced the most physical, family, emotional, and spiritual problems (78%, 33%, 56%, and 22%, respectively). AML patients also had the highest distress level with a mean score of 5.8 (SD 1.7), compared to ALL (1.8), CLL (3.2), and CML (5.1) (P value < .001). Among all the phases of survivorship, the ASP had the highest distress level (mean, 4.8) and the worst quality of life (mean, 2.3). The ASP patients had the most treatment for depression (38%). When comparing races, African Americans and Hispanics (40% and 37%, respectively) were unable to cope with finances, compared to Caucasians (5%), (P value .016). Fear of recurrence was higher in Hispanics (67%), compared to African Americans (40%) and Caucasians (30%) (P value .031). Hispanics (40%) experienced more problems with housing, insurance, and work, as compared to African Americans (20%) and Caucasians (10%) (P value .047). CONCLUSION This study addresses the perceptions and beliefs of leukemia survivors and found that AML and minority patients need further investigation on various aspects of quality of life.

Should we move beyond VEGF inhibition in metastatic colorectal cancer? Lessons from early phase clinical trials

Data from recent clinical trials utilizing bevacizumab or other anti-VEGF agents in patients with metastatic colorectal cancer (mCRC) show improvements in progression-free survival (PFS) but modest, if any, improvements in overall survival (OS). Despite modest improvements, use of bevacizumab beyond first and second progression is routinely done in clinical practice. Recently, the CORRECT trial using regorafenib, a multi-kinase inhibitor with VEGF inhibitory properties, reported modest improvements in PFS and OS when compared to placebo, leading to FDA approval in the third-line setting. Prior to regorafenib, heavily pre-treated patients were often enrolled onto early phase clinical trials with many of these studies reporting efficacy amongst patients with mCRC; however, a collective efficacy analysis of mCRC patients enrolled into early phase clinical trials stratified by class of agents and their mechanism of action has not been done. To assess this, we performed an analysis of efficacy and stratified these findings based on VEGF inhibition versus non-VEGF inhibition in mCRC patients enrolled onto phase I trials at our institution from 3/2004-9/2012. Similar to many reported clinical studies, our data showed that VEGF inhibitors have a statistically significant improvement in PFS when compared to non-VEGF targeting agents; however, no differences in OS were observed between these two different classes of agents. We were not able to identify predictive biomarkers that correlate with efficacy of VEGF inhibitors. This should be further explored in prospective studies in order to identify active agents in this heavily pre-treated population that improve efficacy while minimizing cost and toxicity.

Diagnosis of Kawasaki Disease Using a Minimal Whole-Blood Gene Expression Signature

Importance To date, there is no diagnostic test for Kawasaki disease (KD). Diagnosis is based on clinical features shared with other febrile conditions, frequently resulting in delayed or missed treatment and an increased risk of coronary artery aneurysms. Objective To identify a whole-blood gene expression signature that distinguishes children with KD in the first week of illness from other febrile conditions. Design, Setting, and Participants The case-control study comprised a discovery group that included a training and test set and a validation group of children with KD or comparator febrile illness. The setting was pediatric centers in the United Kingdom, Spain, the Netherlands, and the United States. The training and test discovery group comprised 404 children with infectious and inflammatory conditions (78 KD, 84 other inflammatory diseases, and 242 bacterial or viral infections) and 55 healthy controls. The independent validation group comprised 102 patients with KD, including 72 in the first 7 days of illness, and 130 febrile controls. The study dates were March 1, 2009, to November 14, 2013, and data analysis took place from January 1, 2015, to December 31, 2017. Main Outcomes and Measures Whole-blood gene expression was evaluated using microarrays, and minimal transcript sets distinguishing KD were identified using a novel variable selection method (parallel regularized regression model search). The ability of transcript signatures (implemented as disease risk scores) to discriminate KD cases from controls was assessed by area under the curve (AUC), sensitivity, and specificity at the optimal cut point according to the Youden index. Results Among 404 patients in the discovery set, there were 78 with KD (median age, 27 months; 55.1% male) and 326 febrile controls (median age, 37 months; 56.4% male). Among 202 patients in the validation set, there were 72 with KD (median age, 34 months; 62.5% male) and 130 febrile controls (median age, 17 months; 56.9% male). A 13-transcript signature identified in the discovery training set distinguished KD from other infectious and inflammatory conditions in the discovery test set, with AUC of 96.2% (95% CI, 92.5%-99.9%), sensitivity of 81.7% (95% CI, 60.0%-94.8%), and specificity of 92.1% (95% CI, 84.0%-97.0%). In the validation set, the signature distinguished KD from febrile controls, with AUC of 94.6% (95% CI, 91.3%-98.0%), sensitivity of 85.9% (95% CI, 76.8%-92.6%), and specificity of 89.1% (95% CI, 83.0%-93.7%). The signature was applied to clinically defined categories of definite, highly probable, and possible KD, resulting in AUCs of 98.1% (95% CI, 94.5%-100%), 96.3% (95% CI, 93.3%-99.4%), and 70.0% (95% CI, 53.4%-86.6%), respectively, mirroring certainty of clinical diagnosis. Conclusions and Relevance In this study, a 13-transcript blood gene expression signature distinguished KD from other febrile conditions. Diagnostic accuracy increased with certainty of clinical diagnosis. A test incorporating the 13-transcript disease risk score may enable earlier diagnosis and treatment of KD and reduce inappropriate treatment in those with other diagnoses.

Left versus right: Does location matter for refractory metastatic colorectal cancer (mCRC) patients in phase I clinical trials?

771Background: Location of the primary tumor is prognostic and predictive of efficacy with VEGF-inhibitors (I) vs EGFR-I given first-line to mCRC patients (pts) (ASCO 2016). However, little is known regarding the effect of location on prognosis and prediction in heavily pretreated mCRC pts. We assessed the efficacy of VEGF-I and EGFR-I in regards to location of the primary tumor in pts with refractory mCRC enrolled in early phase studies. Methods: A historical cohort analysis of mCRC pts enrolled amongst 44 phase I trials at the IDD from 3/2004 - 9/2012. Median Progression free survival (mPFS) and overall survival (mOS) were estimated from Kaplan-Meier curves and groups were statistically compared with the log rank test. The magnitude of association between dichotomous factors and survival was estimated with the hazard ratio (HR). Results: 139 pts, median age 59 (33-81), KRAS mut 20 %, wt 31 %, unknown 49 %. ≥ 3 prior lines therapy 73.9 %; Prior EGFR-I 75.5% (100% of KRAS wt). Location: Right 20.9 %, Left...

Risks and benefits of phase I liver dysfunction studies: should patients with severe liver dysfunction be included in these trials?

SummaryIntroduction The goal of organ dysfunction Phase I trials is to characterize the safety and pharmacokinetics of novel agents in cancer patients with liver or kidney dysfunction, but the clinical benefit is not well established. Methods We reviewed 170 patients across 15 liver dysfunction studies at our institution, grouped based on the NCI-Organ Dysfunction Working Group criteria or Child-Pugh Score. Results The median survival for the entire cohort was two months and just one month amongst patients with severe liver dysfunction. Patients with normal or mild liver dysfunction, absence of tumor in liver, good performance status, higher serum albumin and lower bilirubin, aspartate transaminase and alkaline phosphatase had improved survival by univariate analysis. Serum albumin and liver function classification remained significant by multivariate analysis. Conclusion Given poor survival of patients with liver dysfunction, we need better criteria, such as albumin levels, for optimally selecting patients for liver dysfunction studies.