Patricia A Wood

Background: Tisagenlecleucel, an anti-CD19 chimeric antigen receptor T cell therapy, has demonstrated efficacy in children and young adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) in two multicenter phase 2 trials (ClinicalTrials.gov, NCT02435849 (ELIANA) and NCT02228096 (ENSIGN)), leading to commercialization of tisag...

Cytokine release syndrome (CRS) is a systemic inflammatory response associated with chimeric antigen receptor T-cell (CAR-T) therapies. In severe cases, CRS can be associated with coagulopathy and hypofibrinogenemia. We present our global multicenter experience with CRS-associated coagulopathy after tisagenlecleucel therapy in 137 patients with rel...

Tisagenlecleucel is a chimeric antigen receptor–T cell therapy that facilitates the killing of CD19+ B cells. A model was developed for the kinetics of tisagenlecleucel and the impact of therapies for treating cytokine release syndrome (tocilizumab and corticosteroids) on expansion. Data from two phase II studies in pediatric and young adult relaps...

We identified genetic mutations in CD19 and loss of heterozygosity at the time of CD19– relapse to chimeric antigen receptor (CAR) therapy. The mutations are present in the vast majority of resistant tumor cells and are predicted to lead to a truncated protein with a nonfunctional or absent transmembrane domain and consequently to a loss of surface...

Purpose: Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR19) T-cell therapy approved for the treatment of children and young adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL). Experimental design: We evaluated the cellular kinetics of tisagenlecleucel, the effect of patient factors, humoral immunoge...

Background Anti-CD19 CAR T cell therapy has demonstrated high response rates in patients with relapsed or refractory (r/r) B cell malignancies but is associated with significant toxicity. Cytokine release syndrome (CRS) is the most significant complication associated with CAR T cell therapy, and it is critical to have a reproducible and easy method...

Background: In a single-center phase 1-2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). Methods: W...

Tisagenlecleucel (CTL019) is an investigational immunotherapy that involves reprogramming a patient's own T cells with a transgene encoding a chimeric antigen receptor to identify and eliminate CD19-expressing cells. We previously reported that CTL019 achieved impressive clinical efficacy in patients with relapsed/refractory B-cell acute lymphoblas...

10523 Background: The global ELIANA trial (NCT02435849) evaluates the efficacy and safety of CTL019, a single infusion of genetically modified autologous chimeric antigen receptor–expressing T cells targeting CD19+ cells in pediatric and young adult r/r B-ALL pts. Analyses show a complete response rate of 82% with or without complete blood count re...

A single-center trial of CD19 directed, lentiviral transduced chimeric antigen receptor (CAR) T cells (CTL019) for relapsed and refractory (r/r) B-ALL pediatric patients showed rates of CR >90% with prolonged CAR T cell persistence/CR without further therapy in the majority of patients infused (Maude NEJM 2014). We report here the feasibility, safe...

Introduction CTL019 is a novel, investigational, chimeric antigen receptor (CAR) immunotherapy whereby autologous T cells are genetically modified with a chimeric antigen receptor to target CD19 on the surface of malignant as well as healthy B cells. The cellular kinetics of CTL019 have been evaluated in several trials for patients with relapsed/re...

Background: CTL019 is an investigational therapy derived from autologous T-cells expressing a CD19-specific chimeric antigen receptor (CAR). A single center, phase I/IIa trial of CTL019 showed complete and durable remissions in pediatric/young adult patients (pts) with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) (Maude et...

Introduction: Use of chimeric Antigen Receptor (CAR) targeting CD19 (CTL019) as a cell-based immunotherapy has been reported to have positive results with high complete response rates in hematological malignancies, including relapsed/refractory (r/r) acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphomas (NHL). In all the studies reported thu...

BACKGROUND CARs combine a targeting antibody (scFv) domain with intracellular signaling domains. We have previously reported on CTL019 cells expressing an anti-CD19 CAR, which have resulted in up to 100,000x in vivo proliferation, durable anti-tumor activity, and prolonged persistence in pts with B cell tumors, including sustained CRs in adults and...

BACKGROUND: We have shown that infusion of autologous T cells genetically modified to express a chimeric antigen receptor (CAR) consisting of an external anti-CD19 domain, with the CD3z and 4-1BB signaling domains (CTL019 cells), can mediate potent anti-tumor effects in patients (pts) with advanced, R/R CLL and other CD19+ malignancies. In our init...

CTL019 are autologous T cells genetically modified to express a chimeric antigen receptor (CAR) consisting of an external anti-CD19 domain with the CD3z and 4-1BB signaling domains, and mediate potent anti-tumor effects in patients (pts) with advanced, R/R CLL, ALL and NHL. CRS is the most serious toxicity of CTL019 therapy; symptoms can include fe...

BACKGROUND CARs combine a single chain variable fragment (scFv) of an antibody with intracellular signaling domains. We have previously reported on CTL019 cells expressing an anti-CD19 CAR. Infusion of these cells results in 100 to 100,000x in vivo proliferation, durable anti-tumor activity, and prolonged persistence in pts with B cell tumors, incl...

Background: CARs combine a single chain variable fragment (scFv) of an antibody with intracellular signaling domains into a single chimeric protein. We previously reported on CTL019 cells expressing a CAR recognizing CD19 combined with the CD137 and CD3 zeta intracellular activation domain, including 1 sustained CR in a patient with ALL (Grupp, et...

Background: Melatonin secreted only during nightly darkness promotes sleep and sets daily clocks. Cancer disrupts daily rhythms, nighttime sleep, and causes daytime fatigue. Meta-analyses report that melatonin improves cancer response and patient survival. We hypothesized that proper daily timing is essential to melatonin benefit. Methods: Eighty-f...

Background CARs combine a single chain variable fragment (scFv) of an antibody with intracellular signaling domains into a single chimeric protein. We previously reported on CTL019 cells expressing a CAR with intracellular activation plus costimulatory domains. Infusion of these cells results in 100 to 100,000x in vivo proliferation, durable anti-t...

Background Patients (pts) with relapsed, and/or refractory (R/R) CLL have a poor prognosis with few effective treatment options. We have shown that infusion of autologous T cells genetically modified to express a chimeric antigen receptor (CAR) consisting of an external anti-CD19 domain, with the CD3ζ and 4-1BB signaling domains (CTL019 cells), can...

Background: A recently published meta-analysis suggests that melatonin administered concurrently with chemotherapy leads to significant improvements in tumor response and survival in solid tumors, however, the role of melatonin in cancer treatment still remains disputable. We investigated the impact of chronotherapeutic administration of melatonin...

Development of biosimilars to innovative therapeutic biologics promises reduction of healthcare cost and therefore will provide patients worldwide greater access to effective treatments. Because of the differences in raw materials or manufacturing processes, 'equivalence' of bioavailability between a biosimilar and the reference biologic is general...

Cancer patients routinely develop symptoms consistent with profound circadian disruption, which causes circadian disruption diminished quality of life. This study was initiated to determine the relationship between the severity of potentially remediable cancer-associated circadian disruption and quality of life among patients with advanced lung can...

Many cancer patients report poor sleep quality, despite having adequate time and opportunity for sleep. Satisfying sleep is dependent on a healthy circadian time structure and the circadian patterns among cancer patients are quite abnormal. Wrist actigraphy has been validated with concurrent polysomnography as a reliable tool to objectively measure...

The interactions between a therapeutic protein and the surfaces of a delivery device may play a pivotal role in the efficacy of a recombinant protein-based biologic therapy program. Protein adsorption may induce conformational changes and aggregation, resulting in the inactivation of the protein of interest and even malfunction of the delivery devi...

The circadian clock exists in virtually every cell and regulates key biological processes in cells and tissues. Even in cancer cells, DNA synthesis, cell division and tumor growth are gated by the circadian clock. This study examined the gene expression profiles of transplanted mouse breast tumor cells under normal light-dark (LD) as well as consta...

Sphingolipid metabolism is driven by inflammatory cytokines. These cascade of events include the activation of sphingosine kinase (SK), and subsequent production of the mitogenic and proinflammatory lipid sphingosine 1-phosphate (S1P). Overall, S1P is one of the crucial components in inflammation, making SK an excellent target for the development o...

We have recently shown that American ginseng (AG) prevents and treats mouse colitis. Because both mice and humans with chronic colitis have a high colon cancer risk, we tested the hypothesis that AG can be used to prevent colitis-driven colon cancer. Using the azoxymethane (AOM)/dextran sulfate sodium (DSS) mouse model of ulcerative colitis, we sho...

Human breast cancer incidence has seasonal patterns that seem to vary among global populations. The aggregate monthly frequency of breast cancer diagnosis was collected and examined for 2,921,714 breast cancer cases diagnosed across 64 global regions over spans from 2 to 53 years. Breast cancer is consistently diagnosed more often in spring and fal...

The circadian clock controls many cellular processes, some of which are key to tumor suppression, including cell proliferation and apoptosis, DNA repair, metabolism, hormone signaling, and immune function. The association between altered circadian clock function and increased risk of colorectal cancer is increasingly evident from epidemiologic, pre...

Melatonin, a small organic molecule synthesized by the pineal gland and the retina, has a variety of physiologic functions such as circadian clock pacemaker and antioxidant. Retinal melatonin is down-regulated by light and is barely detectable during the day. The absence of melatonin in the retina during prolonged light exposure may contribute to l...

Separation of colorectal cancer cells from other biological materials is important for stool-based diagnosis of colorectal cancer. In this paper, we use conventional dielectrophoresis in a microfluidic chip to manipulate and isolate HCT116 colorectal cancer cells. It is noticed that at a particular alternating current frequency band, the HCT116 cel...

We measured subjectively evaluated depression and anxiety, and objectively measured daily sleep-activity patterns in inpatients and outpatients with advanced non-small cell lung cancer (NSCLC) and determined whether cancer-associated depression and anxiety are accompanied by characteristic circadian rhythm abnormalities. Equal numbers of inpatients...

We report our findings on a hospital-based retrospective pilot cohort with case-controls study, which we carried out to examine genetic, environmental, and occupational risk factors in men with breast cancer. 86 men with breast cancer were diagnosed in eight VA medical centers that agreed to collaborate on this project. A case-control analysis was...

Timeless (Tim), a core circadian clock gene in Drosophila, is retained in mammals but has no apparent mammalian circadian clock function. Mammalian TIM is essential for ATR-dependent Chk1 activation and S-phase arrest. We report that TIM is likewise essential for ATM-dependent Chk2-mediated signaling of doxorubicin-induced DNA double strand breaks....

Period genes ( Per2, Per1) are essential circadian clock genes. They also function as negative growth regulators. Per2 mutant mice show de novo and radiation-induced epithelial hyperplasia, tumors, and an abnormal DNA damage response. Human tumors show Period gene mutations or decreased expression. Other murine clock gene mutations are not associat...

Breast cancer relapse and death occur more often and sooner among young pre-menopausal women. Breast cancer resected during luteal phase cures about a quarter more women than if the operation is performed during follicular phase. We have identified candidate breast cancer gene signatures that may point to the potential mechanisms of cycle stage-dep...

Separation of cancer cells from the other biological cells can be useful for clinical cancer diagnosis and cancer treatment. In this presentation, conventional dielectrophoresis (c-DEP) is used in a microfluidic chip to manipulate and collect colorectal cancer HCT116 cell, which is doped with Human Embryonic Kidney 293 cells (HEK 293). It is notice...

Circadian disruption has been linked with inflammation, an established cancer risk factor. Per3 clock gene polymorphisms have also been associated with circadian disruption and with increased cancer risk. Patients completed a questionnaire and provided a blood sample prior to undergoing a colonoscopy (n = 70). Adjusted mean serum cytokine concentra...

Life has evolved on this planet with regular daily spans of direct solar energy availability alternating with nocturnal spans of dark. Virtually every earth-borne life form has factored this circadian pattern into its biology to ensure the temporal coordination with its resonating environment, a task essential for its individual survival and that o...

The mammalian core clock genes, Periods (Per1 and Per2), have tumor suppressor properties. Decreased expression of Per1 and Per2 has been reported in several types of human cancers. On the other hand, overexpression of Per1 or Per2 inhibits cancer cell growth in culture. The authors have shown that downregulation of Per1 or Per2 enhances cancer gro...

Cell cycle progression is tightly regulated. The expressions of cell cycle regulators, the products of which either promote or inhibit cell proliferation, oscillate during each cell cycle. Cellular proliferation and the expression of cell cycle regulators are also controlled by the circadian clock. Disruption of the circadian clock may thereby lead...

Purpose Per2, a core circadian clock gene, has tumor suppressor properties and is mutated or down regulated in human breast cancers. We have manipulated the expression of this gene in vitro and in vivo to more fully understand how the Per2 clock gene product affects cancer growth. Methods We used siRNA and shRNA to down regulate Per2 expression in...

Supplementary Table 1 shows the circadian variation in tumor size and thymidylate synthase in tumor and normal tissues. Supplementary Table 2 shows the circadian-dependent 5-FU effects on host toxicity, anti-tumor efficacy and toxic-therapeutic index. Supplementary Table 3 shows the circadian variation in tumor histopathology. Supplementary Movie 1...

Erythropoietin (EPO) stimulates red blood cell production, in part by inhibiting apoptosis of the red blood cell precursors. The erythropoietic effects of EPO are circadian stage dependent. Retinal injury due to light occurs through oxidative mechanisms and is manifest by retinal and retinal pigment epithelium (RPE) cells apoptosis. The visual cycl...

Proliferation of intestinal epithelial cells is rhythmic throughout the day. This temporal organization occurs through the interaction between the endogenous peripheral circadian clock and pathways controlling cell cycle progression. Per2, a core clock gene with tumour suppresser function, is critical to clock function and to the regulation of cell...

Circadian clocks gate cellular proliferation and, thereby, therapeutically target availability within proliferative pathways. This temporal coordination occurs within both cancerous and noncancerous proliferating tissues. The timing within the circadian cycle of the administration of drugs targeting proliferative pathways necessarily impacts the am...

Separation of cancer cells from the other biological cells is important for clinical cancer diagnosis and cancer treatment. In this presentation, we use conventional dielectrophoresis (c-DEP) in a microfluidic chip to manipulate and collect colorectal cancer HCT116 cell. It is noticed that at particular AC frequency band, the HCT116 cell are deflec...

Colorectal cancer risk is increased in shift workers with presumed circadian disruption. Intestinal epithelial cell proliferation is gated throughout each day by the circadian clock. Period 2 (Per2) is a key circadian clock gene. Per2 mutant (Per2(m/m)) mice show an increase in lymphomas and deregulated expression of cyclin D and c-Myc genes that a...

Ulcerative colitis (UC) is a dynamic, idiopathic, chronic inflammatory condition associated with a high colon cancer risk. American ginseng has antioxidant properties and targets many of the players in inflammation. The aim of this study was to test whether American ginseng extract prevents and treats colitis. Colitis in mice was induced by the pre...

Ulcerative colitis is a dynamic, chronic inflammatory condition of the colon associated with an increased colon cancer risk. Ginkgo biloba is a putative antioxidant and has been used for thousands of years to treat a variety of ailments. The aim of this study was to test whether the standardized G.biloba extract, EGb 761, is an antioxidant that can...

Human breast cancer incidence, histopathologic grade, invasiveness, and mortality risk vary significantly throughout each year. In order to better understand this seasonal cancer biology, we investigated the circannual pattern of post-resection breast cancer metastasis, under genetically and environmentally controlled conditions. Over a span of 14...

Recognizing that relatively easily detected precancerous lesions precede many cancers, there is a need to investigate the effectiveness of early interventions on the reduction of incidence rates in well-designed large randomized control trials. If early detection can reduce mortality rates of OPCA, evaluation of the capacity of dentists and physici...

Dysregulated cellular proliferation is a characteristic property of cancer. We show that, despite this fact, cancers maintain high amplitude, circadian rhythms in their growth, DNA synthesis, and mitosis. These patterns are accompanied by the daily traverse of BMAL-1 protein between the cytoplasm, where it is produced, and nucleus, where it influen...

Germ-line mutation of the Apc gene has been linked to familial adenomatous polyposis (FAP) that predisposes to colon cancer. Apc(Min/+) mice, heterozygous for the Apc gene mutation, progressively develop small intestinal tumours in a manner that is analogous to that observed in the colon of patients with FAP (Su et al. 1992; Fodde et al. 1994; Mose...

This position paper documents the merit of including for basic and clinical investigations the mapping of circadian and other rhythms and yet broader chronomes, time structures in and around us. Chronobiometry used herein relies on inferential statistical methods and on materials documented earlier. The circadian amplitude of melatonin is shown to...

This study aimed to evaluate whether patients with advanced non-small-cell lung cancer experience disrupted rest-activity daily rhythms, poor sleep quality, weakness, and maintain attributes that are linked to circadian function such as fatigue. This report describes the rest-activity patterns of 33 non-small-cell lung cancer patients who participa...

The frequency of breast cancer metastatic spread is affected by the menstrual cycle phase of its resection. Breast cancer growth, post-resection spread, and cure frequency are each modulated by the estrous cycle in C(3)HeB/FeJ mice. Tumor metastases are 2- to 3-fold more frequent when the resection is done during diestrus as compared with estrus. T...

Background: Circadian coordination in mammals is accomplished, in part, by coordinate, rhythmic expression of a series of circadian clock genes in the central clock within the suprachiasmatic nuclei (SCN) of the hypothalamus. These same genes are also rhythmically expressed each day within each peripheral tissue. Methods: We measured tumor size,...

Among premenopausal women, both post-resection metastatic potential and tumor growth rate are influenced by the menstrual cycle. There is strong support for the former in large retrospective studies of surgical resection timing within the menstrual cycle and the following experiments were conducted to critically evaluate the latter. We studied a tr...

A mammary tumor cell line, designated MTCL, was successfully established from a mouse primary mammary tumor (MTP). The MTCL cells retain cytokeratin and both estrogen receptor (ER) and progesterone receptor (PR) in vitro. In vitro exposure of MTCL cells to progesterone causes a decrease in the cellular (3)H-thymidine uptake, indicating an inhibitio...

Despite the many innovations that have occurred in cancer treatment, the age-specific mortality for most adult tumors has remained stable during the past 30 years. There have been clinically significant improvements in the outcomes of young and middle-aged patients, yet the vast majority of cancer patients are more than 50 years of age, among whom...

Cancer growth and spread is an intricate process dependent upon both tumor and host. This laboratory is interested in the role of the fertility cycle, specifically cyclic changes in steroid hormone levels, in tumor growth and metastases. Our previous studies, using a murine model, have documented that breast cancer growth rate and post-resection me...

The circadian timing of surgery, anticancer drugs, radiation therapy, and biologic agents can result in improved toxicity profiles, tumor control, and host survival. Optimally timed cancer chemotherapy with doxorubicin or pirarubicin (06:00h) and cisplatin (18:00h) enhanced the control of advanced ovarian cancer while minimizing side effects, and i...

We studied the relative RNA expression of clock genes throughout one 24-hour period in biopsies obtained from the oral mucosa and skin from eight healthy diurnally active male study participants. We found that the human clock genes hClock, hTim, hPer1, hCry1, and hBmal1 are expressed in oral mucosa and skin, with a circadian profile consistent with...

Fluoropyrimidines induce cytotoxicity, in part, by inhibiting the proliferation-coordinated enzyme thymidylate synthase (TS), which is essential for DNA synthesis. Tumor TS levels are clinically predictive of post-surgical tumor recurrence and of response to fluoropyrimidine chemotherapy. Fluoropyrimidine drug toxicity and efficacy each vary reprod...

Fluoropyrimidines induce cytotoxicity, in part, by inhibiting the proliferation-coordinated enzyme thymidylate synthase (TS), which is essential for DNA synthesis. Tumor TS levels are clinically predictive of post-surgical tumor recurrence and of response to fluoropyrimidine chemotherapy. Fluoropyrimidine drug toxicity and efficacy each vary reprod...

To compare the relative toxicities of bolus versus infusional 5-FU chemotherapy administrated concurrently during external beam irradiation in patients with locally advanced rectal cancer following surgical extirpation. A total of 26 eligible patients were retrospectively identified as having been treated for rectal adenocarcinoma at the Stratton V...

The mammalian fertility cycle is responsible for tight coordination of molecular, biochemical and cellular events. We have investigated whether timing of 5-fluorouracil (5-FU) chemotherapy within this cycle affects its reproductive toxicology. When this very short half-life, largely S-phase active cytotoxic antimetabolite is administered during the...

Circadian differences in the susceptibility of the marrow to the effects of radiation, myelotoxic drugs, and growth factors suggest that hematopoietic processes vary significant throughout each day. One mechanism possibly responsible for the differing degrees of marrow damage sustained from a fixed dose of a cytotoxic agent at different times of da...

The interactions between therapeutic proteins and delivery device surfaces may have a significant impact on the efficacy of a recombinant protein-based biological therapy program. Protein–surface interactions may induce conformational changes and aggregation, resulting in the inactivation of the protein therapeutic and even malfunction of the deliv...

The physical stability of pharmaceutical proteins in delivery environments is a critical determinant of biological potency and treatment efficacy, and yet it is often taken for granted. We studied both the bioactivity and physical stability of interleukin 2 upon delivery via continuous infusion. We found that the biological activity of the delivere...

Temporal coordination of biologic processes with an approximately 24-h cycle (circadian) is common throughout the animal and plant kingdom and even in some prokaryotic organisms. In all organisms studied, the capability to keep biologic time is an inherited characteristic located intracellularly. These biological clocks anticipate and get the organ...

Cisplatin-based therapy results in a cumulative anemia that is disproportionate to the effects on other blood cells. The severity of this treatment-induced anemia and the resultant transfusion requirement in cancer patients correlate with cisplatin-induced renal tubular dysfunction. Observed/expected serum erythropoietin (EPO) ratios decline with p...

Temporal coordination of biologic processes with an approximately 24-hour cycle (circadian) is ubiquitous throughout the animal and plant kingdoms. In each organism studied, the capability to keep biologic time is an inherited characteristic. These biological clocks anticipate, get the organism ready for, regular environmental changes. The immense...

Circadian coordination of the components of the hematopoietic system, immune system, and host-tumor balance in animals and humans have been demonstrated. Preclinical studies provide evidence that when within-the-day exogenous protein growth modulators such as EPO, G-CSF, IL-1, IL-2, TNF, or IFN are administered to animals, they determine to a large...

Recombinant human tumor necrosis factor-alpha (TNF-alpha) has demonstrable antitumor activity in transplantable murine tumor models and patients with cancer but is highly toxic to both animals and human beings. The narrow therapeutic index of TNF-alpha has limited its anticancer utility. Toxicity associated with many standard anticancer drugs is hi...