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Purpose: Treatments are limited for metastatic melanoma and metastatic triple-negative breast cancer (mTNBC). This pilot phase I trial (NCT03060356) examined the safety and feasibility of intravenous RNA-electroporated chimeric antigen receptor (CAR) T cells targeting the cell-surface antigen cMET. Experimental Design: Metastatic melanoma or mTNBC subjects had at least 30% tumor expression of cMET, measurable disease and progression on prior therapy. Patients received up to six infusions (1 × 10e8 T cells/dose) of CAR T cells without lymphodepleting chemotherapy. Forty-eight percent of prescreened subjects met the cMET expression threshold. Seven (3 metastatic melanoma, 4 mTNBC) were treated. Results: Mean age was 50 years (35–64); median Eastern Cooperative Oncology Group 0 (0–1); median prior lines of chemotherapy/immunotherapy were 4/0 for TNBC and 1/3 for melanoma subjects. Six patients experienced grade 1 or 2 toxicity. Toxicities in at least 1 patient included anemia, fatigue, and malaise. One subject had grade 1 cytokine release syndrome. No grade 3 or higher toxicity, neurotoxicity, or treatment discontinuation occurred. Best response was stable disease in 4 and disease progression in 3 subjects. mRNA signals corresponding to CAR T cells were detected by RT-PCR in all patients’ blood including in 3 subjects on day +1 (no infusion administered on this day). Five subjects underwent postinfusion biopsy with no CAR T-cell signals seen in tumor. Three subjects had paired tumor tissue; IHC showed increases in CD8 and CD3 and decreases in pS6 and Ki67. Conclusions: Intravenous administration of RNA-electroporated cMET-directed CAR T cells is safe and feasible. Significance: Data evaluating CAR T therapy in patients with solid tumors are limited. This pilot clinical trial demonstrates that intravenous cMET-directed CAR T-cell therapy is safe and feasible in patients with metastatic melanoma and metastatic breast cancer, supporting the continued evaluation of cellular therapy for patients with these malignancies.

We conducted a phase I clinical trial of anti-BCMA chimeric antigen receptor T cells (CART-BCMA) with or without anti-CD19 CAR T cells (huCART19) in multiple myeloma (MM) patients responding to third- or later-line therapy (phase A, N = 10) or high-risk patients responding to first-line therapy (phase B, N = 20), followed by early lenalidomide or pomalidomide maintenance. We observed no high-grade cytokine release syndrome (CRS) and only one instance of low-grade neurologic toxicity. Among 15 subjects with measurable disease, 10 exhibited partial response (PR) or better; among 26 subjects responding to prior therapy, 9 improved their response category and 4 converted to minimal residual disease (MRD)–negative complete response/stringent complete response. Early maintenance therapy was safe, feasible, and coincided in some patients with CAR T-cell reexpansion and late-onset, durable clinical response. Outcomes with CART-BCMA + huCART19 were similar to CART-BCMA alone. Collectively, our results demonstrate favorable safety, pharmacokinetics, and antimyeloma activity of dual-target CAR T-cell therapy in early lines of MM treatment.Significance:CAR T cells in early lines of MM therapy could be safer and more effective than in the advanced setting, where prior studies have focused. We evaluated the safety, pharmacokinetics, and efficacy of CAR T cells in patients with low disease burden, responding to current therapy, combined with standard maintenance therapy.This article is highlighted in the In This Issue feature, p. 101

Study procedures. Participant study procedures including cell collection/manufacturing timeline as well as infusion schedule from eligibility confirmation onward.

Purpose:Treatments are limited for metastatic melanoma and metastatic triple-negative breast cancer (mTNBC). This pilot phase I trial (NCT03060356) examined the safety and feasibility of intravenous RNA-electroporated chimeric antigen receptor (CAR) T cells targeting the cell-surface antigen cMET.Experimental Design:Metastatic melanoma or mTNBC subjects had at least 30% tumor expression of cMET, measurable disease and progression on prior therapy. Patients received up to six infusions (1 × 10e8 T cells/dose) of CAR T cells without lymphodepleting chemotherapy. Forty-eight percent of prescreened subjects met the cMET expression threshold. Seven (3 metastatic melanoma, 4 mTNBC) were treated.Results:Mean age was 50 years (35–64); median Eastern Cooperative Oncology Group 0 (0–1); median prior lines of chemotherapy/immunotherapy were 4/0 for TNBC and 1/3 for melanoma subjects. Six patients experienced grade 1 or 2 toxicity. Toxicities in at least 1 patient included anemia, fatigue, and malaise. One subject had grade 1 cytokine release syndrome. No grade 3 or higher toxicity, neurotoxicity, or treatment discontinuation occurred. Best response was stable disease in 4 and disease progression in 3 subjects. mRNA signals corresponding to CAR T cells were detected by RT-PCR in all patients’ blood including in 3 subjects on day +1 (no infusion administered on this day). Five subjects underwent postinfusion biopsy with no CAR T-cell signals seen in tumor. Three subjects had paired tumor tissue; IHC showed increases in CD8 and CD3 and decreases in pS6 and Ki67.Conclusions:Intravenous administration of RNA-electroporated cMET-directed CAR T cells is safe and feasible.Significance:Data evaluating CAR T therapy in patients with solid tumors are limited. This pilot clinical trial demonstrates that intravenous cMET-directed CAR T-cell therapy is safe and feasible in patients with metastatic melanoma and metastatic breast cancer, supporting the continued evaluation of cellular therapy for patients with these malignancies.

mRNA signals corresponding to CAR T cells in peripheral blood

Supplementary Figure 1.: Representative immunohistochemical staining for Subject 74 with metastatic melanoma; lymph node biopsy. Panel A: pS6 staining prior to infusion; Panel B: pS6 staining at post-infusion biopsy; Panel C: Ki-67 staining prior to infusion; Panel D: Ki-67 staining at post-infusion biopsy.

Patient population

Response

Supplementary Figure 2: Representative immunohistochemical staining for Subject 27 with metastatic triple-negative breast cancer; lymph node biopsy. Panel A shows CD8 staining prior to infusion and Panel B shows CD8 staining at the time of post-infusion biopsy.

IHC analysis of paired tumor tissue

IHC analysis of CD8 in preinfusion and postinfusion tumor tissue. Three subjects had preinfusion and postinfusion tumor tissue available for analysis; postinfusion tumor tissue demonstrated an increase in cytoxic CD8+ cells in all 3 subjects.

Adverse events, clinically relevant (# subjects includes those with the given toxicity at least possibly related to study treatment)

Supplemental tables: (1) Subject characteristics. (2) Cytogenetic profiles and high-risk features. (3) Prior treatment exposures and refractoriness. (4) CAR T cell product characteristics. (5) Products that did not meet target dose. (6) Adverse events of grade 3-4. (7) Cytokine release syndrome and ICANS. (8). Maintenance therapy. Supplemental Figures: (1) Study schematic and subject disposition, (2) Correlates of manufacturing success, (3) Hematopoietic recovery, (4) Post-infusion T cell phenotypes, (5) Correlates of in vivo expansion and manufacturing success, (6) Late post-infusion CAR T cell re-expansion, (7) Soluble BCMA, (8) Late-onset clinical responses, (9) MM cell BCMA expression, (10) Pre- and post-treatment Sox2-specific T cell responses in CART-BCMA monotherapy patients, (11) Pre- and post-treatment Sox2-specific T cell responses in CART-BCMA + huCART19 combination therapy patients, (12) Sustained post-treatment SOX2-specific T-cell responses.

We conducted a phase I clinical trial of anti-BCMA chimeric antigen receptor T cells (CART-BCMA) with or without anti-CD19 CAR T cells (huCART19) in multiple myeloma (MM) patients responding to third- or later-line therapy (phase A, N = 10) or high-risk patients responding to first-line therapy (phase B, N = 20), followed by early lenalidomide or pomalidomide maintenance. We observed no high-grade cytokine release syndrome (CRS) and only one instance of low-grade neurologic toxicity. Among 15 subjects with measurable disease, 10 exhibited partial response (PR) or better; among 26 subjects responding to prior therapy, 9 improved their response category and 4 converted to minimal residual disease (MRD)–negative complete response/stringent complete response. Early maintenance therapy was safe, feasible, and coincided in some patients with CAR T-cell reexpansion and late-onset, durable clinical response. Outcomes with CART-BCMA + huCART19 were similar to CART-BCMA alone. Collectively, our results demonstrate favorable safety, pharmacokinetics, and antimyeloma activity of dual-target CAR T-cell therapy in early lines of MM treatment.Significance:CAR T cells in early lines of MM therapy could be safer and more effective than in the advanced setting, where prior studies have focused. We evaluated the safety, pharmacokinetics, and efficacy of CAR T cells in patients with low disease burden, responding to current therapy, combined with standard maintenance therapy.This article is highlighted in the In This Issue feature, p. 101

PDF file - 1065KB, Supplemental Data for Figure 4.

PDF file - 48KB

PDF file - 54KB, Adverse Events Table.

PDF file - 198KB, MAGE-A3 Trojan Peptide Vaccine Reactogenicity.

PDF file - 40KB, ELISA Antibody Responses for the PCV (Prevnar-13(registered trademark)).

Purpose: Myeloma-directed cellular immune responses after autologous stem cell transplantation (ASCT) may reduce relapse rates. We studied whether coinjecting the TLR-3 agonist and vaccine adjuvant Poly-ICLC with a MAGE-A3 peptide vaccine was safe and would elicit a high frequency of vaccine-directed immune responses when combined with vaccine-primed and costimulated autologous T cells.Experimental Design: In a phase II clinical trial (NCT01245673), we evaluated the safety and activity of ex vivo expanded autologous T cells primed in vivo using a MAGE-A3 multipeptide vaccine (compound GL-0817) combined with Poly-ICLC (Hiltonol), granulocyte macrophage colony-stimulating factor (GM-CSF) ± montanide. Twenty-seven patients with active and/or high-risk myeloma received autografts followed by anti-CD3/anti-CD28–costimulated autologous T cells, accompanied by MAGE-A3 peptide immunizations before T-cell collection and five times after ASCT. Immune responses to the vaccine were evaluated by cytokine production (all patients), dextramer binding to CD8+ T cells, and ELISA performed serially after transplant.Results: T-cell infusions were well tolerated, whereas vaccine injection site reactions occurred in >90% of patients. Two of nine patients who received montanide developed sterile abscesses; however, this did not occur in the 18 patients who did not receive montanide. Dextramer staining demonstrated MAGE-A3–specific CD8 T cells in 7 of 8 evaluable HLA-A2+ patients (88%), whereas vaccine-specific cytokine-producing T cells were generated in 19 of 25 patients (76%). Antibody responses developed in 7 of 9 patients (78%) who received montanide and only weakly in 2 of 18 patients (11%) who did not. The 2-year overall survival was 74% [95% confidence interval (CI), 54%–100%] and 2-year event-free survival was 56% (95% CI, 37%–85%).Conclusions: A high frequency of vaccine-specific T-cell responses were generated after transplant by combining costimulated autologous T cells with a Poly-ICLC/GM-CSF–primed MAGE-A3 vaccine. Clin Cancer Res; 20(5); 1355–65. ©2013 AACR.

Maternal smoking during pregnancy and maternal smoking postnatally are important public health concerns worldwide. Smoking adversely affects the woman's general health and is causally related to pregnancy complications and serious health outcomes for the child, such as stillbirth, preterm delivery, low birth weight, and sudden infant death. The purpose of this research was to examine maternal smoking through a quantitative descriptive survey of 164 women, 120 who were pregnant and 44 who were postnatal. Women experienced barriers to quitting smoking, including dealing with stress, being exposed to smokers, not being ready to quit, not knowing how to quit, not looking for or not being able to find information about smoking or quitting smoking, and lacking adequate social and healthcare provider support. On the other hand, women revealed characteristics that suggest they might have had improved potential for quitting smoking, including having negative feelings about smoking, having cut down on smoking, smoking at a low level, having made quit attempts, thinking it would not be hard to quit smoking, being in the preparation stage of behavioral change, and thinking their healthcare providers (HCPs) would help them if they decided to quit. Taken together, those findings suggest that HCPs could offer important assistance to help women achieve smoking cessation. However, more research needs to be conducted to clarify the role and effectiveness of various HCPs in smoking cessation interventions and to identify measures to strengthen their provision of such interventions.

Parents (n = 135) were surveyed in relation to administering antipyretic/analgesic medications to their children (2 months-6 years) at home. Parents usually chose acetaminophen, calculated dosages based on weight but did not always know the child's weight, administered medications with a dropper, and reported having a sick child was moderately stressful. Many children were medicated for pain and/or fever during the week prior to immunization and many weighed more than the age/weight recommended dosages on the label. Community health nurses can facilitate safe administration of medications by integrating knowledge of parents' pain and fever management practices into discussions and anticipatory planning during clinic visits.

Students enrolled in accelerated baccalaureate nursing programs have often proven themselves to be independent, ambitious and self-motivated. Nurse educators are being challenged to adapt their accelerated program curricula, teaching approaches and delivery modes to accommodate the goals, abilities and resources of these adult learners. At the same time, the rapid changes occurring in health care delivery, locally and worldwide, challenge new practitioners to quickly achieve an increasing list of cognitive and psychomotor competencies for effective nursing practice. Since January 2011, faculty members of Memorial University School of Nursing have been engaged in a comprehensive initiative to create a new accelerated program with a redesigned curriculum. Briefly presented key milestones accomplished to date, including articulating the new accelerated program mission statement; determining applicant requirements; formulating a new educational philosophy; seeking governance approval; establishing program outcomes; and, framing the curriculum structure.

There have been tremendous research advances in the past 15 years in knowledge about children's pain, and strategies for recognizing and managing that pain. However, the clinical care of children in pain remains a challenge. Children's pain continues to be frequently unrecognized , dismissed or ineffectively managed. A loud call for change is being voiced by physicians, nurses, children and their families. A review of the literature was conducted to document this issue. Starting with a Medline search of the key word 'child* + pain' and continuing with a snowball technique, articles and resources addressing children's pain were collected. Resources presented or published after 1990 were particularly sought because they theoretically reflect both current knowledge about children's pain and the implementation of this knowledge in practice. Unfortunately, although information on pain is available to help children, in many instances, it is not being used. The purpose of the present paper is twofold -- to present an overview of current knowledge of children's pain, and factors that hinder its effective assessment and management; and to present a mandate for change. Children's postoperative pain is highlighted in this paper as an example of the gap between pain knowledge and clinical practice. Although treatment strategies differ across different types of pain, children's conditions and ages, the principles and mandate for change discussed in this paper are directly relevant to all categories of children's pain.

Cardiorespiratory fitness (CRF) is a strong, independent predictor of morbidity and mortality. Although the majority of adults who increase daily physical activity experience an increase in CRF (VO2 peak), about 10-15% of participants do not increase CRF despite participating in a standardized exercise program. In this study we sought to determine whether exercise combined with a healthy diet was associated with a corresponding improvement in cardiometabolic risk factors despite the absence of change in CRF. We studied 59 sedentary, abdominally obese (waist circumference: 104.6 ± 8.5cm) adults who participated in 3 (women) or 4 (men) months of supervised aerobic exercise. CRF was measured using a standard treadmill test. Cardiometabolic risk factors included fasting triglycerides, total cholesterol, HDL-C, LDL-C, insulin, glucose, systolic and diastolic blood pressure. Participants were asked to exercise 7 days per week for the time required to expend 500 kcals per session for women, and 700 kcals for men. The intensity of exercise was self-selected and ranged between 65-90% of VO2 peak. Men and women were combined for all analyses. To examine the relationship between corresponding changes in cardiometabolic risk factors and CRF, participants were divided into tertiles based on mean change in CRF. A linear trend test was used to characterize the change in cardiometabolic risk factors across CRF change tertiles. The volume (energy expenditure (kcal)) and intensity (%VO2 peak) of exercise performed across tertiles of change in CRF was not different (P>0.10). As expected a significant linear trend across tertiles was observed for change in CRF (P0.10). Without exception, no linear trend was observed for the change in cardiometabolic risk factors across tertiles of change in CRF (P>0.10). This was also true for change in waist circumference and visceral fat (P>0.10). Regression analysis using the total sample confirmed that, with the exception of glucose, the change score for each cardiometabolic risk factor was not related to the change in CRF (P>0.10). Our findings suggest that in abdominally obese adults, improvement in cardiometabolic risk profile is not associated with change in CRF and that increasing physical activity combined with a healthful diet is associated with substantial health benefit in the absence of change in CRF.

Radiation-induced fibrosis (RIF) is an uncommon complication of radiation therapy. RIF most often occurs in the extremities; it is rare in the head and neck. Only a few medical treatments for RIF are available, and they have been mediocre at best. We describe a case of RIF of the face that was treated successfully with a nonmedical modality: manual compression therapy.

Smoking among adolescents is a major public health concern. Most parents would not want their children engaged in this risk-taking behavior. Although a majority of parents of smokers are themselves smokers, many are nonsmokers. The purpose of this grounded theory study was to understand what nonsmoking parents experience due to their adolescent children’s smoking behavior. The purposive sample consisted of 25 parents. The interview data generated the theory that nonsmoking parents struggle to understand their adolescents’ smoking. They experienced four stages: discovering the smoking, facing the problem, reflecting, and waiting it out. Their experience can be examined from a stress paradigm. Programs are needed that provide parents with the knowledge and skills required for effective prevention and intervention strategies.