In response to immune pressure, influenza viruses evolve, producing drifted variants capable of escaping immune recognition. One strategy for inducing a broad-spectrum immune response capable of ...recognizing multiple antigenically diverse strains is to target conserved proteins or protein domains. To that end, we assessed the efficacy and immunogenicity of mRNA vaccines encoding either the conserved stem domain of a group 1 hemagglutinin (HA), a group 2 nucleoprotein (NP), or a combination of the two antigens in mice, as well as evaluated immunogenicity in naïve and influenza seropositive nonhuman primates (NHPs). HA stem-immunized animals developed a robust anti-stem antibody binding titer, and serum antibodies recognized antigenically distinct group 1 HA proteins. These antibodies showed little to no neutralizing activity in vitro but were active in an assay measuring induction of antibody-dependent cellular cytotoxicity. HA-directed cell-mediated immunity was weak following HA stem mRNA vaccination; however, robust CD4 and CD8 T cell responses were detected in both mice and NHPs after immunization with mRNA vaccines encoding NP. Both HA stem and NP mRNA vaccines partially protected mice from morbidity following lethal influenza virus challenge, and superior efficacy against two different H1N1 strains was observed when the antigens were combined. In vivo T cell depletion suggested that anti-NP cell-mediated immunity contributed to protection in the mouse model. Taken together, these data show that mRNA vaccines encoding conserved influenza antigens, like HA stem and NP in combination, induce broadly reactive humoral responses as well as cell-mediated immunity in mice and NHPs, providing protection against homologous and heterologous influenza infection in mice.
Cytokine release syndrome (CRS) immune effector cell–associated neurotoxicity syndrome are the most notable toxicities of CD19 chimeric antigen receptor (CAR) T-cell therapy. In addition, CAR ...T-cell–mediated toxicities can involve any organ system, with varied impacts on outcomes, depending on patient factors and involved organs. We performed detailed analysis of organ-specific toxicities and their association with outcomes in 60 patients with diffuse large B-cell lymphoma (DLBCL) treated with CD19 CAR T cells by assessing all toxicities in organ-based groups during the first year posttreatment. We observed 539 grade ≥2 and 289 grade ≥3 toxicities. Common grade ≥3 toxicities included hematological, metabolic, infectious, and neurological complications, with corresponding 1-year cumulative incidence of 57.7%, 54.8%, 35.4%, and 18.3%, respectively. Patients with impaired performance status had a higher risk of grade ≥3 metabolic complications, whereas elevated lactate dehydrogenase was associated with higher risks of grade ≥3 neurological and pulmonary toxicities. CRS was associated with higher incidence of grade ≥3 metabolic, pulmonary, and neurologic complications. The 1-year nonrelapse mortality and overall survival were 1.7% and 69%, respectively. Only grade ≥3 pulmonary toxicities were associated with an increased mortality risk. In summary, toxicity burdens after CD19 CAR T-cell therapy were high and varied by organ systems. Most toxicities were manageable and were rarely associated with mortality. Our study emphasizes the importance of toxicity assessment, which could serve as a benchmark for further research to reduce symptom burdens and improve tolerability in patients treated with CAR T cells.
•Toxicity burdens in DLBCL patients treated with CAR T cells are high; however, most toxicities are manageable and rarely cause mortality.•A uniform toxicity assessment is crucial for monitoring adverse events and improving experience in patients receiving CD19 CAR T cells.
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Patients who develop chimeric antigen receptor (CAR) T-cell–related severe cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) exhibit hemodynamic ...instability and endothelial activation. The EASIX (Endothelial Activation and Stress Index) score (lactate dehydrogenase LDH; U/L × creatinine mg/dL/platelets PLTs; 109 cells/L) is a marker of endothelial damage that correlates with outcomes in allogeneic hematopoietic cell transplantation. Elevated LDH and low PLTs have been associated with severe CRS and ICANS, as has C-reactive protein (CRP), while increased creatinine is seen only in a minority of advanced severe CRS cases. We hypothesized that EASIX and 2 new modified EASIX formulas (simplified EASIX, which excludes creatinine, and modified EASIX m-EASIX, which replaces creatinine with CRP mg/dL), calculated peri-CAR T-cell infusion, would be associated with development of severe (grade ≥ 3) CRS and ICANS. We included 118 adults, 53 with B-acute lymphoblastic leukemia treated with 1928z CAR T cells (NCT01044069) and 65 with diffuse large B-cell lymphoma treated with axicabtagene ciloleucel or tisagenlecleucel. The 3 formulas showed similar predictive power for severe CRS and ICANS. However, low PLTs and high CRP values were the only variables individually correlated with these toxicities. Moreover, only m-EASIX was a significant predictor of disease response. m-EASIX could discriminate patients who subsequently developed severe CRS preceding the onset of severe symptoms (area under the curve AUC at lymphodepletion, 80.4%; at day −1, 73.0%; and at day +1, 75.4%). At day +3, it also had high discriminatory ability for severe ICANS (AUC, 73%). We propose m-EASIX as a clinical tool to potentially guide individualized management of patients at higher risk for severe CAR T-cell–related toxicities.
•m-EASIX calculated before and early after CAR T-cell infusion can predict severe CRS and ICANS before the onset of severe symptoms.•m-EASIX includes laboratory parameters routinely available in CAR T-cell clinical practice and can be easily calculated at bedside.
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Perineural invasion (PNI) is a pathologic finding observed across a spectrum of solid tumors, typically with adverse prognostic implications. Little is known about how the presence of PNI influences ...locoregional recurrence (LRR) among breast cancers. We evaluated the association between PNI and LRR among an unselected, broadly representative cohort of breast cancer patients, and among a propensity-score matched cohort. We ascertained breast cancer patients seen at our institution from 2008 to 2019 for whom PNI status and salient clinicopathologic features were available. Fine-Gray regression models were constructed to evaluate the association between PNI and LRR, accounting for age, tumor size, nodal involvement, estrogen receptor (ER), progesterone receptor (PR), HER2 status, histologic tumor grade, presence of lymphovascular invasion (LVI), and receipt of chemotherapy and/or radiation. Analyses were then refined by comparing PNI-positive patients to a PNI-negative cohort defined by propensity score matching. Among 8864 invasive breast cancers, 1384 (15.6%) were noted to harbor PNI. At a median follow-up of 6.3 years, 428 locoregional recurrence events were observed yielding a 7-year LRR of 7.1% (95% CI 5.5-9.1) for those with PNI and 4.7% (95% CI 4.2-5.3; p = 0.01) for those without. On univariate analysis throughout the entire cohort, presence of PNI was significantly associated with an increased risk of LRR (HR 1.39, 95% CI 1.08-1.78, p < 0.01). Accounting for differences in salient clinicopathologic and treatment parameters by multivariable Fine-Gray regression modeling, the association between PNI and LRR was potentiated (HR 1.57, 95% CI 1.2-2.07, p = 0.001). We further conducted propensity score matching to balance clinicopathologic parameters and treatments between the two groups (PNI vs not), again showing a similar significant association between PNI and LRR (HR 1.46, 95% CI 1.03-2.08, p = 0.034). PNI is significantly associated with LRR following the definitive treatment of invasive breast cancer. The excess risk conferred by PNI is similar in magnitude to that observed with LVI, or by ER/PR negativity. Breast cancer prognostication and therapeutic decision-making should consider the presence of PNI among other salient risk factors. Larger studies among more uniform breast cancer presentations may elucidate the extent to which these findings apply across breast cancer subtypes and stages.
BACKGROUND
Although survivors of adolescent‐onset cancers are at risk of infertility, the majority desire children. Fertility preservation options are available for adolescents, but sperm banking ...remains underused. To the authors' knowledge, patient factors that influence decisions to bank sperm are poorly understood.
METHODS
A cross‐sectional study of 146 adolescent males who were newly diagnosed with cancer and who completed surveys within 1 week of treatment initiation was performed. Participants, 65% of whom were white, were aged 13 to 21 years (mean, 16.49 years; standard deviation, 2.02 years) and were at risk of infertility secondary to impending gonadotoxic treatment. Participating institutions included 8 leading pediatric oncology centers across the United States and Canada.
RESULTS
Of the patients approached, approximately 80.6% participated. Parent recommendation to bank (odds ratio OR, 4.88; 95% confidence interval 95% CI, 1.15‐20.71 P = .03), higher Tanner stage (OR, 4.25; 95% CI, 1.60‐11.27 P < .01), greater perceived benefits (OR, 1.41; 95% CI, 1.12‐1.77 P < .01), and lower social barriers to banking (OR, 0.88; 95% CI, 0.81‐0.96 P < .01) were found to be associated with adolescent collection attempts, whereas meeting with a fertility specialist (OR, 3.44; 95% CI, 1.00‐11.83 P = .05), parent (OR, 3.02; 95% CI, 1.12‐8.10 P = .03) or provider (OR, 2.67; 95% CI, 1.05‐6.77 P = .04) recommendation to bank, and greater adolescent self‐efficacy to bank (OR, 1.16; 95% CI, 1.01‐1.33 P = .03) were found to be associated with successful sperm banking.
CONCLUSIONS
Adolescents' perceived benefits of sperm banking, higher Tanner stage, and parent recommendation were associated with collection attempts, whereas perceived social barriers decreased this likelihood. Successful banking was associated with greater adolescent self‐efficacy, parent and provider recommendation to bank, and consultation with a fertility specialist. Providers should consult with both adolescents and parents regarding fertility preservation, and interventions should be tailored to address barriers to sperm banking while promoting its benefits.
Among at‐risk adolescent males newly diagnosed with cancer, sperm banking outcomes are associated with adolescent developmental (eg, Tanner stage) and psychological (eg, benefits to banking, self‐efficacy, and social barriers) factors, in addition to parent and provider recommendations and consultation with a fertility specialist. Because adolescent factors drive sperm banking outcomes, providers should prioritize patient participation and desires during the fertility preservation decision‐making process.
Adaptive behaviors, such as exercise and relaxation, are well-demonstrated to provide broad benefits, yet little is known about how emotion precede and/or influence their use. Broadly, literature ...suggests that adaptive health behaviors are enacted for the purpose of regulating negative affective experiences. However, other theoretical work suggests that positive affect precedes adaptive health behaviors, serving to maintain positive affective states. We sought to explicitly test the role of within-person fluctuations in negative and positive emotion in future adaptive behavior. Adults (
n
= 56) who were either psychologically healthy (
n
= 22) or diagnosed with major depression and/or social anxiety disorder (
n
= 34) completed an in-lab diagnostic interview, followed by a 14-day experience sampling diary measuring within-person fluctuations in positive and negative emotion and health behaviors. Within-person levels of positive affect was significantly associated with future positive health behaviors. Prior positive behaviors was also significantly associated with behaviors reported in the next signal. Additionally, mean positive affect was significantly associated with engagement in positive health behaviors. There were no significant associations for within-person or mean negative affect, and there were no group differences. Together, these results support a maintenance model, such that within-person increases in positive affect predicted future report of positive health behaviors.
Relapse and toxicity limit the effectiveness of chimeric antigen receptor T-cell (CAR-T) therapy for large B-cell lymphoma (LBCL), yet biomarkers that predict outcomes and toxicity are lacking. We ...examined radiomic features extracted from pre-CAR-T
F-fluorodeoxyglucose positron emission tomography/computed tomography (
FFDG PET/CT) scans (n = 341) of 180 patients (121 male; median age, 66 years). Three conventional (maximum standardized uptake value SUVmax, metabolic tumor volume MTV, total lesion glycolysis TLG) and 116 novel radiomic features were assessed, along with inflammatory markers, toxicities, and outcomes. At both pre-apheresis and pre-infusion time points, conventional PET features of disease correlated with elevated inflammatory markers. At pre-infusion, MTV was associated with grade ≥ 2 cytokine release syndrome (odds ratio OR for 100 mL increase: 1.08 95% confidence interval (CI), 1.01-1.20, P = 0.031), and SUVmax was associated with failure to achieve complete response (CR) (OR 1.72 95% CI, 1.24-2.43, P < 0.001). Higher pre-apheresis and pre-infusion MTV values were associated with shorter progression-free survival (PFS) (HR for 10-unit increase: 1.11 95% CI, 1.05-1.17, P < 0.001; 1.04 95% CI, 1.02-1.07, P < 0.001) and shorter overall survival (HR for 100-unit increase: 1.14 95% CI, 1.07-1.21, P < 0.001; 1.04 95% CI, 1.02-1.06, P < 0.001). A combined MTV and LDH measure stratified patients into high and low PFS risk groups. Multiple pre-infusion novel radiomic features were associated with CR. These quantitative conventional
FFDG PET/CT features obtained before CAR-T cell infusion, which were correlated with inflammation markers, may provide prognostic biomarkers for CAR-T therapy efficacy and toxicity. The use of conventional and novel radiomic features may thus help identify high-risk patients for earlier interventions.
Background
Adolescent and young adult (AYA) males newly diagnosed with cancer are often faced with making quick decisions about whether to cryopreserve (“bank”) sperm prior to treatment initiation. ...Given that parental influence is crucial among young patients, the present study examines the prevalence of and factors associated with parent recommendation to bank sperm.
Procedure
Parents of 13‐ to 21‐year‐old males newly diagnosed with cancer and at risk for infertility secondary to impending gonadotoxic treatment completed questionnaires typically within one week of treatment initiation. Medical and sociodemographic data, communication factors, and psychological factors were considered in a logistic regression model of parent report of parental recommendation to bank sperm (yes/no).
Results
Surveys from 138 parents (70.3% female) of 117 AYA males (mean age = 16.1 years, SD = 2.0) were analyzed. Over half of parents recommended banking to their sons (N = 82; 59.4%). Parents who received a provider recommendation to bank sperm (odds ratio OR = 18.44, 95% confidence interval CI, 4.20‐81.01, P < 0.001) or who believed in the benefits of banking (OR = 1.22, 95% CI, 1.02‐1.47, P = 0.03) were significantly more likely to recommend sperm banking.
Conclusions
Given parents’ role in influencing sperm banking outcomes, provider recommendation and promotion of banking benefits may influence parents and empower initiation of these sensitive discussions with their sons. Utilization of this approach should yield beneficial outcomes regardless of the banking decision.
To investigate the influence of parental sociodemographic, communication, and psychological factors on sperm collection attempts among at-risk adolescent males newly diagnosed with cancer.
...Prospective, single group, observational study design.
Pediatric oncology centers.
Parents (N = 144) of 122 newly diagnosed adolescent males at increased risk for infertility secondary to cancer therapy.
Survey-based assessment of parent factors associated with adolescent collection attempts.
Attempt of manual collection of sperm.
Parental recommendation to bank sperm (odds ratio OR 3.72; 95% confidence interval CI 1.18-11.76) and perceived self-efficacy to facilitate banking (OR 1.20; 95% CI 1.02-1.41) were associated with an increased likelihood of making a collection attempt.
Parental recommendation to bank is a critical influence for sperm banking among adolescent males newly diagnosed with cancer. These findings highlight the importance of effective communication between parents, patients, and health-care teams when discussing preservation options. Parent perceptions of their ability to facilitate sperm banking at the time of diagnosis should also be targeted in future interventions.
NCT01152268.
Attempts to develop a vaccine to prevent genital herpes simplex virus 2 (HSV-2) disease have been only marginally successful, suggesting that novel strategies are needed. Immunization with HSV-2 ...glycoprotein C (gC-2) and gD-2 was evaluated in mice and guinea pigs to determine whether adding gC-2 to a gD-2 subunit vaccine would improve protection by producing antibodies that block gC-2 immune evasion from complement. Antibodies produced by gC-2 immunization blocked the interaction between gC-2 and complement C3b, and passive transfer of gC-2 antibody protected complement-intact mice but not C3 knockout mice against HSV-2 challenge, indicating that gC-2 antibody is effective, at least in part, because it prevents HSV-2 evasion from complement. Immunization with gC-2 also produced neutralizing antibodies that were active in the absence of complement; however, the neutralizing titers were higher when complement was present, with the highest titers in animals immunized with both antigens. Animals immunized with the gC-2-plus-gD-2 combination had robust CD4+ T-cell responses to each immunogen. Multiple disease parameters were evaluated in mice and guinea pigs immunized with gC-2 alone, gD-2 alone, or both antigens. In general, gD-2 outperformed gC-2; however, the gC-2-plus-gD-2 combination outperformed gD-2 alone, particularly in protecting dorsal root ganglia in mice and reducing recurrent vaginal shedding of HSV-2 DNA in guinea pigs. Therefore, the gC-2 subunit antigen enhances a gD-2 subunit vaccine by stimulating a CD4+ T-cell response, by producing neutralizing antibodies that are effective in the absence and presence of complement, and by blocking immune evasion domains that inhibit complement activation.
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