Purpose

Survivors of cervical cancer experience quality-of-life (QOL) disruptions that persist years after treatment. This study examines the effect of a psychosocial telephone counseling (PTC) intervention on QOL domains and associations with biomarkers.

Patients and methods

We conducted a randomized clinical trial in survivors of cervical cancer, who were ≥ 9 and less than 30 months from diagnosis (n = 204), to compare PTC to usual care (UC). PTC included five weekly sessions and a 1-month booster. Patient-reported outcomes (PROs) and biospecimens were collected at baseline and 4 and 9 months after enrollment. Changes in PROs over time and associations with longitudinal change in cytokines as categorical variables were analyzed using multivariable analysis of variance for repeated measures.

Results

Participant mean age was 43 years; 40% of women were Hispanic, and 51% were non-Hispanic white. Adjusting for age and baseline scores, participants receiving PTC had significantly improved depression and improved gynecologic and cancer-specific concerns at 4 months compared with UC participants (all P < .05); significant differences in gynecologic and cancer-specific concerns (P < .05) were sustained at 9 months. Longitudinal change in overall QOL and anxiety did not reach statistical significance. Participants with decreasing interleukin (IL) -4, IL-5, IL-10, and IL-13 had significantly greater improvement in QOL than those with increasing cytokine levels.

Conclusion

This trial confirms that PTC benefits mood and QOL cancer-specific and gynecologic concerns for a multiethnic underserved population of survivors of cancer. The improvement in PROs with decreases in T-helper type 2 and counter-regulatory cytokines supports a potential biobehavioral pathway relevant to cancer survivorship.

Efficient delivery of antigens is of paramount concern in immunotherapies. We aimed to target antigen presenting cells (APCs) by conjugating CpG oligonucleotides to an E2 protein nanoparticle surface (CpG-PEG-E2). Compared to E2 alone, we observed ~4-fold increase of in vitro APC uptake of both CpG-PEG-E2 and E2 conjugated to non-CpG DNA. Furthermore, compared to E2-alone or E2 functionalized solely with polyethylene glycol (PEG), the CpG-PEG-E2 showed enhanced lymph node retention up to at least 48 hr and 2-fold increase in APC uptake in vivo, parameters which are advantageous for vaccine success. This suggests that enhanced APC uptake of nanoparticles mediated by oligonucleotide display may help overcome delivery barriers in vaccine development.

Background

Sleep disturbances are associated with numerous mood disorders. Similarly, anxiety and depression are associated with modulation of the psychoneuroimmune (PNI) axis. This study hypothesized that changes in both monitored and self-reported measures of sleep would relate to changes in circulating cytokine levels in an emotionally distressed population of cervical cancer survivors.

Methods

Biospecimens, patient-reported outcome (PRO) measures, and actigraphy were collected from cervical cancer survivors enrolled in a biobehavioral clinical trial. Longitudinal changes over a 4-month period were examined. Sleep time measured by actigraphy and PRO were analyzed for correlative changes with emotional distress and serum cytokines (n = 71).

Results

Longitudinal change in the actigraph measure of sleep time was inversely associated with changes in depression and anxiety (test for linear trend, p = 0.02 and p = 0.05 respectively), as well as acute-phase response/pro-inflammatory cytokines (test for linear trend, p = 0.003, interleukin (IL)-2; 0.022, IL-1β; 0.0002, IL-6; and 0.049, tumor necrosis factor α). Conversely, changes in self-reported sleep problems were related to an increase in depression and anxiety (p = 0.001 and p = 0.01 respectively), the T helper 2 (Th2) cytokine IL-5 (p = 0.027), and the counter-regulatory cytokine IL-10 (0.016).

Conclusion

This study showed that an increase in sleep time or decrease in sleep problems corresponded with a reduction in self-reported emotional distress and attenuation of pro-inflammatory, Th2, and counter-regulatory cytokines. Our results support sleep measurement as a meaningful biobehavioral variable in cancer survivorship. This study also indicates that sleep investigators should be aware that choice of methodology might influence concordance with different classes of immune parameters.

Immune checkpoint inhibition is a promising alternative treatment to standard chemotherapies; however, it fails to achieve long-term remission in a significant portion of patients. A previously developed protein nanoparticle-based platform (E2 nanoparticle) delivers cancer antigens to increase antigen-specific tumor responses. While prior work has focussed on prophylactic conditions, the objectives in this study are therapeutic. It is hypothesized that immune checkpoint inhibition, when augmented by antigen delivery using E2 nanoparticles containing CpG oligonucleotide 1826 (CpG) and a glycoprotein 100 (gp100) melanoma antigen epitope (CpG-gp-E2), would synergistically elicit antitumor responses. To identify a regimen primed for obtaining effective treatment results, immune benchmarks in the spleen and tumor are examined. Conditions that lead to significant immune activation, including increases in gp100-specific interferon gamma (IFN-𝜸), CD8 T cells in the spleen, tumor-infiltrating CD8 T cells, and survival time are identified. Based on the findings, the resulting combination of CpG-gp-E2 and anti-programmed cell death protein 1 (anti-PD-1) treatment in tumor-challenged mice yield significantly increased long-term survival; more than 50% of the mice treated with combination therapy were tumor-free, compared with 0% and ≈5% for CpG-gp-E2 and anti-PD-1 alone, respectively. Evidence of a durable antitumor response is also observed upon tumor rechallenge, pointing to long-lasting immune memory.

The immune system is a powerful resource for the eradication of cancer, but to overcome the low immunogenicity of tumor cells, a sufficiently strong CD8(+) T cell-mediated adaptive immune response is required. Nanoparticulate biomaterials represent a potentially effective delivery system for cancer vaccines, as they can be designed to mimic viruses, which are potent inducers of cellular immunity. We have been exploring the non-viral pyruvate dehydrogenase E2 protein nanoparticle as a biomimetic platform for cancer vaccine delivery. Simultaneous conjugation of a melanoma-associated gp100 epitope and CpG to the E2 nanoparticle (CpG-gp-E2) yielded an antigen-specific increase in the CD8(+) T cell proliferation index and IFN-γ secretion by 1.5-fold and 5-fold, respectively, compared to an unbound peptide and CpG formulation. Remarkably, a single nanoparticle immunization resulted in a 120-fold increase in the frequency of melanoma epitope-specific CD8(+) T cells in draining lymph nodes and a 30-fold increase in the spleen, relative to free peptide with free CpG. Furthermore, in the very aggressive B16 melanoma murine tumor model, prophylactic immunization with CpG-gp-E2 delayed the onset of tumor growth by approximately 5.5 days and increased animal survival time by approximately 40%, compared to PBS-treated animals. These results show that by combining optimal particle size and simultaneous co-delivery of molecular vaccine components, antigen-specific anti-tumor immune responses can be significantly increased.

Efficient delivery of antigens is of paramount concern in immunotherapies. We aimed to target antigen presenting cells (APCs) by conjugating CpG oligonucleotides to an E2 protein nanoparticle surface (CpG-PEG-E2). Compared to E2 alone, we observed ~4-fold increase of in vitro APC uptake of both CpG-PEG-E2 and E2 conjugated to non-CpG DNA. Furthermore, compared to E2-alone or E2 functionalized solely with polyethylene glycol (PEG), the CpG-PEG-E2 showed enhanced lymph node retention up to at least 48 hr and 2-fold increase in APC uptake in vivo, parameters which are advantageous for vaccine success. This suggests that enhanced APC uptake of nanoparticles mediated by oligonucleotide display may help overcome delivery barriers in vaccine development.

Purpose

Improvement in health behaviors following cancer diagnosis may contribute to better prognosis and well-being. This study examines the prevalence of health behaviors in cervical cancer survivors who have completed treatment, and associations between health behaviors and quality of life (QOL).

Methods

We recruited 204 women who had completed treatment for cervical cancer to participate in a randomized counseling intervention. Participants provided information on health behaviors (smoking, physical activity, and alcohol consumption); QOL (Functional Assessment of Cancer Therapy-Cervical questionnaire); and depression (Patient-Reported Outcomes Measurement Information System), anxiety (Patient-Reported Outcomes Measurement Information System), and distress (Brief Symptom Inventory) at baseline (9-30 months after diagnosis) and subsequent to the intervention. Data were analyzed using multivariate general linear models.

Findings

Participants ranged in age from 20 to 72 years at diagnosis (mean = 43 years), 41% were Hispanic, and 52% were non-Hispanic white. Three-fourths were stage 1 at diagnosis and 51% were treated with radiation with or without chemotherapy. At baseline, 15% of patients were current smokers, 4% reported alcohol consumption of >10 drinks per week, and 63% reported exercising <3 hours per week. Overall, 67.4% of cervical cancer survivors did not meet recommended national guidelines for at least 1 of these health behaviors. QOL scores were significantly higher for patients with greater physical activity (128 vs 118; P = 0.002) and increased with the number of recommended guidelines met (P for trend = 0.030). Associations between patient-reported outcomes and smoking and alcohol consumption did not reach statistical significance. Participants who met guidelines for all health behaviors also had less depression (P = 0.008), anxiety (P = 0.051), and distress (P = 0.142). Participants who improved their aggregate health behaviors during the 4-month follow-up experienced a greater improvement in QOL than those who did not improve their health behaviors (10.8 vs 4.5; P = 0.026).

Implications

Results indicate that two-thirds of cervical cancer survivors are not meeting national guidelines for smoking, physical activity, and alcohol consumption following completion of definitive treatment. These adverse health behaviors were associated with impaired QOL and higher levels of depression and distress. Positive changes in health behaviors are associated with significant improvement in QOL.

Objective

Benefits of social support (SS) during cancer survivorship are complex. This study examines change in SS over time in cervical cancer (CXCA) survivors who have completed definitive treatment and how changing SS impacts quality of life (QOL) and T-helper type 2 (Th2) cytokines.

Methods

We conducted a randomized trial in 204 CXCA survivors to test if psychosocial telephone counseling (PTC) could improve QOL compared to usual care (UC). Although PTC did not target SS, data were collected at baseline, 4 and 9 months post-enrollment using the Medical Outcomes Survey Social Support scale. Biospecimens were collected to investigate associations with patient-reported outcomes. Data were analyzed using multivariate linear models and stepwise regression.

Results

Participants' mean age was 43. PTC participants experienced increasing SS compared to UC at 4 months (PTC-UC = 5.1; p = 0.055) and 9 months (PTC-UC = 6.0; p = 0.046). Higher baseline SS and increasing SS were independently associated with improved QOL at 4 and 9 months after adjusting for patient characteristics (p < 0.05). Differences between study arms were not statistically significant. Improvements in QOL at 4 months were observed with increases in emotional/informational and tangible SS. Increasing SS predicted significant longitudinal decreases in IL-4 and IL-13 at 4 months that were larger in the PTC arm (interactions p = 0.041 and p = 0.057, respectively).

Conclusion

Improved SS was significantly associated with improved QOL independent of patient characteristics and study arm. Decreasing Th2 cytokines with increasing SS and QOL are consistent with a biobehavioral paradigm in which modulation of the chronic stress response is associated with shifts in immune stance.

Nanoparticles have attracted considerable interest as cancer vaccine delivery vehicles for inducing sufficient CD8+ T cell-mediated immune responses to overcome the low immunogenicity of the tumor microenvironment. Our studies described here are the first to examine the effects of clinically-tested human cancer-testis (CT) peptide epitopes within a synthetic nanoparticle. Specifically, we focused on two significant clinical CT targets, the HLA-A2 restricted epitopes of NY-ESO-1 and MAGE-A3, using a viral-mimetic packaging strategy. Our data shows that simultaneous delivery of a NY-ESO-1 epitope (SLLMWITQV) and CpG using the E2 subunit assembly of pyruvate dehydrogenase (E2 nanoparticle), resulted in a 25-fold increase in specific IFN-γ secretion in HLA-A2 transgenic mice. This translated to a 15-fold increase in lytic activity toward target cancer cells expressing the antigen. Immunization with a MAGE-A3 epitope (FLWGPRALV) delivered with CpG in E2 nanoparticles yielded an increase in specific IFN-γ secretion and cell lysis by 6-fold and 9-fold, respectively. Furthermore, combined delivery of NY-ESO-1 and MAGE-A3 antigens in E2 nanoparticles yielded an additive effect that increased lytic activity towards cells bearing NY-ESO-1+ and MAGE-A3+. Our investigations demonstrate that formulation of CT antigens within a nanoparticle can significantly enhance antigen-specific cell-mediated responses, and the combination of the two antigens in a vaccine can preserve the increased individual responses that are observed for each antigen alone.