12 research outputs found
31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two
Background
The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd.
Methods
We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background.
Results
First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001).
Conclusions
In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival
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Increased Difficulties Managing Chronic Medical Conditions During the COVID-19 Pandemic Are Associated With Increased Alcohol and Cannabis Use Among Unhoused and Unstably Housed Women.
ObjectivesThe COVID-19 pandemic caused dramatic upsurges in stress and anxiety across the United States, as well as increased substance use to cope with pandemic-related stress. Few studies have focused exclusively on extremely disadvantaged individuals who are already at risk for substance use. We sought to understand factors associated with increased alcohol and cannabis use during the first 10 months of the COVID-19 pandemic among unsheltered and unstably housed women.MethodsBetween July and December 2020, we conducted phone surveys with San Francisco unhoused and unstably housed women regarding substance use, health, and health services use since the beginning of the pandemic (March 2020).ResultsAmong 128 participants, increased use of alcohol and cannabis were reported by 15% and 23%, respectively. The odds of increased use of both substances were 4 times higher in participants who also had increased difficulties managing symptoms of a chronic medical condition during the pandemic.ConclusionsAn intentional and comprehensive approach to managing the health of particularly vulnerable individuals during the COVID pandemic could help alleviate its exacerbating influences. Such an approach should include resources, tools and interventions for managing substance use, as well as chronic, non-COVID medical conditions, which are common and strongly tied to substance use in unhoused and unstably housed women
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An integrative methamphetamine treatment alters the leukocyte DNA methylome in sexual minority men with HIV
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Tina's ParTy line: Polysubstance use patterns in sexual minority men living with HIV who use methamphetamine
INTRODUCTIONThis cross-sectional study examined the associations of demographic, structural and psychological factors with distinct typologies of polysubstance use in sexual minority men (SMM) living with HIV who use methamphetamine. METHODSIn total, 161 SMM living with HIV who reported methamphetamine use in the past 3 months were recruited in San Francisco from 2013 to 2017 for a randomised controlled trial. A latent class analysis was conducted by leveraging baseline measures of self-reported use of 15 substances in the past 3 months as well as validated screening measures of hazardous alcohol and cannabis use. Correlates of latent class membership were examined using a three-step categorical latent variable logistic regression. RESULTSFour typologies of substance use were identified: (i) methamphetamine use only (43%); (ii) methamphetamine and crack-cocaine use (22%); (iii) party and play use-methamphetamine, gamma-hydroxybutyrate and amyl nitrites (i.e. poppers) with erectile dysfunction drugs (31%); and (iv) high polysubstance use (4%). SMM of colour and those with a history of incarceration were more commonly classified as engaging in methamphetamine and crack-cocaine use compared to party and play use. Men with higher sexual compulsivity scores were more commonly classified as engaging in party and play use and polysubstance use. DISCUSSION AND CONCLUSIONSThere is substantial heterogeneity in polysubstance use patterns among SMM living with HIV who use methamphetamine. This will inform the development of tailored substance use interventions addressing the unique needs of SMM of colour and targeting sexual compulsivity as a prominent comorbidity for some men
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Randomized Controlled Trial of Motivational Enhancement Interventions to Increase Pre-Exposure Prophylaxis Use in Sexual Minority Men Who Use Stimulants
Although pre-exposure prophylaxis (PrEP) could substantially mitigate HIV risk, sexual minority men (SMM) who use stimulants commonly experience difficulties with engaging in PrEP clinical services. Motivational interviewing (MI) and contingency management (CM) reduce substance use and condomless anal sex in this population, but these motivational enhancement interventions require adaptation to promote engagement along the PrEP care continuum.
PRISM is a pilot sequential multiple assignment randomized trial (SMART) testing the feasibility, acceptability, and preliminary effectiveness of distinct combinations of telehealth MI and CM in 70 cisgender SMM who use stimulants that are not currently taking PrEP. A national sample was recruited via social networking applications to complete a baseline assessment and mail-in HIV testing. Those with non-reactive HIV results are randomized to receive either: 1) a 2-session MI intervention focusing on PrEP use (session 1) and concomitant stimulant use or condomless anal sex (session 2); or 2) a CM intervention with financial incentives for documented evidence of PrEP clinical evaluation by a medical provider (50). At the 3-month follow-up assessment, participants who report they have not filled a prescription for PrEP are randomized a second time to either: 1) Switch to a second-stage intervention (i.e., MI + CM or CM + MI); or 2) Continue with assessments only. Outcomes for both responders and non-responders are reassessed at a 6-month follow-up. The primary outcome is documented evidence of filling a PrEP prescription. Self-reported, secondary outcomes include PrEP clinical evaluation by a medical provider, stimulant use, and condomless anal sex. Qualitative exit interviews are conducted with a sub-group of responders and non-responders to characterize their experiences with the MI and CM interventions.
Implementation of this pilot SMART underscores the challenges in reaching SMM who use stimulants to optimize HIV prevention efforts such that approximately one in ten (104/1,060) eligible participants enrolled. However, 85% (70/82) of enrolled participants with non-reactive HIV results were randomized. Further research is needed to determine the effectiveness of telehealth MI and CM for supporting PrEP use in SMM who use stimulants.
This protocol was registered on clinicaltrials.gov (NCT04205487) on December 19, 2019
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A positive affect intervention alters leukocyte DNA methylation in sexual minority men with HIV who use methamphetamine
•Intervention-related decreases in methylation of β2 and oxytocin receptor genes.•Intervention effects on pathways for neural function and neurotransmitter release.•Accompanied by significant reductions in the self-reported frequency of stimulant use.This epigenomics sub-study embedded within a randomized controlled trial examined whether an evidenced-based behavioral intervention model that decreased stimulant use altered leukocyte DNA methylation (DNAm).Sexual minority men with HIV who use methamphetamine were randomized to a five-session positive affect intervention (n = 32) or an attention-control condition (n = 21), both delivered during three months of contingency management for stimulant abstinence. All participants exhibited sustained HIV virologic control – an HIV viral load less than 40 copies/mL at baseline and six months post-randomization. The Illumina EPIC BeadChip measured leukocyte methylation of cytosine-phosphate-guanosine (CpG) sites mapping onto five a priori candidate genes of interest (i.e., ADRB2, BDNF, FKBP5, NR3C1, OXTR). Functional DNAm pathways and soluble markers of immune dysfunction were secondary outcomes.Compared to the attention-control condition, the positive affect intervention significantly decreased methylation of CpG sites on genes that regulate β2 adrenergic and oxytocin receptors. There was an inconsistent pattern for the direction of the intervention effects on methylation of CpG sites on genes for glucocorticoid receptors and brain-derived neurotrophic factor. Pathway analyses adjusting for the false discovery rate (padj < 0.05) revealed significant intervention-related alterations in DNAm of Reactome pathways corresponding to neural function as well as dopamine, glutamate, and serotonin release. Positive affect intervention effects on DNAm were accompanied by significant reductions in the self-reported frequency of stimulant use.There is an epigenetic signature of an evidence-based behavioral intervention model that reduced stimulant use, which will guide the identification of biomarkers for treatment responses