A Dendritic Cell–Based Vaccine Elicits T Cell Responses Associated with Control of HIV-1 Replication

García, Felipe; Climent, Núria; Guardo, Alberto C.; Gil, Cristina; León, Agathe; Autran, Brigitte; Lifson, Jeffrey D.; Martínez-Picado, Javier; Dalmau, Judith; Clotet, Bonaventura; Gatell, Josep M.; Plana, Montserrat; Gallart, Teresa

doi:10.1126/scitranslmed.3004682

Cited by 192 publications

(191 citation statements)

References 29 publications

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“…This finding, together with that of a recently published study using DC pulsed with autologous virus [7] underscores the central role of DCs in therapeutic vaccination.…”

Section: Discussionmentioning

confidence: 63%

Dendritic cell‐based therapeutic vaccine elicits polyfunctional HIV‐specific T‐cell immunity associated with control of viral load

et al. 2014

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Eur. J. Immunol. 2014Immunol. . 44: 2802Immunol. -2810 Clinical immunology 2803 IntroductionTo date, no effective therapeutic or prophylactic HIV vaccines are yet available. Recent encouraging results from the RV 144 trial showed a modest but statistically significant 31% reduction in the rate of HIV infection in vaccinated healthy volunteers receiving a prophylactic vaccine [1]. However, immune responses that would eradicate or control HIV are likely to be different from those needed to prevent primary infection. Indeed, eradication of HIV infection is likely to depend on the establishment of strong cytotoxic T lymphocytes, while prevention of infection will likely depend on the establishment of antibodies neutralizing the virus [2,3]. In both cases, CD4 + T helper cells are necessary for the establishment of robust and long-lasting immunity. Several candidate vaccines are under evaluation including peptides, inactivated virus, viral vectors, and ex vivo-generated DCs [4]. The latter represents an approach to optimize the induction of immune responses [5]. To date, only two studies, in which DCs have been loaded with chemically inactivated autologous virus, have reported a decrease in viral load [6,7]. Another approach using DCs transfected with RNA isolated from autologous virus yielded immune responses without control of viral replication [8]. However, these very promising data with inactivated autologous virus still need to be reproduced. For large scale use of DC vaccination, it would be advantageous to identify an antigenic cargo that could be used without having to isolate and expand the autologous virus which necessitates antiretroviral treatment interruption. We report here the safety and immunogenicity of a new DC platform loaded with five HIV-1-derived lipopeptides (LP) [9] in HIV-1-infected patients treated with highly active antiretroviral treatment (HAART). The study design included a 6-month analytical treatment interruption (ATI), a period which allowed us to evaluate the effects of vaccine-elicited immune responses on viral replication (Fig. 1). Results Patients and study outcomesTwenty patients were screened and 19 were enrolled within 17 months. Baseline characteristics of patients are reported in Table 1. All patients received the four vaccinations with no changes in vaccine dose. All patients but one completed the trial at 48 weeks.The vaccination was well tolerated. Two patients reached a safety endpoint (CD4 + T-cell counts below 500 cells/μL) during the vaccination phase while no safety endpoints were observed during the ATI phase. Systemic or local adverse events were mild or moderate (grade 1 or 2) and resolved in less than 2 days in the majority of cases. All patients stopped HAART at 24 weeks post inclusion except two of them who stopped at 25 and 26 weeks.Through 48 weeks, eight patients reached the immunology endpoint defining a failure of the strategy: at 28 (two patients), 32 (three patients), 36, 40, and 44 weeks. Three of these patients resumed HAART. No clinical events or pro...

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“…This finding, together with that of a recently published study using DC pulsed with autologous virus [7] underscores the central role of DCs in therapeutic vaccination.…”

Section: Discussionmentioning

confidence: 63%

Dendritic cell‐based therapeutic vaccine elicits polyfunctional HIV‐specific T‐cell immunity associated with control of viral load

et al. 2014

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“…They found that this strategy induced a control of pVL similar to that reported by Lu et al 44 and our group. 55 These data suggest that a combination of autologous antigens administered to patients on cART could have a higher virological effect than heterologous immunogens, although it should be tested in a randomized clinical trial.…”

Section: New Designed Immunogens To Pulse Md-dcmentioning

confidence: 96%

“…11,37,38 Some studies in animal models suggest that animals immunized with DCs loaded with HIV-1 viral lysate, envelope glycoproteins or inactivated virus mount a potent immune response against HIV-1. [39][40][41]42 Although it has been performed at least 13 published clinical trials of DC-based immunotherapy for HIV infection in humans [43][44][45][46][47][48][49][50]55 (reviewed in ref. 9), most of them were non-controlled, nonrandomized studies.…”

Section: Clinical Trials With Md-dcbased Therapeutic Vaccinesmentioning

confidence: 99%

“…The 13 clinical trials published so far suggest that DC immunotherapy in HIV-1 infection can elicit HIV-1 specific immunological responses. However, only five of these studies reported virological responses to immunization, 44,45,51,52,55 three have not assessed virological responses 47,50,53 and five failed to show any response. 43,46,48,49,54 Recently, our group reported the results of a blinded placebo controlled trial of a therapeutic vaccine using autologous MD-DC pulsed with autologous heatinactivated whole HIV.…”

Section: Clinical Trials With Md-dcbased Therapeutic Vaccinesmentioning

confidence: 99%

“…One of the strongest arguments favoring autologous virus come from the clinical trials. Those studies performed with heterologous antigens 43 44 and our group 45,51,55 used whole chemically and heat inactivated virus, respectively. Routy et al 56,57 reported the preliminary results of an immunotherapy trial consisting of MD-DCs and RNA encoding autologous HIV-1 antigens (Gag, Nef, Rev, Vpr) administered monthly in 33 subjects in four intradermal doses in combination with cART, followed by two more doses during a 12-week cART interruption (STI).…”

Section: New Designed Immunogens To Pulse Md-dcmentioning

confidence: 99%

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Dendritic cell based vaccines for HIV infection

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Multiple imputation approach for interval‐censored time to HIV RNA viral rebound within a mixed effects Cox model

et al. 2018

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We present a method to fit a mixed effects Cox model with interval‐censored data. Our proposal is based on a multiple imputation approach that uses the truncated Weibull distribution to replace the interval‐censored data by imputed survival times and then uses established mixed effects Cox methods for right‐censored data. Interval‐censored data were encountered in a database corresponding to a recompilation of retrospective data from eight analytical treatment interruption (ATI) studies in 158 human immunodeficiency virus (HIV) positive combination antiretroviral treatment (cART) suppressed individuals. The main variable of interest is the time to viral rebound, which is defined as the increase of serum viral load (VL) to detectable levels in a patient with previously undetectable VL, as a consequence of the interruption of cART. Another aspect of interest of the analysis is to consider the fact that the data come from different studies based on different grounds and that we have several assessments on the same patient. In order to handle this extra variability, we frame the problem into a mixed effects Cox model that considers a random intercept per subject as well as correlated random intercept and slope for pre‐cART VL per study. Our procedure has been implemented in R using two packages: truncdist and coxme, and can be applied to any data set that presents both interval‐censored survival times and a grouped data structure that could be treated as a random effect in a regression model. The properties of the parameter estimators obtained with our proposed method are addressed through a simulation study.

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A Dendritic Cell–Based Vaccine Elicits T Cell Responses Associated with Control of HIV-1 Replication

Cited by 192 publications

References 29 publications

Dendritic cell‐based therapeutic vaccine elicits polyfunctional HIV‐specific T‐cell immunity associated with control of viral load

Dendritic cell‐based therapeutic vaccine elicits polyfunctional HIV‐specific T‐cell immunity associated with control of viral load

Dendritic cell based vaccines for HIV infection

Multiple imputation approach for interval‐censored time to HIV RNA viral rebound within a mixed effects Cox model

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