Immunogenicity of personalized dendritic-cell therapy in HIV-1 infected individuals under suppressive antiretroviral treatment: interim analysis from a phase II clinical trial

Marcella Vassão de Almeida Baptista; Laís Teodoro da Silva; Sadia Samer; Telma Miyuki Oshiro; Iart Luca Shytaj; Leila B. Giron; Nathalia Mantovani Pena; Nicolly Cruz; Gisele Cristina Gosuen; Paulo Roberto Abrão Ferreira; Edécio Cunha-Neto; Juliana Galinskas; Danilo Dias; Maria Cecilia Araripe Sucupira; Cesar de Almeida-Neto; Reinaldo Salomão; Alberto José da Silva Duarte; Luís Mário Janini; James R. Hunter; Andrea Savarino; Maria Aparecida Juliano; Ricardo Sobhie Diaz

doi:10.1186/s12981-021-00426-z

Immunogenicity of personalized dendritic-cell therapy in HIV-1 infected individuals under suppressive antiretroviral treatment: interim analysis from a phase II clinical trial

Marcella Vassão de Almeida Baptista, Laís Teodoro da Silva, Sadia Samer, Telma Miyuki Oshiro, Iart Luca Shytaj, Leila B. Giron, Nathalia Mantovani Pena, Nicolly Cruz, Gisele Cristina Gosuen, Paulo Roberto Abrão Ferreira, Edécio Cunha-Neto, Juliana Galinskas, Danilo Dias, Maria Cecilia Araripe Sucupira, Cesar de Almeida-Neto, Reinaldo Salomão, Alberto José da Silva Duarte, Luís Mário Janini, James R. Hunter, Andrea SavarinoMaria Aparecida Juliano, Ricardo Sobhie Diaz^*

^*Corresponding author for this work

Medicine, Infectious Diseases Division

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

Background: We developed a personalized Monocyte-Derived Dendritic-cell Therapy (MDDCT) for HIV-infected individuals on suppressive antiretroviral treatment and evaluated HIV-specific T-cell responses. Methods: PBMCs were obtained from 10 HIV⁺ individuals enrolled in trial NCT02961829. Monocytes were differentiated into DCs using IFN-α and GM-CSF. After sequencing each patient’s HIV-1 Gag and determining HLA profiles, autologous Gag peptides were selected based on the predicted individual immunogenicity and used to pulse MDDCs. Three doses of the MDDCT were administered every 15 days. To assess immunogenicity, patients’ cells were stimulated in vitro with autologous peptides, and intracellular IL-2, TNF, and interferon-gamma (IFN-γ) production were measured in CD4⁺ and CD8⁺ T-cells. Results: The protocol of ex-vivo treatment with IFN-α and GM-CSF was able to induce maturation of MDDCs, as well as to preserve their viability for reinfusion. MDDCT administration was associated with increased expression of IL-2 in CD4⁺ and CD8⁺ T-cells at 15 and/or 30 days after the first MDDCT administration. Moreover, intracellular TNF and IFN-γ expression was significantly increased in CD4⁺ T-cells. The number of candidates that increased in vitro the cytokine levels in CD4⁺ and CD8⁺ T cells upon stimulation with Gag peptides from baseline to day 15 and from baseline to day 30 and day 120 after MDDCT was significant as compared to Gag unstimulated response. This was accompanied by an increasing trend in the frequency of polyfunctional T-cells over time, which was visible when considering both cells expressing two and three out of the three cytokines examined. Conclusions: MDDC had a mature profile, and this MDDCT promoted in-vitro T-cell immune responses in HIV-infected patients undergoing long-term suppressive antiretroviral treatment. Trial registration NCT02961829: (Multi Interventional Study Exploring HIV-1 Residual Replication: a Step Towards HIV-1 Eradication and Sterilizing Cure, https://www.clinicaltrials.gov/ct2/show/NCT02961829,

Original language	English (US)
Article number	2
Journal	AIDS Research and Therapy
Volume	19
Issue number	1
DOIs	https://doi.org/10.1186/s12981-021-00426-z
State	Published - Dec 2022

Funding

This work was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo and the Conselho Nacional de Desenvolvimento Científico e Tecnológico (FAPESP 2013/11323-5; CNPq—454700-2014-8; CNPq/DECIT 441817/2018-1), and ViiV Healthcare Investigator Sponsored Study (RD). LTS is a recipient of a fellowship from FAPESP (Ref. 2018/12460). I.L.S. acknowledges support from FAPESP (Ref. 19/17461-7).

Keywords

Dendritic-cell therapy
HIV GAG
HIV cure research
HLA Haplotypes
Precision medicine

ASJC Scopus subject areas

Molecular Medicine
Virology
Pharmacology (medical)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1186/s12981-021-00426-z

Cite this

de Almeida Baptista, M. V., da Silva, L. T., Samer, S., Oshiro, T. M., Shytaj, I. L., Giron, L. B., Pena, N. M., Cruz, N., Gosuen, G. C., Ferreira, P. R. A., Cunha-Neto, E., Galinskas, J., Dias, D., Sucupira, M. C. A., de Almeida-Neto, C., Salomão, R., da Silva Duarte, A. J., Janini, L. M., Hunter, J. R., ... Diaz, R. S. (2022). Immunogenicity of personalized dendritic-cell therapy in HIV-1 infected individuals under suppressive antiretroviral treatment: interim analysis from a phase II clinical trial. AIDS Research and Therapy, 19(1), Article 2. https://doi.org/10.1186/s12981-021-00426-z

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abstract = "Background: We developed a personalized Monocyte-Derived Dendritic-cell Therapy (MDDCT) for HIV-infected individuals on suppressive antiretroviral treatment and evaluated HIV-specific T-cell responses. Methods: PBMCs were obtained from 10 HIV+ individuals enrolled in trial NCT02961829. Monocytes were differentiated into DCs using IFN-α and GM-CSF. After sequencing each patient{\textquoteright}s HIV-1 Gag and determining HLA profiles, autologous Gag peptides were selected based on the predicted individual immunogenicity and used to pulse MDDCs. Three doses of the MDDCT were administered every 15 days. To assess immunogenicity, patients{\textquoteright} cells were stimulated in vitro with autologous peptides, and intracellular IL-2, TNF, and interferon-gamma (IFN-γ) production were measured in CD4+ and CD8+ T-cells. Results: The protocol of ex-vivo treatment with IFN-α and GM-CSF was able to induce maturation of MDDCs, as well as to preserve their viability for reinfusion. MDDCT administration was associated with increased expression of IL-2 in CD4+ and CD8+ T-cells at 15 and/or 30 days after the first MDDCT administration. Moreover, intracellular TNF and IFN-γ expression was significantly increased in CD4+ T-cells. The number of candidates that increased in vitro the cytokine levels in CD4+ and CD8+ T cells upon stimulation with Gag peptides from baseline to day 15 and from baseline to day 30 and day 120 after MDDCT was significant as compared to Gag unstimulated response. This was accompanied by an increasing trend in the frequency of polyfunctional T-cells over time, which was visible when considering both cells expressing two and three out of the three cytokines examined. Conclusions: MDDC had a mature profile, and this MDDCT promoted in-vitro T-cell immune responses in HIV-infected patients undergoing long-term suppressive antiretroviral treatment. Trial registration NCT02961829: (Multi Interventional Study Exploring HIV-1 Residual Replication: a Step Towards HIV-1 Eradication and Sterilizing Cure, https://www.clinicaltrials.gov/ct2/show/NCT02961829,",

keywords = "Dendritic-cell therapy, HIV GAG, HIV cure research, HLA Haplotypes, Precision medicine",

author = "\{de Almeida Baptista\}, \{Marcella Vass{\~a}o\} and \{da Silva\}, \{La{\'i}s Teodoro\} and Sadia Samer and Oshiro, \{Telma Miyuki\} and Shytaj, \{Iart Luca\} and Giron, \{Leila B.\} and Pena, \{Nathalia Mantovani\} and Nicolly Cruz and Gosuen, \{Gisele Cristina\} and Ferreira, \{Paulo Roberto Abr{\~a}o\} and Ed{\'e}cio Cunha-Neto and Juliana Galinskas and Danilo Dias and Sucupira, \{Maria Cecilia Araripe\} and \{de Almeida-Neto\}, Cesar and Reinaldo Salom{\~a}o and \{da Silva Duarte\}, \{Alberto Jos{\'e}\} and Janini, \{Lu{\'i}s M{\'a}rio\} and Hunter, \{James R.\} and Andrea Savarino and Juliano, \{Maria Aparecida\} and Diaz, \{Ricardo Sobhie\}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2022",

month = dec,

doi = "10.1186/s12981-021-00426-z",

language = "English (US)",

volume = "19",

journal = "AIDS Research and Therapy",

issn = "1742-6405",

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de Almeida Baptista, MV, da Silva, LT, Samer, S, Oshiro, TM, Shytaj, IL, Giron, LB, Pena, NM, Cruz, N, Gosuen, GC, Ferreira, PRA, Cunha-Neto, E, Galinskas, J, Dias, D, Sucupira, MCA, de Almeida-Neto, C, Salomão, R, da Silva Duarte, AJ, Janini, LM, Hunter, JR, Savarino, A, Juliano, MA & Diaz, RS 2022, 'Immunogenicity of personalized dendritic-cell therapy in HIV-1 infected individuals under suppressive antiretroviral treatment: interim analysis from a phase II clinical trial', AIDS Research and Therapy, vol. 19, no. 1, 2. https://doi.org/10.1186/s12981-021-00426-z

Immunogenicity of personalized dendritic-cell therapy in HIV-1 infected individuals under suppressive antiretroviral treatment: interim analysis from a phase II clinical trial. / de Almeida Baptista, Marcella Vassão; da Silva, Laís Teodoro; Samer, Sadia et al.
In: AIDS Research and Therapy, Vol. 19, No. 1, 2, 12.2022.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Immunogenicity of personalized dendritic-cell therapy in HIV-1 infected individuals under suppressive antiretroviral treatment

T2 - interim analysis from a phase II clinical trial

AU - de Almeida Baptista, Marcella Vassão

AU - da Silva, Laís Teodoro

AU - Samer, Sadia

AU - Oshiro, Telma Miyuki

AU - Shytaj, Iart Luca

AU - Giron, Leila B.

AU - Pena, Nathalia Mantovani

AU - Cruz, Nicolly

AU - Gosuen, Gisele Cristina

AU - Ferreira, Paulo Roberto Abrão

AU - Cunha-Neto, Edécio

AU - Galinskas, Juliana

AU - Dias, Danilo

AU - Sucupira, Maria Cecilia Araripe

AU - de Almeida-Neto, Cesar

AU - Salomão, Reinaldo

AU - da Silva Duarte, Alberto José

AU - Janini, Luís Mário

AU - Hunter, James R.

AU - Savarino, Andrea

AU - Juliano, Maria Aparecida

AU - Diaz, Ricardo Sobhie

PY - 2022/12

Y1 - 2022/12

N2 - Background: We developed a personalized Monocyte-Derived Dendritic-cell Therapy (MDDCT) for HIV-infected individuals on suppressive antiretroviral treatment and evaluated HIV-specific T-cell responses. Methods: PBMCs were obtained from 10 HIV+ individuals enrolled in trial NCT02961829. Monocytes were differentiated into DCs using IFN-α and GM-CSF. After sequencing each patient’s HIV-1 Gag and determining HLA profiles, autologous Gag peptides were selected based on the predicted individual immunogenicity and used to pulse MDDCs. Three doses of the MDDCT were administered every 15 days. To assess immunogenicity, patients’ cells were stimulated in vitro with autologous peptides, and intracellular IL-2, TNF, and interferon-gamma (IFN-γ) production were measured in CD4+ and CD8+ T-cells. Results: The protocol of ex-vivo treatment with IFN-α and GM-CSF was able to induce maturation of MDDCs, as well as to preserve their viability for reinfusion. MDDCT administration was associated with increased expression of IL-2 in CD4+ and CD8+ T-cells at 15 and/or 30 days after the first MDDCT administration. Moreover, intracellular TNF and IFN-γ expression was significantly increased in CD4+ T-cells. The number of candidates that increased in vitro the cytokine levels in CD4+ and CD8+ T cells upon stimulation with Gag peptides from baseline to day 15 and from baseline to day 30 and day 120 after MDDCT was significant as compared to Gag unstimulated response. This was accompanied by an increasing trend in the frequency of polyfunctional T-cells over time, which was visible when considering both cells expressing two and three out of the three cytokines examined. Conclusions: MDDC had a mature profile, and this MDDCT promoted in-vitro T-cell immune responses in HIV-infected patients undergoing long-term suppressive antiretroviral treatment. Trial registration NCT02961829: (Multi Interventional Study Exploring HIV-1 Residual Replication: a Step Towards HIV-1 Eradication and Sterilizing Cure, https://www.clinicaltrials.gov/ct2/show/NCT02961829,

AB - Background: We developed a personalized Monocyte-Derived Dendritic-cell Therapy (MDDCT) for HIV-infected individuals on suppressive antiretroviral treatment and evaluated HIV-specific T-cell responses. Methods: PBMCs were obtained from 10 HIV+ individuals enrolled in trial NCT02961829. Monocytes were differentiated into DCs using IFN-α and GM-CSF. After sequencing each patient’s HIV-1 Gag and determining HLA profiles, autologous Gag peptides were selected based on the predicted individual immunogenicity and used to pulse MDDCs. Three doses of the MDDCT were administered every 15 days. To assess immunogenicity, patients’ cells were stimulated in vitro with autologous peptides, and intracellular IL-2, TNF, and interferon-gamma (IFN-γ) production were measured in CD4+ and CD8+ T-cells. Results: The protocol of ex-vivo treatment with IFN-α and GM-CSF was able to induce maturation of MDDCs, as well as to preserve their viability for reinfusion. MDDCT administration was associated with increased expression of IL-2 in CD4+ and CD8+ T-cells at 15 and/or 30 days after the first MDDCT administration. Moreover, intracellular TNF and IFN-γ expression was significantly increased in CD4+ T-cells. The number of candidates that increased in vitro the cytokine levels in CD4+ and CD8+ T cells upon stimulation with Gag peptides from baseline to day 15 and from baseline to day 30 and day 120 after MDDCT was significant as compared to Gag unstimulated response. This was accompanied by an increasing trend in the frequency of polyfunctional T-cells over time, which was visible when considering both cells expressing two and three out of the three cytokines examined. Conclusions: MDDC had a mature profile, and this MDDCT promoted in-vitro T-cell immune responses in HIV-infected patients undergoing long-term suppressive antiretroviral treatment. Trial registration NCT02961829: (Multi Interventional Study Exploring HIV-1 Residual Replication: a Step Towards HIV-1 Eradication and Sterilizing Cure, https://www.clinicaltrials.gov/ct2/show/NCT02961829,

KW - Dendritic-cell therapy

KW - HIV GAG

KW - HIV cure research

KW - HLA Haplotypes

KW - Precision medicine

UR - https://www.scopus.com/pages/publications/85122914779

UR - https://www.scopus.com/inward/citedby.url?scp=85122914779&partnerID=8YFLogxK

U2 - 10.1186/s12981-021-00426-z

DO - 10.1186/s12981-021-00426-z

M3 - Article

C2 - 35022035

AN - SCOPUS:85122914779

SN - 1742-6405

VL - 19

JO - AIDS Research and Therapy

JF - AIDS Research and Therapy

IS - 1

M1 - 2

ER -

Immunogenicity of personalized dendritic-cell therapy in HIV-1 infected individuals under suppressive antiretroviral treatment: interim analysis from a phase II clinical trial

Abstract

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ASJC Scopus subject areas

UN SDGs

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