Drastic decrease of the HIV reservoir in a patient treated with nivolumab for lung cancer

Drastic decrease of the HIV reservoir in a patient treated with nivolumab for lung cancer Therapy with immune check point inhibitors (ICPIs) may have dual benefits in HIV infection by acting not only on the cancers frequently associated but also by helping to purge the HIV reservoirs that indefinitely persist despite antiretroviral therapy. Indeed, it is hypothesized that ICPIs could de-repress the blockade of HIV transcription in the reservoirs concentrated in memory CD4 T cells co-expressing ICPs and simultaneously restore functions in exhausted HIV-specific T cells displaying high Programmed Cell Death-1 (PD-1) levels [1]. This hypothesis has not been confirmed yet. Two case reports of HIV-infected patients treated for cancer with an anti-Cytotoxic T-lymphocyte Associated Protein 4 (CTLA-4) [2], or an anti-PD1 [3] monoclonal antibody showed a good safety profile that was recently confirmed by two series of patients treated for melanoma (N = 9) [4] or lung cancer (N = 10) [5]. However, no clear effect on HIV reservoirs was reported despite some transient increase in HIV transcription after anti-CTLA-4, and in HIV-specific T cells after anti-PD1 therapy [2, 3]. Here, we report for the first time a new case with a drastic and sustained decrease of the HIV reservoir paralleling the increase in HIV-specific CD8 T cells under anti-PD1 therapy. A 51-year-old man, smoker, HIV-infected since 1995, diagnosed with stage IIIa epidermal growth factor receptor-/BRAF-/Kras-/Programmed Cell Death Ligand-1- non-small-cell lung cancer in May 2015 was treated with lobectomy and adjuvant chemotherapy (cisplatin and pemetrexed). Relapse occurred <6 months after the end of chemotherapy and nivolumab was introduced as a second line in December 2016, upon the CANCERVIH working group recommandations. CANCERVIH is a national French multidisciplinary network dedicated to HIV-infected patients with cancer. Pre-treatment plasma HIV load was undetectable (<20 copies/ml) under emtricitabin, tenofovir and dolutegravir started in August 2016. Fifteen injections were administered every 14 days until July 2017, with a stable disease, and a good tolerance with stable CD4 and CD8 counts despite a slight CD4 drop at D30 (Figure 1A). The plasma HIV load progressively and modestly increased up to 101 copies/ml at D45, decreasing afterwards to 31 copies/ml at D120. In parallel, T-cell activation slightly increased between D14 and D45 while PD-1+ CD4 and CD8 T cells declined at D30 (Figure 1B and C). Then frequencies of HIV RT- and Nef-specific CD8 T cells markedly increased from D30 to D120 (Figure 1D). Finally, the cell-associated HIV–DNA showed a drastic and persistent decrease from 369 at D0 to 30 copies/106 cells at D120 (Figure 1A). Figure 1. View largeDownload slide Immunovirological modulations under anti-PD-1 therapy in an HIV-infected patient treated for lung cancer. (A) CD4 cell count, interleukin (IL)-6 plasma levels, HIV-1 plasma viral load measured with ultrasensitive technique (USVL), and total HIV-DNA (DNA copies/million cells) through time. (B) PD-1 expression on total CD4+ and CD8+ T cells, on HIV Gag-specific CD8+ T cells, and on HIV RT/Nef-specific CD8+ T cells. Results are expressed as absolute number of total PD-1+ T cells/mm3, or as mean fluorescence intensity (MFI) for HIV-specific T cells. (C) HLA-DR and CD38 activation markers expression on total CD4 and CD8 peripheral T cells. (D) Frequencies of HIV Gag, RT/Nef, and Epstein Barr Virus (EBV)-specific IFNγ+CD8+ T cells (stimulation with optimal CD8 peptides). Figure 1. View largeDownload slide Immunovirological modulations under anti-PD-1 therapy in an HIV-infected patient treated for lung cancer. (A) CD4 cell count, interleukin (IL)-6 plasma levels, HIV-1 plasma viral load measured with ultrasensitive technique (USVL), and total HIV-DNA (DNA copies/million cells) through time. (B) PD-1 expression on total CD4+ and CD8+ T cells, on HIV Gag-specific CD8+ T cells, and on HIV RT/Nef-specific CD8+ T cells. Results are expressed as absolute number of total PD-1+ T cells/mm3, or as mean fluorescence intensity (MFI) for HIV-specific T cells. (C) HLA-DR and CD38 activation markers expression on total CD4 and CD8 peripheral T cells. (D) Frequencies of HIV Gag, RT/Nef, and Epstein Barr Virus (EBV)-specific IFNγ+CD8+ T cells (stimulation with optimal CD8 peptides). Taken together, those results suggest that nivolumab in this patient had induced synergistic ‘shock and kill’ mechanisms: (i) a transient reactivation of HIV replication within infected CD4 T cells together with a T-cell activation and (ii) a decrease in exhausted CD4 and CD8 T cells followed by a durable and major restoration of HIV-specific CD8 T cells function that might have killed the HIV-producing cells, altogether resulting in a drastic and durable diminution of the reservoir. This first report of a successful depletion of the HIV reservoirs opens new therapeutic perspectives towards an HIV cure. Whether this encouraging result is reproducible is also currently being analyzed in the French cohort of HIV-infected people treated with ICPIs (ANRS-CO24, OncoVIHAC cohort). Acknowledgement The authors want to thank the members of the CANCERVIH working group, S Even, K Dorgham, S Sayon, M Veyri. Funding INCA (no grant numbers apply); Agence Nationale de Recherche sur le SIDA et les Hépatites virales (D17256). Disclosure AG: speaker fee from BMS (Bristol Myers Squibb) and travel grant from MSD; AGM: honoraria, grants and travel grants from ViiV Healthcare, Janssen-Cilag, Gilead Sciences and MSD; MAM: personal fees from BMS for participation in boards, personal fees from Lilly, personal fees from MSD, non-financial support from Boehringer, outside the submitted work; BA: No conflict of interest in the cancer and immunotherapy fields; JPS: consultant or advisory role (fees) or meeting invitation from Janssen-Cilag, Roche, BMS, MSD, Pfizer, Novartis, PFO and Gilead. All remaining authors have declared no conflicts interest. References 1 Deeks SG, Lewin SR, Ross AL et al.   International AIDS Society Towards a Cure Working Group. International AIDS Society global scientific strategy: towards an HIV cure 2016. Nat Med  2016; 22( 8): 839– 850. Google Scholar CrossRef Search ADS PubMed  2 Wightman F, Solomon A, Kumar SS et al.   Effect of ipilimumab on the HIV reservoir in an HIV-infected individual with metastatic melanoma. AIDS  2015; 29( 4): 504– 506. Google Scholar CrossRef Search ADS PubMed  3 Le Garff G, Samri A, Lambert-Niclot S et al.   Transient HIV-specific T cells increase and inflammation in an HIV-infected patient treated with nivolumab. AIDS  2017; 31( 7): 1048– 1051. Google Scholar CrossRef Search ADS PubMed  4 Heppt MV, Schlaak M, Eigenlter TK et al.   Checkpoint blockade for metastatic melanoma and Merkel cell carcinoma in HIV-positive patients. Ann Oncol  2017; 28( 12): 3104– 3106. Google Scholar CrossRef Search ADS PubMed  5 Samri A, Lavolé A, Even S et al.   Immunovirological evolution in HIV-infected patients treated with anti-PD-1 therapy. International Aids Society Conference 2017. Abstract #MOPEB0362. © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Annals of Oncology Oxford University Press

Drastic decrease of the HIV reservoir in a patient treated with nivolumab for lung cancer

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Oxford University Press
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© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
ISSN
0923-7534
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1569-8041
D.O.I.
10.1093/annonc/mdx696
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Abstract

Therapy with immune check point inhibitors (ICPIs) may have dual benefits in HIV infection by acting not only on the cancers frequently associated but also by helping to purge the HIV reservoirs that indefinitely persist despite antiretroviral therapy. Indeed, it is hypothesized that ICPIs could de-repress the blockade of HIV transcription in the reservoirs concentrated in memory CD4 T cells co-expressing ICPs and simultaneously restore functions in exhausted HIV-specific T cells displaying high Programmed Cell Death-1 (PD-1) levels [1]. This hypothesis has not been confirmed yet. Two case reports of HIV-infected patients treated for cancer with an anti-Cytotoxic T-lymphocyte Associated Protein 4 (CTLA-4) [2], or an anti-PD1 [3] monoclonal antibody showed a good safety profile that was recently confirmed by two series of patients treated for melanoma (N = 9) [4] or lung cancer (N = 10) [5]. However, no clear effect on HIV reservoirs was reported despite some transient increase in HIV transcription after anti-CTLA-4, and in HIV-specific T cells after anti-PD1 therapy [2, 3]. Here, we report for the first time a new case with a drastic and sustained decrease of the HIV reservoir paralleling the increase in HIV-specific CD8 T cells under anti-PD1 therapy. A 51-year-old man, smoker, HIV-infected since 1995, diagnosed with stage IIIa epidermal growth factor receptor-/BRAF-/Kras-/Programmed Cell Death Ligand-1- non-small-cell lung cancer in May 2015 was treated with lobectomy and adjuvant chemotherapy (cisplatin and pemetrexed). Relapse occurred <6 months after the end of chemotherapy and nivolumab was introduced as a second line in December 2016, upon the CANCERVIH working group recommandations. CANCERVIH is a national French multidisciplinary network dedicated to HIV-infected patients with cancer. Pre-treatment plasma HIV load was undetectable (<20 copies/ml) under emtricitabin, tenofovir and dolutegravir started in August 2016. Fifteen injections were administered every 14 days until July 2017, with a stable disease, and a good tolerance with stable CD4 and CD8 counts despite a slight CD4 drop at D30 (Figure 1A). The plasma HIV load progressively and modestly increased up to 101 copies/ml at D45, decreasing afterwards to 31 copies/ml at D120. In parallel, T-cell activation slightly increased between D14 and D45 while PD-1+ CD4 and CD8 T cells declined at D30 (Figure 1B and C). Then frequencies of HIV RT- and Nef-specific CD8 T cells markedly increased from D30 to D120 (Figure 1D). Finally, the cell-associated HIV–DNA showed a drastic and persistent decrease from 369 at D0 to 30 copies/106 cells at D120 (Figure 1A). Figure 1. View largeDownload slide Immunovirological modulations under anti-PD-1 therapy in an HIV-infected patient treated for lung cancer. (A) CD4 cell count, interleukin (IL)-6 plasma levels, HIV-1 plasma viral load measured with ultrasensitive technique (USVL), and total HIV-DNA (DNA copies/million cells) through time. (B) PD-1 expression on total CD4+ and CD8+ T cells, on HIV Gag-specific CD8+ T cells, and on HIV RT/Nef-specific CD8+ T cells. Results are expressed as absolute number of total PD-1+ T cells/mm3, or as mean fluorescence intensity (MFI) for HIV-specific T cells. (C) HLA-DR and CD38 activation markers expression on total CD4 and CD8 peripheral T cells. (D) Frequencies of HIV Gag, RT/Nef, and Epstein Barr Virus (EBV)-specific IFNγ+CD8+ T cells (stimulation with optimal CD8 peptides). Figure 1. View largeDownload slide Immunovirological modulations under anti-PD-1 therapy in an HIV-infected patient treated for lung cancer. (A) CD4 cell count, interleukin (IL)-6 plasma levels, HIV-1 plasma viral load measured with ultrasensitive technique (USVL), and total HIV-DNA (DNA copies/million cells) through time. (B) PD-1 expression on total CD4+ and CD8+ T cells, on HIV Gag-specific CD8+ T cells, and on HIV RT/Nef-specific CD8+ T cells. Results are expressed as absolute number of total PD-1+ T cells/mm3, or as mean fluorescence intensity (MFI) for HIV-specific T cells. (C) HLA-DR and CD38 activation markers expression on total CD4 and CD8 peripheral T cells. (D) Frequencies of HIV Gag, RT/Nef, and Epstein Barr Virus (EBV)-specific IFNγ+CD8+ T cells (stimulation with optimal CD8 peptides). Taken together, those results suggest that nivolumab in this patient had induced synergistic ‘shock and kill’ mechanisms: (i) a transient reactivation of HIV replication within infected CD4 T cells together with a T-cell activation and (ii) a decrease in exhausted CD4 and CD8 T cells followed by a durable and major restoration of HIV-specific CD8 T cells function that might have killed the HIV-producing cells, altogether resulting in a drastic and durable diminution of the reservoir. This first report of a successful depletion of the HIV reservoirs opens new therapeutic perspectives towards an HIV cure. Whether this encouraging result is reproducible is also currently being analyzed in the French cohort of HIV-infected people treated with ICPIs (ANRS-CO24, OncoVIHAC cohort). Acknowledgement The authors want to thank the members of the CANCERVIH working group, S Even, K Dorgham, S Sayon, M Veyri. Funding INCA (no grant numbers apply); Agence Nationale de Recherche sur le SIDA et les Hépatites virales (D17256). Disclosure AG: speaker fee from BMS (Bristol Myers Squibb) and travel grant from MSD; AGM: honoraria, grants and travel grants from ViiV Healthcare, Janssen-Cilag, Gilead Sciences and MSD; MAM: personal fees from BMS for participation in boards, personal fees from Lilly, personal fees from MSD, non-financial support from Boehringer, outside the submitted work; BA: No conflict of interest in the cancer and immunotherapy fields; JPS: consultant or advisory role (fees) or meeting invitation from Janssen-Cilag, Roche, BMS, MSD, Pfizer, Novartis, PFO and Gilead. All remaining authors have declared no conflicts interest. References 1 Deeks SG, Lewin SR, Ross AL et al.   International AIDS Society Towards a Cure Working Group. International AIDS Society global scientific strategy: towards an HIV cure 2016. Nat Med  2016; 22( 8): 839– 850. Google Scholar CrossRef Search ADS PubMed  2 Wightman F, Solomon A, Kumar SS et al.   Effect of ipilimumab on the HIV reservoir in an HIV-infected individual with metastatic melanoma. AIDS  2015; 29( 4): 504– 506. Google Scholar CrossRef Search ADS PubMed  3 Le Garff G, Samri A, Lambert-Niclot S et al.   Transient HIV-specific T cells increase and inflammation in an HIV-infected patient treated with nivolumab. AIDS  2017; 31( 7): 1048– 1051. Google Scholar CrossRef Search ADS PubMed  4 Heppt MV, Schlaak M, Eigenlter TK et al.   Checkpoint blockade for metastatic melanoma and Merkel cell carcinoma in HIV-positive patients. Ann Oncol  2017; 28( 12): 3104– 3106. Google Scholar CrossRef Search ADS PubMed  5 Samri A, Lavolé A, Even S et al.   Immunovirological evolution in HIV-infected patients treated with anti-PD-1 therapy. International Aids Society Conference 2017. Abstract #MOPEB0362. © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Journal

Annals of OncologyOxford University Press

Published: Feb 1, 2018

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