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Transient HIV-specific T cells increase and inflammation in an HIV-infected patient treated with nivolumab

2017; Lippincott Williams & Wilkins; Volume: 31; Issue: 7 Linguagem: Inglês

10.1097/qad.0000000000001429

1473-5571

G. Le Garff, Assia Samri, Sidonie Lambert-Niclot, Sophie Even, A. Lavolé, Jacques Cadranel, Jean‐Philippe Spano, Brigitte Autran, Anne‐Geneviève Marcelin, Amélie Guihot,

Immunotherapy and Immune Responses

Immune checkpoint inhibitors (ICIs) can reverse T-cell anergy and boost immune responses against tumours. Nivolumab, an ICI directed against programmed death-1 (PD-1), has become the new standard of care for second-line treatment of advanced nonsmall cell lung cancer (NSCLC) [1–3]. It is thought to be an even clever therapeutic option in HIV-infected patients [4], as the overexpression of PD-1 on exhausted HIV-specific T cells allows ICIs to reactivate PD-1+ T cells and to improve HIV-specific immune responses [5–7]. So far, two case reports involving HIV-infected patients with melanoma treated with ICIs have shown encouraging safety results but distinct viral effects [8,9]. Upon ipilimumab treatment, CD4+ and CD8+ cell counts, as well as the cell-associated HIV-RNA transiently increased [9]. Upon pembrolizumab, no rebound of HIV viral load was observed [8]. The question of whether anti-PD-1 could be a tool for HIV cure is still pending. Here, we report for the first time the detailed immunovirological evolution upon nivolumab in an HIV-infected patient with lung cancer. The CD4+ and CD8+ cell counts were analysed on an FC500 flow-cytometer. Phenotypic and functional analysis used a 5-laser-beam LSR-Fortessa cytometer on the CyPS platform. Intracellular-cytokine-staining assay used 15-mer peptides targeting HIV-Gag, reverse transcriptase and Nef and 9-mer Epstein–Barr virus (EBV) peptides [10,11]. The plasma IL-6 levels were quantified using the Simoa-Quanterix SIMOA HD-1 analyzer (Quanterix Corporation, Lexington, Massachusetts, USA). Plasma viral load was quantified using the Amplicor monitors assay [12]. HIV-1 DNA was amplified in LTR gene by real-time PCR [13]. A 53-year-old man, smoker, HIV-infected since 1993, was diagnosed with advanced NSCLC in May 2014. After a decompressive radiotherapy, six cisplatin/gemcitabine and four taxotere chemotherapy cures, nivolumab was started in September 2015. The patient was virally suppressed with CD4+ and CD8+ T-cell counts of 204 and 1142 cells/μl, respectively, upon abacavir, lamivudine and dolutegravir. Seven nivolumab injections were administered, causing Grade I hepatic toxicity. Tumoral stability was reported after six injections. Nivolumab was discontinued after the seventh injection due to disease progression and the patient finally passed away in June 2016. During follow-up, no significant changes of ultrasensitive HIV viral load were observed, but a slight two-fold increase in HIV-cell-associated DNA levels (116 at D0, 213 copies/106 peripheral blood mononuclear cells at D30, Fig. 1a). The immunological follow-up showed a marked increase of IL-6 plasma levels peaking at D14 and returning to normal beyond D60. The CD4+ and CD8+ cell counts peaked at D60 to 413 and 1380 cells/μl, respectively, returning to baseline values at D120, together with a slight CD4+/CD8+ ratio increase (0.18–0.30 from D0 to D60). The CD4+ and CD8+ cell activation status showed discordant changes with a modest CD38 increase on CD8+ T cells, whereas human leukocyte antigen – antigen D related on CD4+ and CD8+ T cells remained within normal values (Fig. 1b). The immune check point expression on total CD4+ and CD8+ T cells displayed a marked decrease of both PD-1 and LAG3 at D30 (Fig. 1c, d). In contrast, Tim-3 expression increased on CD4+ and CD8+ T cells during follow-up and returned to baseline values at D120 (Fig. 1c, d). The almost undetectable IFNγ+ Gag-specific CD8+ T cells at baseline (below 0.1%) increased at D30 (0.4%) then returned to baseline values, whereas reverse transcriptase-, Nef-specific CD8+ T cells remained very low (Fig. 1e). Furthermore, PD-1 expression was down-modulated on IFN-γ+ Gag-specific CD8+ T cells at D30 (Fig. 1c). Frequencies of IL-2+ and TNF-α+ HIV and EBV-specific T cells showed no significant modification (data not shown). Finally, the CD4+ T cell differentiation status remained stable (Fig. 1f), whereas transitional-memory CD8+ population increased (+64%) and RA-re-expressing effector-memory decreased (−41%) 4 months after treatment initiation (Fig. 1g).Fig. 1: Immunovirological modulation of antiprogrammed death-1 therapy in an HIV-infected patient treated for lung cancer.(a) CD4+ cell count, IL-6 plasma levels, HIV-1 plasma viral load measured with ultrasensitive technique, and total HIV-DNA (DNA copies/million cells) through time. (b) Expression of activation markers on CD4+ and CD8+ peripheral T cells. (c) Immune check point expression on total CD8+ T cells, on HIV Gag (pool 1)-specific T cells and on HIV RT/Nef (pool 2)-specific T cells. Results are expressed as mean fluorescence intensity for HIV-specific T cells or number of total immune check point positive CD8+ T cells/μl. (d) Immune check point expression on total CD4+ T cells. (e) Frequencies of IFNγ+CD8+ T cells specific for HIV Gag and RT/Nef and for EBV (optimal CD8+ peptides). (f), (g) Percentages of CD4+ (f) and CD8+ (g) subpopulations of T cells: CM, central memory (CD45RA−CCR7+CD27+); EBV, Epstein–Barr virus; EM, effector memory (CD45RA−CCR7−CD27−); EMRA, RA-re-expressing effector memory T cells (CD45RA+CCR7−CD27−); N, naïve (CD45RA+CCR7+CD27+); TM, transitional memory (CD45RA−CCR7−CD27+).We describe here the immunovirological effects of nivolumab in an HIV-infected patient. A slight increase in HIV-specific IFNγ+CD8+ cells occurred together with an increase in CD4+ and CD8+ cell counts, in the CD8+ transitional-memory population and in IL-6 plasma levels, contrasting with a decrease of PD-1 expression on T cells. Taken together, these data suggest that nivolumab is successful at enhancing the capacities of HIV-specific CD8+ transitional-memory cells to proliferate and to secrete cytokines [5,6,14], expanding the PD-1 low T-cell subset [15]. Those changes had no or little impact on HIV replication or reservoirs. The transient increase in inflammation has not been reported before and might result either from the PD-1/programmed death-ligand 1 (PD-L1) pathway disruption in immune cells or from a rapid HIV replication in tissues that would have immediately been controlled by the stimulated HIV-specific CD8+ T cells. These first results are encouraging and remain to be confirmed in other HIV-patients treated with anti-PD-1/PD-L1-blocking antibodies. Acknowledgements The authors want to thank the members of the CANCERVIH working group. They thank Karim Dorgham for IL-6 plasma levels measurements. They thank Benedicte Hoareau for help with flow cytometry analysis and Marianne Veyri who is the CANCERVIH national secretary. Authorship contributions: G.L.G. recruited and took care of the patient. A.L., J.C., A.G. and J.-P.S. validated the therapeutic attitude. S.E., A.S., B.A. and A.G. designed and performed the immunological assays and analysis. S.L. and A.-G.M. performed the virological assays and analysis. A.G., A.S. and B.A. wrote the article. J.-P.S. is the CANCERVIH national coordinator. Conflicts of interest There are no conflicts of interest.