Assessment of the Feasibility and Safety of Durvalumab for Treatment of Solid Tumors in Patients With HIV-1 Infection: The Phase 2 DURVAST Study | Allergy and Clinical Immunology | JAMA Oncology | JAMA Network
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Figure.  T-cell Count and Plasma Viremia
T-cell Count and Plasma Viremia

There were no significant changes in CD4+ T-cell counts (A), CD8+ T-cell counts (B), or plasma viral load (C) when comparing pretreatment samples with last samples after treatment. D, Four patients achieved a partial response (dark blue lines); 5 patients achieved stable disease (orange lines) that in 4 cases continued for more than 24 weeks; and 7 patients had progressive disease (light blue lines) as their best response. IQR indicates interquartile range.

Table 1.  Baseline Characteristics of All Treated Patients
Baseline Characteristics of All Treated Patients
Table 2.  Adverse Events
Adverse Events
1.
Franceschi  S, Lise  M, Clifford  GM,  et al; Swiss HIV Cohort Study.  Changing patterns of cancer incidence in the early- and late-HAART periods: the Swiss HIV Cohort Study.   Br J Cancer. 2010;103(3):416-422. doi:10.1038/sj.bjc.6605756PubMedGoogle ScholarCrossref
2.
Winstone  TA, Man  SFP, Hull  M, Montaner  JS, Sin  DD.  Epidemic of lung cancer in patients with HIV infection.   Chest. 2013;143(2):305-314. doi:10.1378/chest.12-1699PubMedGoogle ScholarCrossref
3.
Mendoza  P, Gruell  H, Nogueira  L,  et al.  Combination therapy with ant–HIV-1 antibodies maintains viral suppression.   Nature. 2018;561(7724):479-484. doi:10.1038/s41586-018-0531-2PubMedGoogle ScholarCrossref
4.
Brahmer  J, Reckamp  KL, Baas  P,  et al.  Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer.   N Engl J Med. 2015;373(2):123-135. doi:10.1056/NEJMoa1504627PubMedGoogle ScholarCrossref
5.
Garassino  MC, Cho  BC, Kim  JH,  et al; ATLANTIC Investigators.  Durvalumab as third-line or later treatment for advanced non–small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study.   Lancet Oncol. 2018;19(4):521-536. doi:10.1016/S1470-2045(18)30144-XPubMedGoogle ScholarCrossref
6.
Larkin  J, Chiarion-Sileni  V, Gonzalez  R,  et al.  Combined nivolumab and ipilimumab or monotherapy in untreated melanoma.   N Engl J Med. 2015;373(1):23-34. doi:10.1056/NEJMoa1504030PubMedGoogle ScholarCrossref
7.
Fromentin  R, DaFonseca  S, Costiniuk  CT,  et al.  PD-1 blockade potentiates HIV latency reversal ex vivo in CD4+ T cells from ART-suppressed individuals.   Nat Commun. 2019;10(1):814. doi:10.1038/s41467-019-08798-7PubMedGoogle ScholarCrossref
8.
Gonzalez-Cao  M, Martinez-Picado  J, Karachaliou  N, Rosell  R, Meyerhans  A.  Cancer immunotherapy of patients with HIV infection.   Clin Transl Oncol. 2019;21(6):713-720. doi:10.1007/s12094-018-1981-6PubMedGoogle ScholarCrossref
9.
Cook  MR, Kim  C.  Safety and efficacy of immune checkpoint inhibitor therapy in patients with HIV infection and advanced-stage cancer: a systematic review.   JAMA Oncol. 2019;5(7):1049-1054. doi:10.1001/jamaoncol.2018.6737PubMedGoogle ScholarCrossref
10.
Zheltkova  V, Argilaguet  J, Peligero  C, Bocharov  G, Meyerhans  A.  Prediction of PD-L1 inhibition effects for HIV-infected individuals.   PLoS Comput Biol. 2019;15(11):e1007401. doi:10.1371/journal.pcbi.1007401PubMedGoogle Scholar
11.
Kim  ES, Bruinooge  SS, Roberts  S,  et al.  Broadening eligibility criteria to make clinical trials more representative: American Society of Clinical Oncology and Friends of Cancer Research joint research statement.   J Clin Oncol. 2017;35(33):3737-3744. doi:10.1200/JCO.2017.73.7916PubMedGoogle ScholarCrossref
12.
Uldrick  TS, Ison  G, Rudek  MA,  et al.  Modernizing clinical trial eligibility criteria: recommendations of the American Society of Clinical Oncology–Friends of Cancer Research HIV Working Group.   J Clin Oncol. 2017;35(33):3774-3780. doi:10.1200/JCO.2017.73.7338PubMedGoogle ScholarCrossref
13.
Uldrick  TS, Gonçalves  PH, Abdul-Hay  M,  et al; Cancer Immunotherapy Trials Network (CITN)-12 Study Team.  Assessment of the safety of pembrolizumab in patients with HIV and advanced cancer—a phase 1 study.   JAMA Oncol. 2019;(Jun):2. doi:10.1001/jamaoncol.2019.2244PubMedGoogle Scholar
14.
Blanch-Lombarte  O, Gálvez  C, Revollo  B,  et al.  Enhancement of antiviral CD8+ T-cell responses and complete remission of metastatic melanoma in an HIV-1–infected subject treated with pembrolizumab.   J Clin Med. 2019;8(12):E2089. doi:10.3390/jcm8122089PubMedGoogle Scholar
15.
Trautmann  L, Janbazian  L, Chomont  N,  et al.  Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction.   Nat Med. 2006;12(10):1198-1202. doi:10.1038/nm1482PubMedGoogle ScholarCrossref
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    Brief Report
    April 9, 2020

    Assessment of the Feasibility and Safety of Durvalumab for Treatment of Solid Tumors in Patients With HIV-1 Infection: The Phase 2 DURVAST Study

    Author Affiliations
    • 1Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Dexeus University Hospital, Barcelona, Spain
    • 2Medical Oncology Department, Catalan Institute of Oncology (ICO), Germans Trias i Pujol Hospital, Badalona, Spain
    • 3IrsiCaixa AIDS Research Institute, University Hospital Germans Trias i Pujol, Badalona, Spain
    • 4ICMHO, Hospital Clinic, Barcelona, Spain
    • 5Hospital Universitario Virgen del Rocío, Sevilla, Spain
    • 6Hospital Universitario la Fe de Valencia, Valencia, Spain
    • 7Hospital Universitario La Paz, Madrid, Spain
    • 8Consorci Sanitari de Terrassa, Barcelona, Spain
    • 9Infection Biology Laboratory, University Pompeu Fabra, Barcelona, Spain
    • 10Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain
    • 11University of Vic–Central University of Catalonia (UVic-UCC), Vic, Spain
    • 12Germans Trias i Pujol Research Institute and Hospital (IGTP), Badalona, Spain
    • 13Alicante University Hospital, Alicante, Spain
    • 14Puerta de Hierro Hospital, Madrid, Spain
    • 15Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
    • 16Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
    • 17NanoString Technologies, Seattle, Washington
    JAMA Oncol. 2020;6(7):1063-1067. doi:10.1001/jamaoncol.2020.0465
    Key Points

    Question  Is treatment with durvalumab feasible and safe in patients with HIV-1 infection and advanced cancer?

    Findings  In this nonrandomized, open-label, phase 2 study of 20 patients with HIV-1 infection and advanced solid tumors receiving suppressive antiretroviral therapy, treatment with durvalumab was feasible and safe. There were no drug-related grade 3 to 4 adverse events, and the disease control rate was 50%.

    Meaning  Patients with cancer with controlled HIV-1 infection should have access to antitumoral immunotherapy with durvalumab.

    Abstract

    Importance  Therapies targeting the programmed cell death 1 (PD-1) receptor or its ligand (PD-L1), such as the humanized monoclonal antibody durvalumab, have shown durable clinical responses in several tumor types. However, concerns about the safety and feasibility of PD-1/PD-L1 blockade in HIV-1–infected individuals have led to the exclusion of these patients from clinical trials on cancer immunotherapies.

    Objective  To evaluate the feasibility and safety of durvalumab treatment in patients with advanced cancer and virologically controlled HIV-1 infection.

    Design, Setting, and Participants  The DURVAST study was a nonrandomized, open-label, phase 2 clinical trial in patients with any solid tumor type in which anti–PD-1 or anti–PD-L1 antibodies have approved indications or for which there are data of antitumoral activity with no other available curative therapy. All patients had basal undetectable plasma viremia while undergoing combination antiretroviral therapy.

    Interventions  Treatment consisted of intravenous infusion of durvalumab (1500 mg every 4 weeks) until disease progression or unacceptable toxic effects.

    Main Outcomes and Measures  Adverse events were graded with the use of the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. Tumor response was evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1.

    Results  A total of 20 HIV-1–infected patients with advanced cancer were enrolled; 16 (80%) were male, the median (range) age was 54 (30-73) years, and 12 (60%) had progressed with previous cancer treatment lines. A median (range) of 4 (1-16) cycles of durvalumab were administered. Drug-related adverse events were observed in 50% of patients, and all were grade 1 and 2 (mainly diarrhea, asthenia, and arthromyalgia). Four of 16 response-evaluable patients (25%) had a partial response. Five patients (31%) had stable disease, including 4 with durable stable disease (disease control rate of 50%). CD4+ and CD8+ T-cell counts and plasma HIV-1 viremia remained stable throughout the study.

    Conclusions and Relevance  Durvalumab treatment was feasible and safe in HIV-1–infected patients with cancer receiving combination antiretroviral therapy. HIV-1–infected patients on suppressive antiretroviral therapy with advanced cancer should have access to cancer immunotherapy treatments.

    Trial Registration  ClinicalTrials.gov Identifier: NCT03094286

    Introduction

    Progresses in human immunodeficiency virus type 1 (HIV-1) therapy have converted the once fatal infection into a chronic condition, yet the search for a widely applicable strategy to cure remains elusive. Individuals with HIV-1 infection have chronic antigenic immune stimulation and inflammation, even with low plasma HIV-1 RNA levels and preserved CD4+ counts, which contributes to increased incidence of non–AIDS-defining cancers,1 such that non–small cell lung cancer (NSCLC) is now the leading cause of cancer deaths in individuals receiving effective combination antiretroviral therapy (cART).2 During infection, HIV-1 is reverse transcribed and integrated as a provirus into the host genome. Although the vast majority of infected cells die with cART, a small percentage survive and harbor as integrated proviruses that comprise the latent reservoir.3

    Although therapy with immune checkpoint inhibitors that block inhibitory receptors is now well established for the treatment of different tumor types,4-6 in most cancer clinical trials HIV-1 infection is an exclusion criterion because of fears of virus reactivation, immune reconstitution syndrome, or other toxic effects. Programmed cell death 1 (PD-1) receptor confers a selective advantage for latently infected cells persisting during cART and provides a rationale for the assessment of immune checkpoint inhibitor therapy in HIV-1–infected persons with cancer.7 Retrospective analysis8,9 and recent theoretical considerations10 suggest that patients infected with HIV-1 and treated with immune checkpoint inhibitors have good tolerance and antitumoral responses. We conducted a prospective phase 2 study of the humanized anti–programmed cell death ligand 1 (anti–PD-L1) antibody durvalumab in cART-stabilized HIV-1–infected patients with advanced cancer.

    Methods

    Twenty patients were enrolled and treated with durvalumab at the fixed dose of 1500 mg every 4 weeks until disease progression or unacceptable toxic effects. Eligible patients comprised HIV-1–infected individuals receiving effective cART with advanced solid tumors in which anti–PD-1/PD-L1 antibodies had approved indications or data of antitumoral activity. The complete inclusion and exclusion criteria are provided in the trial protocol (Supplement 1). The protocol was approved by the institutional review boards of the 8 hospitals involved. Written informed consent was obtained from each patient.

    The primary objective of the DURVAST study was to explore the feasibility of durvalumab treatment in HIV-1–infected persons with cancer. Feasibility was defined as the ability to receive at least a median number of 4 cycles of durvalumab. Data analysis was performed from January 2019 through June 2019. The complete study objectives, assessments, and statistical analysis are provided in the eMethods in Supplement 2.

    Results

    A total of 20 HIV-1–infected participants with advanced cancer were enrolled between May 2017 and June 2018 (Table 1; eFigure 1 in Supplement 2); 16 (80%) were male, the median (range) age was 54 (30-73) years, and 12 (60%) had progressed with previous cancer treatment lines. Fourteen patients had NSCLC, 2 had melanoma, 1 had small cell lung cancer, 2 had anal carcinoma, and 1 had bladder carcinoma. All patients were on stable cART with undetectable HIV-1 plasma viremia (Table 1). At the time of the data cutoff, the median duration of follow-up was 12.7 months. Patients received a median (range) of 4 (1-16) study treatment cycles. Eight patients were still on treatment at the time of the data cutoff, with a median (range) number of 11 (5-16) cycles (eFigure 1 in Supplement 2).

    There were no grade 3 or 4 drug-related adverse events (AEs). The most common AEs were diarrhea (grade 1 and 2, both in 2 patients [10%]), arthromyalgia (grade 1 and 2 in 11 patients [55%] and 2 patients [10%], respectively), and asthenia (grade 1 and 2 in 9 patients [45%] and 2 patients [10%], respectively). No AEs with a potential immunologic cause, such as pneumonitis, hypothyroidism, or hypophysitis, occurred. All AEs are provided in Table 2 and eTable 1 in Supplement 2. There were 4 early deaths, not drug related (additional data are provided in eResults in Supplement 2). Finally, there were no AEs related to HIV-1 reactivation. Both the CD4+ and CD8+ T-cell counts remained stable throughout the course of treatment (Figure, A and B), including 1 patient with a long-lasting response (>14 months) with basal CD4+ T-cell counts of 164 cells/mm3 and a CD4+/CD8+ T-cell ratio of 0.67. Similarly, the plasma viremia remained undetectable (Figure, C).

    Four of 16 response-evaluable patients (25%) had a partial response with a duration of response of more than 4 months, 6 months, 12 months, and 14 months (Figure, D). Five of the 16 patients (31%) had stable disease (Figure, D), including 4 patients with durable stable disease (>6 months, >8 months, >12 months, and >16 months), with a disease control rate of 50% (Figure, D). Additional results of antitumoral activity are provided in the eResults in Supplement 2.

    Discussion

    Patients infected with HIV-1 who are receiving suppressive cART have a near-normal life expectancy, and now cancer, mainly NSCLC, is one of the leading causes of mortality.2 Previous retrospective data supported the safety of treatment with anti–PD-1/PD-L1 antibodies in HIV-1–infected patients.8,9 However, until recently, most cancer clinical trials have excluded HIV-1–infected patients.11,12

    The DURVAST study demonstrates that immunotherapy with durvalumab in HIV-1–infected people is feasible and safe, with no grade 3 or 4 drug-related AEs. These results complement previous data reported from the phase 1 study conducted by Uldrick et al13 in 30 patients with cancer with HIV-1 infection treated with pembrolizumab. Similar to our results, pembrolizumab was well tolerated without unexpected toxic effects and no signs of viral reactivation. Our results are also consistent with previous studies of durvalumab treatment in pretreated HIV-1–uninfected people with NSCLC, in whom the incidence of grade 3 AEs ranged from 8% to 18% and grade 4 AEs appeared in less than 1%.5

    Moreover, the antitumoral activity of durvalumab in our study was higher than anticipated. Among 16 patients evaluable for response, the disease control rate was 50%, including long-lasting responses (Figure, D). Although the number of patients was small, it is not possible to rule out the fact that HIV-1 infection by itself, or the cART treatment, was positively associated with antitumoral activity. Our results suggest a longer duration of clinical benefit in patients treated with integrase strand-transfer inhibitors (eTable 2 in Supplement 2). We speculate the possibility that integrase strand-transfer inhibitors could be associated with antitumoral immune response of durvalumab. Conversely, the antitumoral activity found with pembrolizumab in the study from Uldrick et al13 was low, with only 1 of 19 patients with non–AIDS-defining cancers having a partial response, probably owing to the inclusion in this study of nonimmunosensitive tumor types, such as cholangiocarcinoma, breast cancer, and pancreatic cancer.

    In agreement with the Uldrick et al study,13 our results confirm that treatment with durvalumab is also safe regarding sustained control of HIV-1 infection. All patients continued cART treatment, and plasma viremia remained undetected. In addition, CD4+ and CD8+ T-cell counts were stable throughout durvalumab treatment. Although other studies exclude patients with low basal CD4+ T-cell counts, we found no correlation of clinical benefit with basal CD4+ or CD8+ T-cell counts (eTable 6 in Supplement 2). Of note, 1 patient with NSCLC with a CD4+ T-cell count of less than 200 cells/mm3 had no side effects and a long-lasting partial response, suggesting that treating patients with low basal CD4+ T-cell counts might be safe. Although an increase in viral transcription could be hypothetically associated with PD-1 blockade in CD4+ T lymphocytes infected by HIV-1, the maintenance of cART precludes the reactivation of the viral reservoir (eFigure 7 in Supplement 2).7,14 Thus, reinvigoration of CD8+ PD-1+ T lymphocytes on induction of viral reactivation could in fact be associated with reduced viral reservoirs.15

    Limitations

    This study is limited by the small sample size, which does not allow completely ruling out the existence of unexpected complications owing to the use of durvalumab to treat HIV-1–infected individuals with cancer. Nevertheless, data from previous studies and retrospective case series also support the feasibility and safety of treatment with anti–PD-1/PD-L1 antibodies in this context.

    Conclusions

    In summary, treatment with durvalumab in patients with advanced tumors and HIV-1 infection is feasible and safe. Larger studies are needed to validate the suggested favorable antitumoral activity of durvalumab in HIV-1–infected people. HIV-1–infected patients with advanced cancer should have access to cancer therapies with immune checkpoint inhibitors.

    Back to top
    Article Information

    Accepted for Publication: February 12, 2020.

    Corresponding Authors: Maria Gonzalez-Cao, MD, PhD, Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Dexeus University Hospital, C/ Sabino Arana 5, 080028 Barcelona, Spain (mgonzalezcao@oncorosell.com); Javier Martinez-Picado, PhD, IrsiCaixa AIDS Research Institute, University Hospital Germans Trias i Pujol, Ctra. de Canyet s/n, 08916 Badalona, Spain (jmpicado@irsicaixa.es).

    Published Online: April 9, 2020. doi:10.1001/jamaoncol.2020.0465

    Author Contributions: Dr Gonzalez-Cao had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Martinez-Picado and Rosell contributed equally to the work.

    Study concept and design: Gonzalez-Cao, Bracht, Clotet, Massuti, Cao, Martinez-Picado, Rosell.

    Acquisition, analysis, or interpretation of data: Gonzalez-Cao, Morán, Dalmau, Garcia-Corbacho, Bracht, Bernabe, Juan, de Castro, R. Blanco, Drozdowskyj, Argilaguet, Meyerhans, J. Blanco, Prado, Carrillo, Provencio, Molina-Vila, Mayo de las Casas, Garzon, Huang, Martinez-Picado.

    Drafting of the manuscript: Gonzalez-Cao, Bracht, Argilaguet, Massuti, Martinez-Picado, Rosell.

    Critical revision of the manuscript for important intellectual content: Gonzalez-Cao, Morán, Dalmau, Garcia-Corbacho, Bracht, Bernabe, Juan, de Castro, R. Blanco, Drozdowskyj, Meyerhans, J. Blanco, Prado, Carrillo, Clotet, Provencio, Molina-Vila, Mayo de las Casas, Garzon, Cao, Huang, Rosell.

    Statistical analysis: Gonzalez-Cao, Bracht, Drozdowskyj, Rosell.

    Obtained funding: Massuti, Rosell.

    Administrative, technical, or material support: Gonzalez-Cao, Morán, Dalmau, Bracht, Bernabe, Juan, Drozdowskyj, Mayo de las Casas, Garzon, Huang, Rosell.

    Study supervision: Gonzalez-Cao, Morán, Garcia-Corbacho, Juan, de Castro, J. Blanco, Clotet, Rosell.

    Conflict of Interest Disclosures: Dr Gonzalez-Cao reported receiving grants from AstraZeneca Spain during the conduct of the study and personal fees from AstraZeneca, Bristol-Myers Squibb, Roche, Merck Sharp & Dohme, Pierre Fabre, and Takeda outside the submitted work. Dr Morán reported receiving travel expenses from AstraZeneca and travel expenses and advisory board fees from Roche and Boehringer Ingelheim outside the submitted work. Dr Dalmau reported receiving grants from AstraZeneca Farmacéutica Spain during the conduct of the study. Dr Juan reported receiving honoraria and advisory fees from AstraZeneca, Roche, Boehringer Ingelheim, Bristol-Myers Squibb, and Merck Sharp & Dohme, and advisory fees from Eli Lilly and Company and Pfizer outside the submitted work. Dr de Castro reported receiving personal fees and nonfinancial support from AstraZeneca, Hoffmann-La Roche, Merck Sharp & Dohme, and Bristol-Myers Squibb outside the submitted work. Dr R. Blanco reported receiving personal fees and nonfinancial support from Merck Sharp & Dohme and personal fees from Boehringer Ingelheim, Roche, AstraZeneca, and Bristol-Myers Squibb outside the submitted work. Dr J. Blanco reported receiving personal fees from AlbaJuna Therapeutics and institutional grants from Merck Sharp & Dohme and HIPRA outside the submitted work. Dr Prado reported receiving grants from AstraZeneca during the conduct of the study. Dr Clotet reported receiving grants from AstraZeneca during the conduct of the study and personal fees from Aelix Therapeutics, AlbaJuna Therapeutics, and Merck Sharp & Dohme outside the submitted work. Dr Massuti reported receiving grants from Servier and AstraZeneca, grants and personal fees from Roche and Merck Sharp & Dohme, and personal fees from Bristol-Myers Squibb, Takeda, Pfizer, and Boehringer Ingelheim outside the submitted work. Dr Provencio reported receiving grants and personal fees from AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Roche, and Takeda outside the submitted work. Dr Huang reported receiving nonfinancial support (supplied reagents) from NanoString Technologies outside the submitted work. Dr Martinez-Picado reported receiving institutional grants from AstraZeneca during the conduct of the study; institutional grants from Grifols; institutional grants and educational/consultancy fees from Gilead, Merck Sharp & Dohme, and ViiV Healthcare; and educational/consultancy fees from Janssen outside the submitted work. No other disclosures were reported.

    Funding/Support: This study was sponsored by the Spanish Lung Cancer Group (SLCG) and supported by the AstraZeneca Group. A Marie Skłodowska-Curie Innovative Training Networks European Grant (ELBA No. 765492), the Spanish Association Against Cancer (AECC) (grant No. PROYE18012ROSE), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (Integration of Chinese and Western Medicine) supported in part the associated translational study.

    Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Additional Contributions: Eva Pereira, MsD, and Maria Fernandez, BsC, technical assistants for the Spanish Lung Cancer Group, provided administrative support, and Lourdes Franquet, BsC, assistant at Dr Rosell Oncology Institute laboratory, provided editing assistance. They received no financial compensation for this work.

    Additional Information: We thank the Spanish Lung Cancer Group (SLCG) as clinical trial sponsor.

    References
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    Franceschi  S, Lise  M, Clifford  GM,  et al; Swiss HIV Cohort Study.  Changing patterns of cancer incidence in the early- and late-HAART periods: the Swiss HIV Cohort Study.   Br J Cancer. 2010;103(3):416-422. doi:10.1038/sj.bjc.6605756PubMedGoogle ScholarCrossref
    2.
    Winstone  TA, Man  SFP, Hull  M, Montaner  JS, Sin  DD.  Epidemic of lung cancer in patients with HIV infection.   Chest. 2013;143(2):305-314. doi:10.1378/chest.12-1699PubMedGoogle ScholarCrossref
    3.
    Mendoza  P, Gruell  H, Nogueira  L,  et al.  Combination therapy with ant–HIV-1 antibodies maintains viral suppression.   Nature. 2018;561(7724):479-484. doi:10.1038/s41586-018-0531-2PubMedGoogle ScholarCrossref
    4.
    Brahmer  J, Reckamp  KL, Baas  P,  et al.  Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer.   N Engl J Med. 2015;373(2):123-135. doi:10.1056/NEJMoa1504627PubMedGoogle ScholarCrossref
    5.
    Garassino  MC, Cho  BC, Kim  JH,  et al; ATLANTIC Investigators.  Durvalumab as third-line or later treatment for advanced non–small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study.   Lancet Oncol. 2018;19(4):521-536. doi:10.1016/S1470-2045(18)30144-XPubMedGoogle ScholarCrossref
    6.
    Larkin  J, Chiarion-Sileni  V, Gonzalez  R,  et al.  Combined nivolumab and ipilimumab or monotherapy in untreated melanoma.   N Engl J Med. 2015;373(1):23-34. doi:10.1056/NEJMoa1504030PubMedGoogle ScholarCrossref
    7.
    Fromentin  R, DaFonseca  S, Costiniuk  CT,  et al.  PD-1 blockade potentiates HIV latency reversal ex vivo in CD4+ T cells from ART-suppressed individuals.   Nat Commun. 2019;10(1):814. doi:10.1038/s41467-019-08798-7PubMedGoogle ScholarCrossref
    8.
    Gonzalez-Cao  M, Martinez-Picado  J, Karachaliou  N, Rosell  R, Meyerhans  A.  Cancer immunotherapy of patients with HIV infection.   Clin Transl Oncol. 2019;21(6):713-720. doi:10.1007/s12094-018-1981-6PubMedGoogle ScholarCrossref
    9.
    Cook  MR, Kim  C.  Safety and efficacy of immune checkpoint inhibitor therapy in patients with HIV infection and advanced-stage cancer: a systematic review.   JAMA Oncol. 2019;5(7):1049-1054. doi:10.1001/jamaoncol.2018.6737PubMedGoogle ScholarCrossref
    10.
    Zheltkova  V, Argilaguet  J, Peligero  C, Bocharov  G, Meyerhans  A.  Prediction of PD-L1 inhibition effects for HIV-infected individuals.   PLoS Comput Biol. 2019;15(11):e1007401. doi:10.1371/journal.pcbi.1007401PubMedGoogle Scholar
    11.
    Kim  ES, Bruinooge  SS, Roberts  S,  et al.  Broadening eligibility criteria to make clinical trials more representative: American Society of Clinical Oncology and Friends of Cancer Research joint research statement.   J Clin Oncol. 2017;35(33):3737-3744. doi:10.1200/JCO.2017.73.7916PubMedGoogle ScholarCrossref
    12.
    Uldrick  TS, Ison  G, Rudek  MA,  et al.  Modernizing clinical trial eligibility criteria: recommendations of the American Society of Clinical Oncology–Friends of Cancer Research HIV Working Group.   J Clin Oncol. 2017;35(33):3774-3780. doi:10.1200/JCO.2017.73.7338PubMedGoogle ScholarCrossref
    13.
    Uldrick  TS, Gonçalves  PH, Abdul-Hay  M,  et al; Cancer Immunotherapy Trials Network (CITN)-12 Study Team.  Assessment of the safety of pembrolizumab in patients with HIV and advanced cancer—a phase 1 study.   JAMA Oncol. 2019;(Jun):2. doi:10.1001/jamaoncol.2019.2244PubMedGoogle Scholar
    14.
    Blanch-Lombarte  O, Gálvez  C, Revollo  B,  et al.  Enhancement of antiviral CD8+ T-cell responses and complete remission of metastatic melanoma in an HIV-1–infected subject treated with pembrolizumab.   J Clin Med. 2019;8(12):E2089. doi:10.3390/jcm8122089PubMedGoogle Scholar
    15.
    Trautmann  L, Janbazian  L, Chomont  N,  et al.  Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction.   Nat Med. 2006;12(10):1198-1202. doi:10.1038/nm1482PubMedGoogle ScholarCrossref
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