Immune Checkpoint Inhibitors and Infections

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Possible impact of new immunomodulators on infection and infection management

Immune checkpoint inhibitors and infections

Prof Olivier Lambotte Service de Médecine Interne – Immunologie Clinique CHU Bicêtre Université Paris Sud UMR 1184 Inserm / CEA / Paris Sud [email protected] eLibrary © by author Liens d’intérêt / COI

• BMS • MSD • Astra Zeneca

• Genzyme • LFB • CSL Behring ESCMID• Janssen eLibrary © by author Immune checkpoint inhibitors and infections

1. The rationnal 2. A revolution in oncology 3. Induction of auto-immunity: the immune-related adverse events (irAEs): a source of infection ? 4. The immune check points inhibitors as new anti-infectious agents?

ESCMID eLibrary © by author Immune checkpoints are key-regulators of our immune system • The immunologic basis • The immune checkpoints are various molecules limiting the activation of the immune system:

- To limit, or switch off an immune response - To avoid auto-immunity +++ (mouse models and in humans: CTLA4 gene inactivation = autoimmune syndrome in infancy) ESCMID eLibrary © by author ,Figures The world of the checkpoint inhibitors blocking activation of T lymphocytes

• Expression on T lymphocytes • Activation induced • Described for most of them in humans on tumor-specific and virus-specific T cells

• Ligands expressed on numerous cells of the immune system but also on cells from various organs • Pathways PD-1 and CTLA4 the most studied ESCMID eLibraryNguyen et al. Nature Rev Immunol 2015 © by author The tumor cell and its microenvironnement exploit the PD-1 / PD-L1 axis to avoid the killing of cancer cells by cancer-specific T cells

ESCMID eLibrary © by author Immune checkpoint blockade = restauration of the anti- tumoral immune response

ESCMIDSoularue et al. Gut 2018 eLibrary © by author The immune checkpoint inhibitors are a new strategy in oncology

Historical paradigm: New paradigm: target the target the tumor cells immune cells

CHEMO

Tumor cell Nat Rev CancerESCMID 2011 eLibraryCourtesy A Marabelle © by author Immune checkpoint inhibitors and infections

HSCOC Mel RCC Anti-PD-1 Skin SCC NSCLC

NKT Hodgkin Nivolumab Lymphoma PMBCL HNSCC Pembrolizumab PCNSL

Sarcoma Already has been ! Bladder

Anti-PD-L1 Thyroid MCC

Atezolizumab ER+ BC PD-1/ HCC Durvalumab PDa-PDL1 (L)1 Avelumab Salivary Blockade MSI

Cervical Gastric Major indications in France MMRd TNBC Non small cell lung cancer GBM Endo Mesoth Urothelial tumors metrial elioma Thymic DLBCL Carcinoma Head and neck cancer Eso /FL Ovarian phageal = an increasing number of patients !! Anal Biliary SCLC ESCMID eLibraryTract © by author From the metastatic state to adjuvant and neo-adjuvant !

Eggermont et al. NEJM 2016 Forde et al. NEJM 2018

• Feasability • 2 nivolumab infusions • 5 patients by 22 with an irAE dont 1 grade 3 ESCMID eLibrary © by author How does it work? The ICIs are able to restore a functional cytotoxic immune response correlating with the clinical efficacy

Herbst et al. Nature 2014

ESCMID eLibrary © by author The ICIs are a revolution in oncology

• 25-40% of responses in metastatic diseases with monotherapy • The future is the « combo » ! +++

Anti PD-1 + …

ESCMID eLibraryTang et al. Annals Oncol 2018 © by author Immune checkpoint inhibitors and infections

Immune checkpoint inhibitor administration

To identify and manage properly irAEs has become mandatory for oncologists ESCMID eLibraryChampiat et al. Annals Oncol. 2015 © by author YervoyTM, package insert, BMS 2011 COLITIS Ipilimumab Steroids +/- anti-TNFα Peripheral neuropathies Guillain Barré Sd irAEs grades 3-5 3% 30% Myasthenia possible Meningitis Steroids and specific treatment (IgIV…)

Hypophysitis 8% Thyroïditis with hypo/hyperT Surrenal insufficiency Type 1 diabetes Steroids +/- MMF Hypophysite 5% Tt= opotherapy

Rash, pruritus >> Lyell Sd, 40% Stevens Johnson Sd irAEs grade 3-4 ≈ 20% 1-4% grades III-IV 50%

Topical steroids Prieto et al. Clin Cancer Res, 2013, Andrews et al. ESCMIDCancer Manag Res 2012; Hodi et al. NEJMeLibrary 2010 © by author Immune related adverse events with anti-PD1 and anti-PDL1 Mean Frequencies (range) in 13+4 studies (grade 1 to 5) (Brahmer et al. JCO 2010-2013, Topalian et al. Nejm 2012, JCO 2014, Weber et al. JCO 2013, Robert et al, NEJM 2014, Lancet 2014, Ansell et al. NEJM 2014, Hamid et al. NEJM 2013, Westin et al. Lancet Oncol 2014, Motzer et al. NEJM 2015, Garon et al. NEJM 2015, Brahmer et al NEJM 2015) Brahmer et al. NEJM 2012, Powles et al. Nature 2014, Herbst et al. Nature 2014) ENDOCRINOPATHIES 10% -15% LUNGS SKIN Thyroïditis with hypo/hyper 3% (0 – 8%) Adrenal insufficiency, Hypophysitis Interstitial Pneumonia (with grade 5) 30% Vitiligo, rash, sicca sd Tt= hormonal replacement Check for other diagnosis Follow TSH CT scan and spirometry for grade >=2 LIVER Bronchoscopy with BAL 5% (0 – 10%) Treatment with steroids + ATB Cytolysis > cholestase Rare: Guillain Barre Steroids myasthenia GUT 13% (2,5 – 27%) Diarrhea and abdominal pain ARTHRALGIA MYALGIA CT scan and rectoscopy Collins et al. Ann 8% - 2,5% (0 - 16%) Oncol 2017 Polyarthritis, PMR, myositis (check for myocarditis) Treatment with steroids +/- Treatment with steroids +/- MTX anti-TNFa anti-TNFα Pancreatitis ESCMID eLibraryirAEs grade 3-4 ≈ 10% © by author IrAEs and combinations…

• Majoration of toxicities • Majoration of toxicities • Nivolumab + ipilimumab (Wolchok et al. NEJM 2013) • Carboplatine – paclitaxel +/- 53% of irAEs grade 3-4 pembrolizumab (Paz-Ares NEJM 2018) 38% treated with steroids and 3 with immunosuppressants Combo : 30% irAEs with 11% grade 3-5

ESCMID eLibrary © by author What are the infectious risks for cancer patients treated with ICIs?

1. No intrinsic infectious risk related to the molecules (Redelman-Sidi G et al. Clin Microbiol Infect 2018) 2. The risk could be related to the use of steroids and immunosuppressants in immunocompromised patients with metastatic cancer ?

ESCMID eLibrary © by author Clin Infect Dis. 2016 Dec

• 740 patients treated over a 4-years period • 58 severe infections in 54 patients • 73% ipilimumab (anti-CTLA-4) • 46% received steroids • 16% received infliximab • 9 ESCMIDdeaths eLibrary © by author Conclusion : infectious complications of immune checkpoint inhibitors are thoseESCMIDrelated to the steroids given for irAEs managementeLibrary © by author Be careful ! A new symptom in a patient treated with immune checkpoint inhibitor could be an infection rather than an irAE !

• Infections are differential diagnosis of irAEs (Kyi et al. J Immunother Cancer 2014, Pradere et al. Eur J Cancer 2017…) - CMV colitis or Clostridium difficile infection - Pulmonary aspergillosis, pneumocystosis, flu… - Hepatitis E Cancer progression • A symptom = systematic investigations New symptom irAEs

Unrelated disease (infection ?) Some recommendations: Pneumocystis prophylaxis if prednisone ≥ 20mg/d ≥ 3 weeks Look for an opportunistic infection if the patient’s status worsens after the start of immunosuppressiveESCMID treatment eLibrary © by author What are the infectious risks for cancer patients treated with ICIs?

1. No intrinsic infectious risk related to the molecules (Redelman-Sidi G et al. Clin Microbiol Infect 2018) 2. The main risk is related to the use of steroids and immunosuppressants in immunocompromised patients with metastatic cancer 3. Is there a risk of Immune Reconstitution Syndrome in patients with chronic infection? = Exclusion in clinical trials of • Chronic viral hepatitis • HIV infection ESCMID eLibrary © by author Hepatitis B and C: risk of fulminant hepatitis?

• Risk = reactivation of virus-specific T lymphocytes with an IRIS ?

> 100 cases reported: no severe hepatitis with liver failure ESCMID eLibrary © by author Efficacy and safety of anti-PD-1 in B and C chronic hepatitis: clinical trial in Hepatocellular carcinoma

OS : 82% 63% 81% 70%

Lancet 2017 • Similar Overall Survival • HBV treated with neg DNA, HCV no rule • No difference in irAEs with other patients • Reduction of HCV VL < 6 mois • NoESCMID HBV reactivation eLibrary © by author Is a chronic viral infection is a contraindication for the use of immune checkpoint inhibitors?

• Hepatitis B and C: NO, but monitoring of liver enzymes, and better to have negative HBV DNA • HIV : ? IRIS? NO!

MoreESCMID than 50 reported cases: no IRIS or unexpected eLibraryirAE © by author ANRS CO24 ONCOVIHAC A Multicenter Observational Cohort for HIV Infected Patients with a Cancer treated by Immune-Checkpoint Inhibitors (icpi)

Pr. J.P. Spano & Pr. O. Lambotte

Observational study: 30 patients enrolled, 10 deaths due to the cancer Clinical research ancillary study (PI Brigitte Autran): - Immunological studies - Virological studies - 10 patients enrolled with prospective follow-up and samplings In both studies, no unexpected safety warning ESCMID eLibrary 1 © by author Tuberculosis Involvement of the PD-1/PD-L1 pathway to limit inflammation in tuberculosis primary infection but… The PD-1/PD-L1 pathway favors Koch bacilli persistance (Sakais et al. PLoS Pathogen 2016)

 Several observations of TB reactivation in patients treated with anti-PD-1 (without steroids!)

ESCMID eLibrary © by author Infections in patients receiving immunotherapy in oncology

Immune checkpoint inhibitor administration

Infectious risks related to chronic infection? Minimal++ Infectious risks YES related to steroids and immunosuppressive drugs

ESCMID eLibraryChampiat et al. Annals Oncol. 2015 © by author How to optimize the management of infections in patients treated with immune checkpoint inhibitors ?

ESCMID eLibrary © by author How to optimize the management of infections in patients who will be treated / are treated with immune checkpoint inhibitors ? 1. Perform HIV, HBV, HCV serologic testing for ALL cancer patients… Ramsey et al. JAMA Oncol 2019

1. Get an IGRA for patients at risk for tuberculosis ? For all ?

2. Vaccinations allowed !! • Wijn DH et al. Eur J Cancer. 2018 : a cohort study during two years Influenza vaccination in patients with lung cancer receiving anti-programmed death receptor 1 immunotherapy does not induce immune-related adverse events.

Anti-PD-1 in vaccination optimization : a perspective ? … (Pan E et al. Front Immunol. 2018) ESCMID eLibrary © by author How to optimize the management of infections in patients treated with immune checkpoint inhibitors ?

1. Set up a network of organ specialists and internists in Paris Sud University 2. Set up a dedicated meeting for discussion and management of difficult situations (national meeting iTOX, twice / month, conf call.) 3. Creation at G Roussy of a prospective registry of the irAEs: REISAMIC (2014) 4. Identification of a reference center at Paris Sud University [email protected]

ESCMID eLibrary © by author Immune checkpoint inhibitors and infections

ESCMID eLibrary © by author The immune check points inhibitors as new anti- infectious agents?

• PD-1 blockade on virus-specific or pathogen-specific T cells could lead to a « boost » of the anti-viral / anti-microbial immune response leading to a better control / cure of the pathogen

ESCMID eLibrary © by author Changing the paradigm also in chronic infections !

Historic paradigm: New paradigm: Target the infected cell Target the immune cells

Lymphocyte ARV, bNabs, LRAs… +

ESCMIDInfectedTumor CellCell eLibraryAnti PD1,… © by author Some exemples ? LCMV infections in mouse models

Hepatitis B and C Lymphocyte

HIV

2013

66 patients nivolumab The scientific rationale is present HIV RNA viral load decrease in 5 patients Trials in discussion includingESCMID2 to undetectable eLibrary © by author Some exemples ?

HIV Strong scientific rationale for blocking the PD-1/PD-L1 pathway (> 200 publications)

 14 macaques without antiretroviral treatment  4 doses anti-PD-1 (n=9)  Ig control (n=5) Anti-PD-1 in HIV-infected patients:  Improvement of CD4, CD8, B cell responses • 4 clinical trials in cancer patients  Increase of survival • 3 trials in patients without cancer as ESCMID eLibrarypathophysiological studies clinicaltrials.gov © by author Some exemples ?

JC Virus

2019 8 patients including to 2 HIV-infected 2 improvements 4 stable diseases 2 worsenings and deaths 1-3 infusions Boost of JC-specific immune responses 2 irAEs (rash / flare of psoriasis) ESCMID eLibrary © by author Some exemples ?

Sepsis

Involvement of the PD-1/PD-L1 pathway to limit the inflammation but could favor a secondary phase of immunodepression

Sepsis

To block the PD-1 / PD-L1 axis could reduce the immunosuppression induced by the sepsis

- Experimental data in animal models - Ex vivo data in humans

- Clinical trials

- NCT02960854: Randomized, Double-Blind, Parallel Group Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of BMS-936558 (Nivolumab) in ParticipantsESCMID With Severe Sepsis or Septic Shock, eLibrary Phase 1 (ended Janv 2018) © by author Conclusion and perspectives… • Infectious risk exists, mainly due to steroids and immunosuppressive drugs used to control irAEs • Importance of a network of specialists in each cancer center to help and work with oncologists • Need for educational programs for all the actors involved in the management of a cancer patient treated with immune checkpoint inhibitor including infectiologists… • Immuno-modulation is a new weapon in infectious diseases but…

• Normal flora enriched in Faecalibacterium genus and Firmicutes: improvement of overall survival but risk of colitis increased • Flora enriched in Bacteroides : the opposite

• Deleterious effect of an antibiotherapy given prior the anti-PD-1… ? ESCMID eLibrary © by author 1/ Autoimmunity and anti-CTLA4

• Personal prior history of autoimmune disease (Johnson et al. JAMA Oncol 2016) • 30 patients treated with ipilimumab • Age: 59,5 (30-80) • 50% will have a flare of their disease (27%) or an other irAE (33%) • Symptoms starting between the 2nd and the 6th week [day 3 to M7] • Treatment with steroids (5-30mg) with disappearance of the irAE (1 case needed infliximab) ESCMID• 50% patients: no flare nor other irAE eLibrary © by author An autoimmune disease is not de facto a contraindication for the use of immunotherapy: prospective data of the Reisamic registry An increase frequency of irAEs with earlier occurrence No difference for the OS

In AID+, 44% of irAEs, with 55% of flares In AID-, 29%

Immunotherapy kept on in 75% of the patients

Danlos et al.ESCMID ACR 2017, SNFMI 2017, EJC 2018 eLibrary © by author ESCMID eLibraryKyi et al. J Immunother Cancer 2014 © by author ESCMID eLibrary © by author 2014

Overall Survival at 1 year in a metastatic disease: 72% - 42%

Some patients are and stay in response despite the stop of the ICI ESCMID eLibrary © by author Nivolumab and lung cancer (NSCLC)

Brahmer et al. NEJM 2015 • Phase III, 272 patients • Nivolumab versus docetaxel • The overall survival is higher than the Progression free survival (42% vs 21%) = new concept • AE ≥ grade 3

• 7% Nivo vs 55% docetaxel et al al 2015 NEJM et

• Set up at G Roussy cancer center of a prospective registry for irAEs: Registre REISAMIC • Pr Lambotte (HUPS) / Pr Soria / Dr Marabelle (DITEP, GR) / Pharmacology dpt • Since June 2014: all the patients with legal use approval for nivolumab / pembrolizumab / (anti-PD-L1) have been enrolled in the database (n=900) • Prospective recording of all averse events grade > 2 and all irAEs grade > 1 • 25% irAEs (grade 2-5) • Possibility to open the database for other centers ESCMID eLibrary © by author