How transformation in the management of hematologic cancer will impact the invasive fungal disease ecosystem

Dimitrios P. Kontoyiannis MD, ScD, PhD (Hon), FACP, FIDSA, FAAM, FECMM, FAAAS

Texas 4000 Distinguished Endowed ProfessorDeputy Head-Research, Division of Internal Medicine

29° ECCMID 21-24 April 2018Madrid, Spain

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Disclosures

Research support and/or honoraria* from:

Merck, Inc

Astellas, Inc

Cidara, Inc

Amplyx, Inc

Last 12 months ESCMID eLibrary

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Major events in the supportive care of patients with hematological cancer pertaining to mycology

1960’s 1970s 1980’s 2000 2018

Platelet transfusionsDecreased death from bleeding

Autopsy studies(NCI) showing IFIs as a cause of death

Recognition of neutropenia and infection risk

Invasive candidiasis major threat(wave 1)

Decades of newantifungal agents(broad-spectrum triazoles,echinocandins)

Introduction of fluconazole advances in allogeneic HSCT, GvHD, CMV as IFI risk factors

Anti-StaphpenicillinsReduced mortality from S. aureus

Empirical therapy for Gram negative rods->Decreased mortality in neutropenic patients

1990’s

Azole-resistant Candida and invasive aspergillosis(wave 2)

2010

Complex epidemiology, antifungal resistant yeast and molds(wave 3)

Era of targeted therapies for hematological malignancies, immunotherapy improvements in allogeneic HSCT and availability

?

Major events in supportive care of patients with hematologic cancer-pertaining to mycology

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Annual number of HSCTs in USA by transplant type

Reduction of transplant-relatedmorbidity and mortality (reduced-Intensity conditioning, PBSC)

Improved control of CMV

Expanded donor pools(Haplo-HSCT)

GVHD biomarkers? Targeted immunosuppression

Targeted therapies forGVHD, graft vs- tumor effect

Microbiome?Source: CIBMTR

Improved control of CMV and fungal diseases

Major advances:

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Increasing treatment options for hematologic malignancies

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AMLPrognostic relevance of integrated genomic profiling

an explosion of new drugs

under testing

Patel JP et al. N Engl J Med. 2012;366:1079-1089.

Gene Overall Frequency, %

FLT3 (ITD, TKD) 37 (30, 7)

NPM1 29

DNMT3A 23

NRAS 10

CEBPα 9

TET2 8

WT1 8

IDH2 8

IDH1 7

KIT 6

RUNX1 5

MLL-PTD 5

ASXL1 3

PHF6 3

KRAS 2

PTEN 2

TP53 2

HRAS 0

EZH2 0 ESCMID eLibrary

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New therapies for AML

…for many populations,

including those at high risk or defined by

molecular abnormalities

Novel cytotoxic agents (CPX-351, vosaroxin)

Emerging/next-generation HMAs

(SGI-110; CC-486; ASTX727)

Targeted therapies

(FLT3i, IDHi, Bcl-2, SINE, HDAC)

Immune checkpoint inhibitors

(Nivolumab, Pembrolizumab)

Novel antibodies

(Gemtuzumab, IMGN 33 and 123,

AMG-330, Xmab-CD33/CD123)

AML with actionable mutations, molecular, or

high-risk features (eg, age)

Combination therapy with HMAs for older patients

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A new era for drug toxicity and interactions of azoles with targeted therapies?

ABL1 CEBPA HRAS MYD88 SF3B1

ASXL1 CSF3R IDH1 NOTCH1 SMC1A

ATRX CUX1 IDH2 NPM1 SMC3

BCOR DNMT3A IKZF1 NRAS SRFS2

BCORL1 ETV6/TEL JAK2 PDGFRA STAG2

BRAF EZH2 JAK3 PHF6 TET2

CALR FBXW7 KDM6A PTEN TP53

CBL FLT3 KIT PTPN11 U2AF1

CBLB GATA1 KRAS RAD21 WT1

CBLC GATA2 MLL RUNX1 ZRSR2

CDKN2A GNAS MPL SETBP1

AG120

AG221

Idasanutinib

Decitabine

Sorafenib

Midstaurin

Quizartinib

ASP2215

Azacitidine

Decitabine

Vemurafenib

Cobimetinib

Cobimetinib

TKI

PONATINIB

Slide: Cristina Papayannidis, M.D.

58% of new therapies in Phase I-III clinical trials have relative or absolute contraindications for triazole prophylaxis of CYP 3A4, QTc prolongation) ESCMID eLibrary

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Immune-based approaches for AML

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CAR-T cell treatments for AML and ALL

Ideal antigen: CD33, CD123, TIM3, CLEC12… others?

Off target activation of macro/monocytes: CRS, prolonged cytopenia

CARTox guidelines (Nature Reviews Clin Oncol 2017)

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How do new therapies affect the risk for fungal disease?

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The Good:

Epigenetic therapy in MDS

Hypo-methylating agents: azacitidine, decitabine

Equivalent to best supportive care and low-dose ARA-C in high-risk disease;superior in low-risk diseaseNature Reviews Clin Oncol 2010 ESCMID eLibrary

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Do all patients with MDS need antifungal prophylaxis?

Impact of epigenetic therapeutics on the management of AML/MDS

274/948 courses (28%) associated with grade 4 neutropenia (< 0.5x109/L for >10 days)• 12% associated with febrile neutropenic episode• Only 4 invasive fungal infection documented• Incidence: 0.42% per treatment cycle, 3.3% among

patients with grade 4 neutropenia

Fenaux et al. J Clin Oncol 2010;28:562-569.

Pomares H et al. Mycoses 2016; 59: 516–519. ESCMID eLibrary

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The bad…

Chamilos G, Lionakis MS, Kontoyiannis DP. Clin Infect Dis 2018; 66: 140–148. ESCMID eLibrary

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Ibrutinib: a “game-changing drug” in B-cell malignancies

(accelerated FDA Approval in 2013)

Byrd et al., J Clin Oncol, 2014, 32:3039-3048

Burger JA et al. N Engl J Med 2015;373:2425-2437

RESONATE-2 (CLL, frontline ibrutinib)

4 year follow up: only 12% of patients

D/C due to AEs (AF, bleeding, infection) ESCMID eLibrary

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Uncommon opportunistic infections in lymphoma patients treated with ibrutinib

39% IA

5% PCP

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Early onset aspergillosis in patients treated with ibrutinib

Retrospective surveillance (French Innovative Leukemia Organization for CLL)

33 cases of IFI from 16 Cancer Centers from 2013-2017

Invasive aspergillosis in 27/33 (81%) within 3 months of ibrutinib treatment

CNS aspergillosis in 11/27 (40%)

All refractory/relapsed CLL

Additional predisposing factors in most of patients (steroids in 7, neutropenia in 5)

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Increased susceptibility of mice for of IA with pharmacological or genetic ablation of BTK

Increased susceptibility of mice for of IA upon pharmacological of genetic ablation of BTK

Stadler N et al., Haematologica 2017 102:e191-194 Lionakis MS et al., Cancer Cell 2017 31, 833-843 ESCMID eLibrary

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Is ibrutinib associated with increased risk of cerebral aspergillosis?

Type of IA Time after

treatment

Age/Sex Type of

Cancer

Status of

Malignancy

Concomitant

steroids

Outcome Ref

CNS 1 month N/A CLL PD Yes Dead Ruchlemer et al.

CNS 2 month N/A CLL PD Yes Alive Ruchlemer et al.

CNS 2 month N/A CLL PD Yes Alive Ruchlemer et al.

Lungs 6 wks 62/M CLL PD No Alive Arthus et al.

CNS, lungs 2 wks 76/F PCNSL Active Yes Dead Lionakis et al.

CNS, lungs 2 wks 65/M PCNSL Active Yes Dead Lionakis et al.

CNS, lungs 3 months 87/F PCNSL Active Yes Dead Lionakis et al.

Lungs 4 months 60/M PCNSL Active Yes Alive Lionakis et al.

Lungs 2 months 53/M PCNSL Active Yes Alive Lionakis et al.

Lungs 1 month 64/M PCNSL Active Yes Alive Lionakis et al.

CNS, lungs 2 wks 49/M PCNSL Active Yes Alive Lionakis et al.

Sinusitis, CNS 3 wks 75/F CLL PD No Alive Baron et al.

CNS, lungs 2 months 76/NA CLL PD No Dead Jain et al.

Lungs 7 months 67/M CLL N/A No Dead Kreiniz et al.

Chamilos G et al. Clin Infect Dis. 2018 Jan 6;66(1):140-148

CNS aspergillosis in 9/14 (64%)

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Is ibrutinib associated with increased risk of early aspergillosis?

Type of IA Time after

treatment

Age/Sex Type of

Cancer

Status of

Malignancy

Concomitant

steroids

Outcome Ref

CNS 1 month N/A CLL PD Yes Dead Ruchlemer et al.

CNS 2 month N/A CLL PD Yes Alive Ruchlemer et al.

CNS 2 month N/A CLL PD Yes Alive Ruchlemer et al.

Lungs 6 wks 62/M CLL PD No Alive Arthus et al.

CNS, lungs 2 wks 76/F PCNSL Active Yes Dead Lionakis et al.

CNS, lungs 2 wks 65/M PCNSL Active Yes Dead Lionakis et al.

CNS, lungs 3 months 87/F PCNSL Active Yes Dead Lionakis et al.

Lungs 4 months 60/M PCNSL Active Yes Alive Lionakis et al.

Lungs 2 months 53/M PCNSL Active Yes Alive Lionakis et al.

Lungs 1 month 64/M PCNSL Active Yes Alive Lionakis et al.

CNS, lungs 2 wks 49/M PCNSL Active Yes Alive Lionakis et al.

Sinusitis, CNS 3 wks 75/F CLL PD No Alive Baron et al.

CNS, lungs 2 months 76/NA CLL PD No Dead Jain et al.

Lungs 7 months 67/M CLL N/A No Dead Kreiniz et al.

IA within the first 4

months (> 93%)

Chamilos G et al. Clin Infect Dis. 2018 Jan 6;66(1):140-148 ESCMID eLibrary

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Does pre-existing brain pathology exacerbate ibrutinib-associated aspergillosis?

Chamilos G et al. Clin Infect Dis. 2018 Jan 6;66(1):140-148

Type of IA Time after

treatment

Age/Sex Type of

Cancer

Status of

Malignancy

Concomitant

steroids

Outcome Ref

CNS 1 month N/A CLL PD Yes Dead Ruchlemer et al.

CNS 2 month N/A CLL PD Yes Alive Ruchlemer et al.

CNS 2 month N/A CLL PD Yes Alive Ruchlemer et al.

Lungs 6 wks 62/M CLL PD No Alive Arthus et al.

CNS, lungs 2 wks 76/F PCNSL Active Yes Dead Lionakis et al.

CNS, lungs 2 wks 65/M PCNSL Active Yes Dead Lionakis et al.

CNS, lungs 3 months 87/F PCNSL Active Yes Dead Lionakis et al.

Lungs 4 months 60/M PCNSL Active Yes Alive Lionakis et al.

Lungs 2 months 53/M PCNSL Active Yes Alive Lionakis et al.

Lungs 1 month 64/M PCNSL Active Yes Alive Lionakis et al.

CNS, lungs 2 wks 49/M PCNSL Active Yes Alive Lionakis et al.

Sinusitis, CNS 3 wks 75/F CLL PD No Alive Baron et al.

CNS, lungs 2 months 76/NA CLL PD No Dead Jain et al.

Lungs 7 months 67/M CLL N/A No Dead Kreiniz et al.

45% of cases of CNS aspergillosis

in pts with brain pathology

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Is ibrutinib the only risk factor?

Type of IA Time after

treatment

Age/Sex Type of

Cancer

Status of

Malignancy

Concomitant

steroids

Outcome Ref

CNS 1 month N/A CLL PD Yes Dead Ruchlemer et al.

CNS 2 month N/A CLL PD Yes Alive Ruchlemer et al.

CNS 2 month N/A CLL PD Yes Alive Ruchlemer et al.

Lungs 6 wks 62/M CLL PD No Alive Arthus et al.

CNS, lungs 2 wks 76/F PCNSL Active Yes Dead Lionakis et al.

CNS, lungs 2 wks 65/M PCNSL Active Yes Dead Lionakis et al.

CNS, lungs 3 months 87/F PCNSL Active Yes Dead Lionakis et al.

Lungs 4 months 60/M PCNSL Active Yes Alive Lionakis et al.

Lungs 2 months 53/M PCNSL Active Yes Alive Lionakis et al.

Lungs 1 month 64/M PCNSL Active Yes Alive Lionakis et al.

CNS, lungs 2 wks 49/M PCNSL Active Yes Alive Lionakis et al.

Sinusitis, CNS 3 wks 75/F CLL PD No Alive Baron et al.

CNS, lungs 2 months 76/NA CLL PD No Dead Jain et al.

Lungs 7 months 67/M CLL N/A No Dead Kreiniz et al.

Refractory of relapsed malignancy

in 100% of patients

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Is ibrutinib the only risk factor?

Type of IA Time after

treatment

Age/Sex Type of

Cancer

Status of

Malignancy

Concomitant

steroids

Outcome Ref

CNS 1 month N/A CLL PD Yes Dead Ruchlemer et al.

CNS 2 month N/A CLL PD Yes Alive Ruchlemer et al.

CNS 2 month N/A CLL PD Yes Alive Ruchlemer et al.

Lungs 6 wks 62/M CLL PD No Alive Arthus et al.

CNS, lungs 2 wks 76/F PCNSL Active Yes Dead Lionakis et al.

CNS, lungs 2 wks 65/M PCNSL Active Yes Dead Lionakis et al.

CNS, lungs 3 months 87/F PCNSL Active Yes Dead Lionakis et al.

Lungs 4 months 60/M PCNSL Active Yes Alive Lionakis et al.

Lungs 2 months 53/M PCNSL Active Yes Alive Lionakis et al.

Lungs 1 month 64/M PCNSL Active Yes Alive Lionakis et al.

CNS, lungs 2 wks 49/M PCNSL Active Yes Alive Lionakis et al.

Sinusitis, CNS 3 wks 75/F CLL PD No Alive Baron et al.

CNS, lungs 2 months 76/NA CLL PD No Dead Jain et al.

Lungs 7 months 67/M CLL N/A No Dead Kreiniz et al.

71% of patients also

received corticosteroids

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How will targeted therapies for malignant and autoimmune diseases affect the epidemiology of IFI?

A surge of therapies with SMKIs targeting antifungal immune signaling pathways

BTK inhibitors

PI3K inhibitors

Syk inhibitors

NOX inhibitors

MAPK inhibitors

JAK/STAT inhibitors

Additional IA cases associated with biological therapies

TNF inhibitors

eculizumab

Chamilos G, Lionakis MS, Kontoyiannis DP. Clin Infect Dis 2018; 66: 140–148. ESCMID eLibrary

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Other SMKIs are associated invasive aspergillosis: the sorafenib story

Type of IFI Sites of

infection

Type of cancer Age/Sex Concomitant

corticosteroids

Comorbiditie

s

Subacute invasive

aspergillosis*

lung Hepatocellular

carcinoma

64/M No DM, Asthma

Invasive

aspergillosis

pneumonia Thyroid cancer N/A Yes N/A

Invasive

aspergillosis

pneumonia Salivary gland

carcinoma

N/A No N/A

Talaromyces

marneffei infection

disseminated AML 67/M No N/A

*Bazaz R & DW Denning, Clin Infect Dis 2018 Jan 23Chamilos G, Lionakis MS, Kontoyiannis DP, Clin Infect Dis 2018 ESCMID eLibrary

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Checkpoint inhibitors-good, bad or ugly?

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Check point inhibitors: A revolution in modern oncology

DiesendruckY & Benhar Drug Res Updates 2017

Schematic representation of immune checkpoint blockade by targeted mAbs. A ‘Two signal model' of T cell

activation. Antigen-presenting cells (APC) display tumor specific antigens on their surface by MHC-II molecules,

recognized by T cell receptor (TCR). A second signal, mediated by CD28 binding to B7 costimulatory molecules (such as

CD80 or CD86) is required for full activation. CTLA-4 is up-regulated shortly after T-cell activation, down-regulating the

immune response to maintain tolerance. PD-1 is expressed by tumor infiltrating lymphocytes (TILs) after antigen

exposure, and its interaction with its ligands results in T cells inhibition in the tumor microenvironment. B. Antibodies

targeting these immune checkpoints, such as ipilimumab (anti CTLA-4) or nivolumab (anti PD-1) block the inhibitory

signal, thus markedly enhancing the immune response to the tumor. ESCMID eLibrary

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FDA approval of checkpoint inhibitors

20+ approvals in 3 years

Cancer type/Therapy

Ipilimumab

(YEVROY)

(CTLA-4i)

Pembrolizumab

(KEYTRUDA)

(PD-1i)

Nivolumab

(OPTIVO)

(PD-1i)

Atezolizumab

(TECENTRIQ)

(PD-L1i)

Avelumab

(BAVENCIO)

(PD-L1i)

Durvalumab

(IMFINZI)

(PD-L1i)

Metastatic melanoma 2011 2014, 2015

2014,

2015

(Nivo + IPI)

Squamous cell lung cancer

(NSCLC)2015

Non-squamous non-

small cell lung cancer

(NSCLC)

2017

Non-small cell lung cancer

(NSCLC)2015, 2016 2015 2016

Renal cell cancer 2015

Squamous cell carcinoma

of the head and neck

(SCCHN)

2016 2016

Urothelial carcinoma 2017 2017 2016 2017 2017

Hodgkin lymphoma 2016

Colorectal cancer 2017

Merkel cell carcinoma 2017 ESCMID eLibrary

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Hypomethylating agents and immune regulation

T cell

Tumor cell

TCR++Upregulate tumor cell antigen (PRM1, NY-ESO, WT1) and

ERV expression1

++Upregulate antigen processing and

presentation2 (MHC-1)

CD28

CD80/86

++Upregulate expression of costimulatory

molecules3 (CD40L, CD28)

Tumor antigen

Antigen bound to MHC class I

--Upregulate expression of PD1, PDL1, and to lesser

extent CTLA4

1. Sato T et al. Cold Spring Harb Perspect Med. 2017;7(5). 2. Li H et al. Oncotarget. 2014;5:587-598. 3. Wang LX et al. PLoS One. 2013;8:e62924. 3. Al-Atrash, Daver N et al., Pharmacologic Reviews4. Daver N, Kantarjian H et al, Leukemia 2018 ESCMID eLibrary

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AZA+Nivo in Relapsed AML

OS (censored for SCT) by response (N = 70): 33%

Slide courtesy N Daver, MD ESCMID eLibrary

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Growing literature that CPI can enhance T-cell mediated antifungal activity

Spec, A, Shindo, Y, Burnham, CA et al. T cells from patients with Candida sepsis display a suppressive immunophenotype. Crit Care. 2016; 20: 15

Krummey, SM, Floyd, TL, Liu, D, Wagener, ME, Song, M, and Ford, ML. Candida-elicited murine Th17 cells express high Ctla-4 compared with Th1 cells and are resistant to costimulation blockade. J Immunol. 2014; 192: 2495–2504

Chang, KC, Burnham, CA, Compton, SM et al. Blockade of the negative co-stimulatory molecules PD-1 and CTLA-4 improves survival in primary and secondary fungal sepsis. CritCare. 2013; 17: R85

Barrios, CS, Johnson, BD, Henderson, JD Jr, Fink, JN, Kelly, KJ, and Kurup, VP. Enhanced expression of CTLA-4 and concurrent downregulation of CD28 on lung cells of mice exposed to Aspergillus antigen. J Allergy Clin Immunol. 2005; 115: pS258

Campanelli, AP, Martins, GA, Souto, JT et al. Fas-Fas ligand (CD95-CD95L) and cytotoxic T lymphocyte antigen-4 engagement mediate T cell unresponsiveness in patients with paracoccidioidomycosis. J Infect Dis. 2003; 187: 1496–1505

McGaha, T and Murphy, JW. CTLA-4 down-regulates the protective anticryptococcal cell-mediated immune response. Infect Immun. 2000; 68: 4624–4630

Grimaldi, D, Pradier, O, Hotchkiss, RS, and Vincent, JL. Nivolumab plus interferon-γ in the treatment of intractable mucormycosis. Lancet Infect Dis. 2017; 17: 18

Lázár-Molnár, E, Gácser, A, Freeman, GJ, Almo, SC, Nathenson, SG, and Nosanchuk, JD. The PD-1/PD-L costimulatory pathway critically affects host resistance to the pathogenic fungus Histoplasma capsulatum. Proc Natl Acad Sci USA. 2008; 105: 2658–2663

. Stephen-Victor E, Karnam A, Fontaine T, et al. Aspergillus fumigatus Cell Wall α-(1,3)-Glucan Stimulates Regulatory T-Cell Polarization by Inducing PD-L1 Expression on Human Dendritic Cells. J Infect Dis. 2017 5;216(10):1281-1294

Daver N, Kontoyiannis DP. Checkpoint inhibitors and aspergillosis in AML: the double hit hypothesis. Daver N, Kontoyiannis DP .Lancet Oncol. 2017 ;18(12):1571 ESCMID eLibrary

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Survival differences between non treatment nasally infected immunosuppressed mice

(control) vs. PD-1 treatment of infected mice

Robinson P… Kontoyiannis DP. Unpublished

0 2 4 6 8

0

2 0

4 0

6 0

8 0

1 0 0

D a y (s )

Pe

rc

en

t s

urv

iva

l

C o n tro l M ic e n = 1 5

P D -1 T M T M ic e n = 2 0

P value 0.0301

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Checkpoint inhibitor therapy is associated with frequent, pleiotropic, immune-related adverse effects

Treatment: long termglucocorticosteroidsand TNF inhibition(Infliximab) for

GC-refractory cases

Postow MA et al. NEJM 2018 ESCMID eLibrary

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Opportunistic infections in patients treatedfor immune related adverse effects during checkpoint inhibitor therapy

Retrospective study of 740 patients with melanoma at MSKCC (2010-2014) who received immune checkpoint blockers.

Serious infection occurred in 54 patients (7.3%) Fungal infection in 6 ( PJP in 3, IPA in 2)

Average time to infection: 135d, 805 within 6 months

Risk factors for serious infections: corticosteroids (odds ratio [OR], 7.71; and use of infliximab (OR, 4.74)

Use of a combination of ipilimumab and nivolumab was associated with increased risk of serious infection, whereas use of pembrolizumab was inversely associated

Del Castillo M et al. CID 2016, Kyi C et al. J immunother Cancer 2014, Arriola E et al. OncoImmunology 2015, Uslu U et al. J Immunother 2015, ESCMID eLibrary

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Some future questions-1How we evaluate best IFI epidemiology in the new era?

RCTs excluded cancer patients with active infections!

How study the full range of CPI effects on the immune

system?

Human studies vs murine studies

Best treatment strategies of IFIs developing post CPI-immune AEs, or in the setting of restarting or changing CPIs

Natural history of IFIs in hematology patients receiving various CPIs

Synergy of CPIs with antifungals that have adjunct immuno-potentiating action (e.g., echinocandins)

CPIs and IRIS-like manifestations in patients with IFIS

35

Some interesting future questions

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What else is out there?

Novel biomarkersInnovative imagingImmunogenetics

New drugs

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Point of care diagnostics

Lateral-Flow Technology

Immunochromatographic assays into POC diagnostic assays

Murine monoclonal antibody, JF5 IgG3Binds to an extracellular

glycoprotein antigen secreted during growth of Aspergillus

Distinguishes between hyphaeand conidia

A. Brightfield B. Epifluroescence

Convincingclinical

validation

As GM, LFD

sensitivity is reduced

by mold-active

antifungals

Thornton C, et al. Clin Vaccine Immunol 2008, Hoenigl M et al. Mycoses 2018 ESCMID eLibrary

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Diagnosing invasive molds by breath?

In Vitro volatile metabolite profiles of molds

Fungal cultures inoculated in parallel with matched media controls

Adsorption/concentration onto a sorbent bed

Thermal Desorption

Gas Chromatography-Tandem Mass Spectrometry

Koo S, et al. Clin Infect Dis 2014, Koshy S et al. ID week 2017, abst 1776 ESCMID eLibrary

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Diagnosing invasive molds by breath?

Sens: 0.94 (0.81, 0.95)

Spec: 0.93 (0.79, 0.98)

LR+ 13.4, LR-: 0.06

Koo S, et al. Clin Infect Dis 2014 ESCMID eLibrary

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Diagnosing invasive mold disease by urine samples?

Urinary Excreted Galactomannan-like Antigens for IA

Novel IgM MAb476 that recongizes GM-like (Galf) antigens

Antigenuria a clinically relevant target

Guinea pigs

Clinical samples

Detection with lateral flow device

POC diagnostic

Urine GM/

Urine creatinine

ratio to diagnose

IA

Reischies FM et al.

JCM 2016

Dufresne SF, et al. PLoS ONE. 2012;7:e42736. ESCMID eLibrary

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Radiolabeled Ga or Zn-labeled siderophore uptake in PET

Gliotoxin and methylated gliotoxin detection

Detection of Aspergillus siderophores in serum as secondary metabolites

Nuclear magnetic resonance metabolomics

Other metabolite-based diagnostic tools for aspergillosis

Savelieff MG, Pappalardo L. PLoS Pathog. 2017 ESCMID eLibrary

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Improved CT imaging of invasive mold disease?

CT pulmonary angiography for IMD:

A good idea from Switzerland, refined in Italy

14 cases

Histological documentation of lesions in 8 cases

Vessel occlusion sign (VOS) observed in 4/5 histologically-documented mould disease cases (80%)

1 false negative: mucormycosis

No VOS in 9/9 patients with non-fungal causes of infection

Sonnet S et al. AJR 2005;184:746-751 ESCMID eLibrary

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Specific PET imaging for invasive mold disease

Rolle AM et al. PNAS 2016, Davies G et al. Theragnostics 2017

Future targeting of invasive fungal disease? Immuno PET and targeting antibodies

Previous proof of

concept

Gamma-imaging

with-labeled

cyclic peptide

targeted to A.

fumigatus hyphae

in a mouse model of

IPA

Yang Z, Kontoyiannis

DP et al

Nucl Med Biol 2009

Regular PET/CT.

Chamilos G..

Kontoyiannis DP.

Med Myc 2008

mAB JF5 is the basis of Aspergillus LFA

Hyphal-specific->good for monitoring of response?

Long half life->single injection

Humanized version of Ab (hJF5) to enter clinical trials in 2018! ESCMID eLibrary

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Engineering

specificity

of Dectin-1 on CAR

T cells as a new

platform

for treatment

Naïve T cells Dectin-1 expressing

T cells

Kumaresan PR, ….Kontoyiannis DP, Cooper LJ. PNAS 2014.

POSA loading in CAR-T cells?

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Current estimate of IFI risk based on underlying disease: crude and “qualitative”

Chronic granulomatous disease

Allogeneic HSCT with graft versus host disease

AML/MDS treated with remission-induction chemotherapy

Lung or heart transplantation

Small-bowel transplantation

Liver transplantation

Allogeneic HSCT without graft versus host disease

Acute myeloblastic leukemia during consolidation phase

Acute lymphoblastic leukemia

Heart transplantation

Chronic lymphocytic leukemia

Myelodysplastic syndrome

Multiple myeloma

COPD with acute exacerbation

AIDS

Non-Hodgkin’s lymphoma

Autologous HSCT

Kidney transplantation

Solid tumor

Autoimmune disorder

HIGH RISK

INTERMEDIATERISK

LOWRISK

Herbrecht et al. Ann NY Acad Sci 2012;1272:23-30. ESCMID eLibrary

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BoScore2018: Individualized prediction of risk for invasive mold disease

Risk of invasive mold disease within 60 days of admission

No Yes

No Yes

No Yes

No Yes

No Yes

No Yes

No Yes

Uncontrolled malignancy

High-risk chemotherapy

High-dose corticosteroids

Lymphopenia < 50/mm

CMV disease or viremia

PMN< 100 /mm3 > 10 days

Previous history of mould disease

0 1 2 3 4 5 6 7 8 9 10 11Score

1 5 10 20 30 40 50 60 70 80

Probability (%) of developing

invasive mold disease within

60 days

0 5 10 15 20 25 30 35 40 45Total score

Stanzani M… Kontoyiannis DP, Lewis RE. 2018 submitted ESCMID eLibrary

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Immunogenetics

Why do “similar” patients have different attack rates of and IFI (and outcome)?

Differences in exposure and virulence of offending fungus?

Host genetic differences in immunity (e.g., pattern recognition receptors such as Toll-like receptors (TLRs) and the C-type lectin receptors (CLRs) and/or pharmacology?

Lionakis MS & Levitz SM. Annu Rev Immunol 2017 ESCMID eLibrary

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The challenge with genetic studies

“Locating, from scratch, the gene related to a disease is like trying to find a burned-out light bulb in a house located somewhere between the East and West coasts without knowing the state, much less the town or street the house is on”

Francis S. Collins, Quoted in Philip Elmer-Dewitt, et al.

'The Genetic Revolution', Time magazine (17 Jan 1994), 46-53 ESCMID eLibrary

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Genetic polymorphisms and risk stratification:

maturation but not maturity!

Solution: Well designed large prospective whole-genome association studies (IA seems to be a polygenic disease)

Incorporation of fungal genetics, microbiome and/or mycobiome

Incorporation of validated clinical risk models and specific imaging diagnostics

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Antifungals in the pipeline

Improved echinocandin-like drugs?- CD-101, rezafungin (Cidara)

- SCY-078 (Scynexis)

Improved triazole-like drugs?- VT-1161, VT-1129, VT-1598 (Viamet)

Novel mechanisms- F901318 (F2G)

- APX001 (Amplyx)

- VL-2397 (Vical)

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Full• New mechanisms of activity• Activity for resistant pathogens• IV and oral formulations• Few or no drug-drug interactions• Favorable safety profiles• Interesting future for combination therapy (new mechanisms)?

Empty• Small biotechs

• Crowded field for clinical trials of uncommon infections

• Proof of principle: clinical efficacy for new mechanisms of action

• Unknown toxicity, resistance potential

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Future questions

How we evaluate best epidemiology in the new era?

How to study new antineoplastic effects on the immune system?

How the new biomarkers perform according to disease severity?

How biomarkers/imaging helps us on when to stop therapy?

What is the relevance of the in vitro resistance of fungi ?

What is a cost effective risk stratification? Clinical score cards?

Immunogenetics?

Pharmacogenetics?

Combinations?

Should we invest more to the idea of Theragnostics?

How we incorporate new antifungals to a congested scene of existing antifungals?

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The future?

Golconde, 1953Renè MagritteMenil Collection, Houston,TX

Dutch Proverbs, 1559Pieter Bruegel the ElderGemäldegalerie, Staatliche Museen, Berlin

Manage patients in groups?

Manage patients as individuals?

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Acknowledgements

UT M.D. Anderson Cancer CenterKontoyiannis Group

Michail Lionakis, MDG Chamilos , MDNathan Albert, B.ScGregory Lamaris, MDRonen-Ben Ami, MDGeorge Pongas, MDSarah Georgiadou, MDAnne-Pauline Bellanger , PharmDElena Barbu, PhDMarisa Gomes, MDSetareh Davoudi, MDFazal Shirazi, PhDAndreas Kyvernitakis, MDMinas Economides, MDKumar Kumaresan, PhDSang Taek Heo, MDLuke Jung, MDS Aitken, PharmDFrank Tverdek, PharmDYing Jiang, MSN Raman, PhDS Wuster, MD, PhDE Magira, MD

The University of HoustonCollege of Pharmacy

Russell E Lewis, Pharm.DRandy Prince, Pharm DN Beyda, PharmD

Non-MDACC CollaboratorsThomas J Walsh, MD, Cornell UniversityAshraf Ibrahim, PhD, UCLAAntony Mikos, PhD, Rice UniversityD Perlin, PhD, Rutgers University Nir Osherov, PhD, Tel Aviv UniversityG Chamilos, MD Univ of CreteN Sipsas, MD, Univ of Athens

MDACC CollaboratorsSam Shelburne, MD, PhDJeff Tarrrand, MDEdith Marom, MDKaty Rezvani, MD, PhDS Bose, MDN Daver, MDKaleigh Marx, PharmD Caitlin Early, PharmDA Dippo, PharmDG Einsenhoffer, PhD ESCMID eLibrary

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Special gratitude to my friends

especiallyGeorge Samonis, MDRussell E Lewis,

PharmD

Thank you to my patients and to all my colleagues in ID, Leukemia, SCT services at MDACC

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And above all

My family

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See you at the next meeting!

Thank you!

(and see you

In Athens!)

For more information:

WWW.ICHS.ORG

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