New frontiers in primary immunodeficiency diseases (PIDs) What have we learnt and what should we expect Alain Fischer Hôpital Necker Enfants Malades, Inserm, Université Paris-Descartes,
Institut Imagine, Collège de France, Paris
What I learned as a resident with Claude Griscelli in 1977 !
Where do we stand (T cell ID) T lymphocyte: molecules involved in signaling recognition of an antigen down to the nucleus
Fig 5 NRDP
Identified genetic defects causing T cell ID
Primary immunodeficiencies • Clinical scope • How many patients • How many diseases • Diagnosis
• Understanding pathophysiology • Treatments • Screening
• Challenges
Clinical scope From recurrent and/or severe infection(s) broad to restricted spectrum of vulnerability to autoimmunity and inflammation,
allergy, cancer and associated features Titre de la présentation
From elephant to man, a shared concern, many "niches" accessible to microbes Skin
Internal organs Gut
Urogenital tract
Respiratory tract
x 100 for the elephant !! A subtle balance that is disturbed in PIDs causing infections and inflammation C. Reis e Sousa, S. Zelenay
Skin lungs Gut
2 m2 130 m2 300 m2
1014 bacteria (gut) > 1015 virus L. de Vinci
Clinical scope From recurrent and/or severe infection(s) broad to restricted spectrum of vulnerability to autoimmunity and inflammation,
allergy, cancer and associated features Titre de la présentation
Autoimmunity, inflammation and allergy
26 % of pts have >1 autoimmune and/or inflammatory manifestation 19 % of pts have >1 allergic manifestation 5.5 % have both data recorded from 1,900 PID pts -french registryongoing study diagnostic hurdle pathophysiological paradox therapeutic challenge significant prognostic impact
Type of autoimmune and inflammatory manifestations associated with T cell PIDs Frequency (%) • Cytopenias • Endocrine glands, diabetes
60 11
• Hepatitis
6
• SLE like
5
• Arthritis
5
• Vasculitis
4
• IBD
4
• Glomerulonephritis
2.5
• Granulomas
1
• Int. Pneumonia
1
343 pts, 80 manifestations
Clinical scope From recurrent and/or severe infection(s) broad to restricted spectrum of vulnerability to autoimmunity and inflammation,
allergy, cancer and associated features Titre de la présentation
Cancer occurrence in PID patients data from the french PID registry
4632 patients
262 patients with cancer (5.6 %)
Ataxia telangiectasia 22% Severe congenital neutropenia 6.5 % All others 4.5%
Multiple mechanisms Therapeutic challenge
Other hemopathies 4%
Solid tumors 38%
HL 11%
NHL 47%
Clinical scope From recurrent and/or severe infection(s) broad to restricted spectrum of vulnerability to autoimmunity and inflammation,
allergy, cancer and associated features Titre de la présentation
Associated clinical features
Several genes involved in PID also exert function in other tissues
How many patients ? French registry
7 / 100,000 people living in France Half children < 15 years
Estimated incidence from most recent data : 1/ 3 000 live births Can vary ++ as a function of consanguinity rate
How many diseases (genes) ? Number of PID
300 AR
AD
XL
total
Close to 300 !
250 200
2,000 150 genes involved in immune responses Genes coding for RNA only (RMRP) 100 Mutations in non coding regulatory elements (« enhancers ») Non monogenic PIDS (CVID ?) 50 0
Capucine Picard
Advances in genomics
Next Generation Sequencing Highthrouphput sequencers
PGM IonTorrent
HiSeq2500 MiSeq
Throughput
Bioinformatic tools
Genetic diagnosis of PID « Yesterday » clinical symptoms +/- family history
immunological tests
hypothesis
sequencing of « candidate genes »
long/costly/failures ++
« Tomorrow » clinical symptoms +/- family history
immunological tests
more rapid less costly more efficient 55% success rate Preliminary results in Paris (C. Picard)
hypothesis strong (e.g. XLA) hypothesis weak or complex or absent validation
candidate gene(s)
diagnostic gene panel
270+ genes (NGS) +
-
exome sequencing
genome sequencing
What for a genetic diagnosis of PID ?
To give a « name » to the disease, precise diagnosis, very much appreciated by the patients and their families
To understand To better assess the prognosis
To design a targeted therapy Genetic counseling
Titre de la présentation
Screening ??
Primary immunodeficiencies • Clinical scope • How many patients • How many diseases • Diagnosis
• Understanding pathophysiology • Treatments • Screening
• Challenges
B cell immunodeficiencies – Ig production
T cell deficiencies
Severe combined immunodeficiencies
Deficiencies of innate immunity
Primary immunodeficiencies • Clinical scope • How many patients • How many diseases • Diagnosis
• Understanding pathophysiology • Treatments • Screening
• Challenges
Treatment of PIDS • Supportive care (nutrition ++) • Antiinfectious (curative/prevention) new class of antifungal, viral drugs
• Immunosuppressive !!
• Immunoglobulin substitution • Stem cell therapy • Gene therapy Titre de la présentation • Targeted therapy
Treatment of PIDS • Supportive care (nutrition ++) • Antiinfectious (curative/prevention) new class of antifungal, viral drugs
• Immunosuppressive !!
• Immunoglobulin substitution • Stem cell therapy • Gene therapy Titre de la présentation • Targeted therapy
Allogeneic hematopoietic stem cell replacement Bone marrow Lymphoid progenitor
T lymphocyte NK lymphocyte
PID
B lymphocyte
Stem cells
Erythrocyte Self renewal
Granulocyte
Myeloid progenitor
Allogeneic transplantation (1968)
Denfritic cell Macrophage
Osteoclast Platelets
PID
PIDs treated by allogeneic hematopoietic stem cell transplantation
SCID
n=16
T cell immunodeficiencies (« CID »)
n=34
Innate immunodeficiencies
n=10
HLH
n=7
Autoimmune PID
n=10
Autoinflammatory PID
n=3
Total
n=80
4,000 pts in the european registry Significant advances : early transplantation,
better donor choice, better preparation, improved strategy, improved supportive care, gain in experience…
Wiskott Aldrich syndrome european data (2006-2013)
Survival
SCETIDE/EBMT/ESID
T. Güngör et al, The Lancet 2014
Survival
Treatment of PIDS • Supportive care (nutrition ++) • Antiinfectious (curative/prevention) new class of antifungal, viral drugs
• Immunosuppressive !!
• Immunoglobulin substitution • Stem cell therapy • Gene therapy Titre de la présentation • Targeted therapy
Autologous transplantation of gene modified stem cells Bone marrow Lymphoid progenitor
T lymphocyte NK lymphocyte
PID
B lymphocyte
Stem cells
Erythrocyte Self renewal
Granulocyte
Myeloid progenitor
Denfritic cell Macrophage
Osteoclast Platelets
PID
Principle of gene therapy of SCID X1 T lymphocyte NK lymphocyte B lymphocyte Erythrocyte stem cell
Granulocyte Dendritic cell Macrophage Osteoclast Platelets
« therapeutic gene"
Ex vivo gene therapy of SCID - principle Bone marrow
Blood progenitor cell
gene gc LTR Virus
RNA
Cytoplasm DNA
Nucleus
Chromosome
Cell selection
gc mRNA
Vector
Cell proliferation
Cell Culture
SCID : severe combined immunodeficiency
Gene therapy of inherited blood disorders and beyond Bone marrow Lymphoid progenitor
T lymphocyte NK lymphocyte
SCID X1 ADA SCID WAS
B lymphocyte
>100 patients succesfully treated since 1999
Stem cells
Erythrocyte Self renewal
Granulocyte
Myeloid progenitor
ongoing projects : other SCID, Macrophage CGD,LAD,HLH,IPEX, … Osteoclast
Denfritic cell
Platelets
international collaboration
Gene therapy today
Gene addition
Non physiological regulation of the gene
Gene therapy tomorrow ??
Gene addition
Non physiological regulation
Gene repair
« off targets » Level of efficacy ??
Treatment of PIDS • Supportive care (nutrition ++) • Antiinfectious (curative/prevention) new class of antifungal, viral drugs
• Immunosuppressive !!
• Immunoglobulin substitution • Stem cell therapy • Gene therapy Titre de la présentation • Targeted therapy
Targeted therapies
(1)
• IgG substitution !!! • Adenosine deaminase – pegylated ADA • Cytokines : interferon alpha HSV encephalitis (TLR3 pathway deficiency) interferon gamma susceptibilty to mycobacterial infections (some) • Anticytokines IL1 inhibitors Interferon type I inhibitors Interferon gamma inhibitors
autoinflammatory syndromes Aicardi Gouttieres syndrome ,.. HLH
Targeted therapies
(2)
• TTC7A def.
Rho Kinase inhibitor
• CTLA4 def.
CTLA4 Ig
• APDS (PI3 kinase, gof)
mTORC inhibitor PI3K inhibitor
• STAT1 (gof)
JAK inhibitor
• STING (gof)
specific inhibitor ? JAK inhibitor
• XMEN (MAGT1 def.)
Mg ++
• More to come !!
Gof: gain of function mutations
Primary immunodeficiencies • Clinical scope • How many patients • How many diseases • Diagnosis
• Understanding pathophysiology • Treatments • Screening
• Challenges
Rationale for PID newborn screening (NBS) the SCID case Outcome of HSCT as a function of preexisting infection
No infections
Infections
European data SCETIDE/EBMT/ESID
Implementation of SCID NBS in the US
« TREC assay »
J. Puck et al with the support of the JMF Initiation of implementation elsewhere…
Conclusions and challenges • World wide access to adequate care, networks, training, role of patients’association
• NBS of all PIDs requiring early intervention (T cell PIDs, HLH, LAD,..) • Development of targeted therapies
• Development of gene therapy • Long term assessment of patients sequelae, non immune manifestations
• Pediatric to adult transition in care
Titre• de la présentation Global care (psychosocial) • A need to pursue research on these many directions
Titre de la présentation
I. André-Schmutz
B. Bader-Meunier
A. Durandy
S. Hacein-Bey-Abina
F. Mazerolles
G. Menasché
S. Blanche
M. Cavazzana
G. de Saint Basile
S. Kracker
S. Latour
A. Magerus
N. Mahlaoui
D. Moshous
B. Neven
C. Picard
P. Quartier
J.L. Casanova J.P. di Santo E. Haddad C. Hivroz P. Revy
F. Rieux-Laucat
J.P. de Villartay
E. Six
K. Imai N. Jabado F. Le Deist R. Seger
And the many international collaborators And the patients and their families !!!
