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Plasmapheresis
immune globulin(?)
danazol
Corticosteroids,
intravenous immune globulin,
https://t.me/med1917
anti-D immune globulin,
danazol, vinca alkaloids
Platelet
Antibody
against CD20,
intravenous
staphylococcal
protein A(?)
FCγ
receptor
Platelet
transfusion
Splenectomy
Bone marrow
Autoimmune hematological disorders 313
Macrophage
B-cell
Antibody
against CD154
Figure21.7 Standard and novel treatment strategies in ITP. Standard treatments include corticosteroids, intravenous immunoglobulin,
danazol, and vinca alkaloids. Their sites and modes of action are illustrated. New therapies include monoclonal antibodies against CD154
(CD40ligand) and CD20 (on B- cells, leading to transient B- cell depletion). Reproduced from Cines DB, Blanchette VS. (2002) Immune
thrombocytopenic purpura. New England Journal of Medicine, 346, 995–1008.
T-cell
vinca alkaloids, danazol, azathioprine, combination chemotherapy, and dapsone.
Azathioprine,
cyclophosphamide,
cyclosporin,
corticosteroids,
Now that we have a clearer understanding of the immuno-
logical mechanisms involved in autoimmune disease, we
Thrombopoietin
corticosteroids
have started to develop more targeted therapies. We are now
Targeted versus untargeted therapies
forautoimmune disease
Until now, most of our treatments for autoimmune disease
have been untargeted and unselective in their modes of
action. In disorders such as ITP, the therapeutic aim has
been to induce global immunosuppression in the hope that,
as part of this process, the ITP- related component of the
immune system will be suppressed and that this will help
reduce the quantity of autoantibody produced. For antibodymediated autoimmune diseases, what remains unclear is
whether the B- cell population that is generating the antiplatelet autoantibody is the primary problem, or whether
events downstream, such as those involving antigen presentation or T- cell regulation, are disturbed, and simply driving
the passive B- cells, resulting in the autoantibody phenotype.
developing treatments designed to target Tother effectors within the immune system. For ITP, these
include Campath-
1H and anti- CD20. Although these agents
are not entirely specific because they deplete the B- cell compartment, they should reduce the quantity of autoantibody
produced. Other therapies that may be of benefit in ITP are
mycophenolate mofetil and anti- CD40ligand.
Campath- 1H
Campath- 1H is a humanized IgG monoclonal antibody
that targets the CD52 antigen, present in mature human
lymphocytes (T- and B- cells) and monocytes. Campath- 1H
is effective in the treatment of malignant B- cell disorders,
especially B- cell chronic lymphocytic leukemia, in which it
has been shown to be effective in clearing lymphocytes from
both blood and bone marrow.
cells, B- cells, and
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314 Molecular Hematology
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Campath- 1H has been used in a variety of autoimmune
diseases, including rheumatoid arthritis, vasculitis, and
Wegener granulomatosis. There is ongoing interest in the use
of Campath- 1H for the treatment of autoimmune hematological disease that is refractory to first- and second- line
therapies. One recent study of the use of Campath- 1H in
autoimmune neutropenia, autoimmune hemolytic anemia,
pure red cell aplasia, ITP, and combined hemolytic anemia
and ITP (Evans syndrome) has shown responses in 15 of 21
patients treated; in six patients, the response was sustained.
Campath- 1H therefore appears to be an effective agent in
severe refractory autoimmune disease. The drug is well
tolerated, but because it can precipitate bleeding during
administration, it should not be given in the presence of
active bleeding (or active infection).
Anti- CD20 monoclonal antibody therapy
Rituximab, a genetically engineered chimeric human/
mouse anti- CD20 monoclonal antibody, has been developed as a treatment for B- cell lymphoproliferative disease
(non- Hodgkin lymphoma). The antibody is an IgG κ immunoglobulin comprising murine light- and heavy- chain
variable- region sequences and human constant- region
sequences. The antigen- binding domain binds to the CD20
antigen on B- cells, while the Fc domain mediates B- cell lysis
through recruitment of immune effector cells. Because of its
specificity for B- cells, rituximab has been viewed as a potential treatment for autoimmune disease, the rationale being
the reduction or elimination of autoantibody- producing
B- cells with concomitant improvement of the autoimmune
disease. A recent study by Stasi and colleagues reports on the
efficacy of rituximab in the treatment of 25 patients with
chronic refractory ITP. Patients were treated if their platelet
counts were below 20 × 109/L irrespective of symptoms, or at
higher platelet counts if bleeding or bruising was problematic. All patients had received between two and five previous
treatments; eight had failed splenectomy. Rituximab was
administered in the same manner and dose as that used in
non-
Hodgkin lymphoma. After four courses, 40% of patients
achieved a platelet count of at least 50 × 109/L; five achieved
complete remission (platelets >100 × 109/L) and five partial
remission (platelets 50–100 × 109/L). Responses were seen
during treatment with rituximab, with a peak response up to
four weeks after the end of treatment; 28% had responses
that lasted for more than six months.
The results suggest that the use of rituximab resulted in
responses similar to those given by other second- line agents
used in ITP (including vinca alkaloids, cyclophosphamide,
and azathioprine), around 40–50%, but sustained responses
to these agents are usually seen in fewer than 20% of patients
(i.e. lower than for rituximab). Rituximab would appear to be
useful for some patients with chronic symptomatic refractory
ITP in whom there is a definite need to elevate the platelet
count to a safe level.
The mechanism of action of rituximab in ITP has been
+
assumed to be due to selective depletion of CD20
B- cells
that subsequently affect autoantibody development. This
concept was recently shattered when it was demonstrated,
using a variety of sophisticated techniques to analyze T- cell
parameters, that only when the abnormal T- cell subsets were
normalized was rituximab therapy effective. The reasons for
these results are not clear, but may relate to how B- cell populations may be either important in maintaining autoreactive
T- cell activation patterns or, by decreasing the total mass of
B- cells, may cause a collapse of autoreactive T- cell stimulation and normalization of the T- cell repertoire even as the
B- cells begin to return months after the therapy. What is
perhaps more enlightening is the demonstration that the
abnormal Treg populations are indirectly targeted by rituximab therapy; the anti- CD20 treatment reverses the Treg
deficiency in patients with ITP and normalizes the autoimmunity. Taken together, these studies truly lend credence to
the notion that attacking T- cells in ITP, even indirectly by the
destruction of B- cells, is perhaps the only way to reduce
platelet destruction effectively.
Costimulatory blockade
Therapies such as Campath- 1H and anti- CD20may not
produce lasting remission if the autoimmune B- cells are
driven by dysregulated T- cells, and a novel agent, CTLA4- Ig, has been evaluated in psoriasis in an attempt to
block T- cell costimulation, thereby inducing anergy in
the T- cell compartment. CTLA- 4- Ig, a fusion protein
between CTLA- 4 and the Fc portion of human immunoglobulin, binds to B7- 1 and B7- 2, blocking T- cell costimulation (Figure21.8). This small trial showed that, at least
within this group of patients, CTLA- 4- Ig was able to
improve the disorder and was shown to be safe. CTLA- 4- Ig
may have applications within other autoimmune disorders, including ITP. If a drug such as CTLA-
4- Ig were
shown to be effective in ITP, not only would it provide an
additional targeted treatment modality, but would also
provide useful evidence of T- cell dysfunction in this disease.
Interestingly, the CTLA- 4 gene has been mapped as a susceptibility gene in autoimmune thyroid disease and type 1
diabetes in humans.
Other options: Helicobacter pylori eradication
This bacterium is the main cause of gastritis and peptic
ulcer disease. It has also been implicated in the development of gastric adenocarcinoma and mucosa- associated
lymphoid tumors and in some autoimmune disorders.
Previous studies of H. pylori in ITP showed improvement
in platelet counts after eradication of the bacterium in
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Antibody
Fc receptor
Cytokine proteins orchestrate
https://t.me/med1917
CTLA-4
Autoimmune hematological disorders 315
Y
Y
Y
X
Y
Antigen-presenting
cell
Figure21.8 Costimulatory blockade may be beneficial in some autoimmune diseases. CTLA- 4linked to human immunoglobulin Fc
(CTLA- 4- Ig) blocks the critical second signal between antigen- presenting cells and T- cells, resulting in T- cell anergy. This should result in a reduction
in antibody production and amelioration of disease if the autoimmune disease is antibody- mediated. CTLA- 4- Ig treatment has been shown to be
of benefit to patients with psoriasis. Similarly, anti- CD40ligand also blocks the second signal with similar results, and has been shown to be of
value in refractory ITP.
patients shown to be positive for H. pylori. More recently,
Emilia and colleagues looked for the presence of H. pylori
in 30 patients with chronic refractory ITP. Helicobacter
pylori was found in 13 of 30 patients (43.3%). Standard triple therapy for H. pylori eradication resulted in a complete
response in 4 of 12 patients in whom the bacterium was
eradicated, and partial response in 2 of 12 (16.6%). The
responses were maintained for a median of 8.33 months. In
addition, there are other anecdotal reports of improvements in platelet counts in adults and children with ITP
after eradication of H. pylori. Larger studies are required to
confirm these earlier findings, but from the available data,
triple therapy appears to offer a non- immunosuppressive
therapy for patients with refractory ITP and possibly other
autoimmune diseases.
On the other hand, platelets express Toll- like receptor
(TLR)4 and this has been shown to be responsible for the
thrombocytopenia induced by lipopolysaccharide administration invivo. It now appears that bacterial products such as
lipopolysaccharide together with IgG bound to platelets can
significantly enhance Fc- mediated platelet phagocytosis by
mononuclear phagocytes. This suggests that infectious
agents, in combination with antiplatelet antibodies, could
affect platelet destruction in vivo and may be at least one
explanation of why thrombocytopenia worsens in some
patients with ITP during infections and, alternatively,
resolves in other patients with ITP who are treated with bacterial eradication therapy.
Thrombopoietin receptor agonists
Thrombopoietin receptor agonists (TPO- RAs) are a class of
medications used in the treatment of ITP. They work by
stimulating the production and maturation of platelets from
T cell B cellT cell B cellT cell
megakaryocytes in the bone marrow. There are three TPORAs that are currently approved for the treatment of ITP:
Eltrombopag: Eltrombopag is a small molecule TPO- RA
medication used to treat patients with ITP who have not
responded to other treatments, such as corticosteroids. It
works by stimulating the production of platelets from
megakaryocytes in the bone marrow. It is taken orally as
tablets, with the dose adjusted based on the patients’ platelet count.
Romiplostim: Romiplostim is a peptibody TPO- RA. It works
by mimicking the action of thrombopoietin, a natural hormone that stimulates the production of platelets from
megakaryocytes in the bone marrow. Romiplostim is
given as a subcutaneous injection once a week, with the
dose adjusted based on the patients’ platelet count. The
medication has been shown to increase the platelet count
in patients with ITP and reduce the need for other
treatments.
Avatrombopag: Avatrombopag is a more recent small mol-
ecule TPO- RA used to treat thrombocytopenia in adults
with chronic liver disease who are scheduled to undergo
a medical or dental procedures and ITP. It works by
stimulating the production of platelets from megakaryocytes in the bone marrow. Avatrombopag is taken
orally as tablets, with the recommended dose being
60 mg once daily for five days before the scheduled procedure (Figure21.9).
TPO- RAs are generally well- tolerated but may be associated with some side effects, such as headache, fatigue, nausea, and muscle pain. TPO- RAs may also increase the risk of
blood clots in some predisposed patients, so patients taking
these medications need to be monitored closely for signs of
thrombosis.
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316 Molecular Hematology
OH
3
PromactaNplateThrombopoietin
(C)(B)(A)
https://t.me/med1917
O
Fc
domain
Figure21.9 Structures of thrombopoietin (TPO) and synthetic c- mpl ligands. (A) Native TPO is a 332- amino- acid glycoprotein with a
molecular mass of 60–70 kDa. It is the major humoral regulator of platelet production. (B) Nplate (romiplostim) is a 60- kDa synthetic “peptibody”
that does not share any amino acid homology to native TPO. It comprises a human immunoglobin Fc domain linked via polyglycine to two divalent
mpl- binding peptide regions. The Fc component extends the half- life of the drug in the circulation, while the peptide “warhead” binds to the TPO
receptor, c- mpl, and activates signaling. (C) Promacta (eltrombopag) is an orally bioavailable hydrazone small molecule with a molecular mass of
546
Da. Unlike TPO and Nplate, which bind the extracellular domain of c- mpl, Promacta is reported to bind to the transmembrane region of
c- mpl. From Kuter DJ. (2007) New thrombopoietic growth factors. Blood, 109, 4607–4616. © American Society of Hematology.
Novel therapies for the treatment
ofITP
domain
(including spacer regions)
OH
NH
N
H
C
3
O
NN
CH
3
CH
treatment of chronic ITP in adults who have not responded
to other treatments.
Neonatal Fc receptor (FcRn) blockade: the normal function
Human and animal studies have been helpful in learning
how the immune system works in both health and disease,
but can such information be translated into better patient
care? Until recently, the treatment strategy for ITP has been
to induce global immunosuppression in the hope that the
autoimmune process may be abrogated or stopped. In some
cases, treatment is effective, but it is clear from longitudinal
follow- up studies of patients with ITP that there is very significant morbidity and mortality associated with our current
treatments. Infection plays a major role in the death of
patients with autoimmune disease, and such fatalities are
usually induced by immunosuppression. Now that we have a
better understanding of the components of the immune system and how these interact in disease, we should be able to
develop targeted therapies that aim to modify specific components of the immune system while leaving most of the
immune system intact and able to fight infection.
Such therapeutic advances are in fact being made, and
many of these have been developed through knowledge concerning specific components of the immune system in disease. We have now been able to develop targeted therapies
for ITP and the following list is a summary:
Fostamatinib: Fostamatinib is an oral spleen tyrosine kinase
(SYK) inhibitor that has been shown to increase platelet
counts in patients with chronic ITP. It works by blocking
the activation of immune cells that destroy platelets.
Fostamatinib was approved by the US FDA in 2018 and in
2019 by the European Medicines Agency (EMA) for the
of FcRn is to prolong the half- life of IgG by recycling IgG
from endothelial endosomes. By blocking FcRn IgG recycling is prevented, which reduces both normal and pathologic IgG levels. Efgartigimod is a human IgG- derived Fc
fragment mutated at 5 residues, which increases its affinity
for FcRn. This therapy has been approved for myasthenia
gravis and has completed trials in primary ITP.
B- cell inhibitors: Newer B- cell inhibitors, such as ofatu-
mumab, target B- cells, which are involved in the production of autoantibodies that attack platelets in ITP. These
medications have shown promising results in increasing
platelet counts in patients with chronic ITP.
Bruton tyrosine kinase (BTK) inhibitors: BTK inhibitors,
such as ibrutinib and acalabrutinib, have been shown to
reduce autoantibody production and increase platelet
counts in patients with chronic ITP. However, platelet
aggregation with these drugs may increase bleeding in
patients with ITP. Recently, studies with rilzabrutinib have
shown efficacy in ITP with no platelet aggregation noted.
Complement inhibitors: Complement inhibitors, such as
sutimlimab, target the complement system, which is
involved in the destruction of platelets in ITP. Studies so far
appear promising with 57% response rate in ITP at 14 days.
Novel immunomodulatory agents: Other novel immu-
nomodulatory agents, such as T- regulatory cell inducers,
PI3K inhibitors, and checkpoint inhibitors, are currently
being investigated for the treatment of ITP and show
promising results in clinical trials.
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Autoimmune hematological disorders 317
Antibody molecule
https://t.me/med1917
Anti-FcγR
Anti-FcRn
syk inhibotor
Anti-FcγRIIb
Macrophage
(AP cell)
Complement
inhibition
Tc cell-mediated
platelet destruction
Complement
Platelet
phagocytosis
CD80
MHC II
CD40 CD154
Anti-CD40L
CD80
CD28
CD28
TCR
+
CD4
T cell
Anti-Blys (BAFF)
Cytotoxic
T cell
Rituximab
B7
CTLA4
CD154 CD40
IL-2
IFN-γ
Anti-CD40L
Anti-CD20
CTLA4-ig
Thrombopoietin
receptor agonists
CD154
CD40
CD8
TCR
MHC I
CD28
CD80
Platelets
BTKI
B cell Plasma cell
Megakaryocyte
Platelet autoantibody production
Anti-CD38
Daratumumab
Impaired megakaryocyte
maturation
Reduced platelet formation
Legend
Normal platelet
Dying platelet
Complement
Figure21.10 Shows the sites of action of novel targeted therapies. Stimulatory drugs are shown in green and inhibitory agents are in red.
Conclusions
Autoimmune diseases are complex immunological disorders
affecting 7% of the population. Until recently, our understanding of the pathogenesis and treatment of these disorders was
severely limited. However, with a greater understanding of the
immune system in health and autoimmune disease, we are able
to identify underlying abnormalities leading to the development
of autoimmunity. With this new knowledge, we have been able
to modify our therapies by replacing nonpressive treatment with more subtle targeted therapies.
selective immunosup-
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318 Molecular Hematology
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Up and Long- Term
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Chapter22
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Molecular therapeutics
inhematology: gene therapy
William M. McKillop1 and Jeffrey A. Medin
1
Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA
2
Departments of Pediatrics and Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA
Introduction, 321
General comments on gene transfer/therapy, 322
Viral vectors for gene transfer, 323
Oncoretroviral gene transfer, 324
Lentiviral gene transfer, 330
Adenoviral gene transfer, 332
Introduction
Approved clinical investigation of gene transfer into
humans began with the seminal trial of Rosenberg and colleagues, which involved transplantation of genetically
altered lymphocytes into patients. This landmark trial was
closely followed by studies of therapeutic gene transfer
using other hematopoietic cells. Studies involving the
blood system have therefore been central to the development of human gene therapy. Gene marking or gene therapy protocols are under increasingly intensive investigation
worldwide as the field has grown to over 3600 approved
clinical trials by the summer of 2023. Gene therapy trials
represent nearly 1% of all planned trials in 2023, up from
just 0.25% of all trials in 2014. Importantly, some of the
first successes in the entire field of gene therapy have
recently been realized. Shenzhen SiBiono GeneTech Co.
Ltd. obtained a drug license from the State Food and Drug
Administration of China for Gendicine, an adenovirusbased therapy designed to treat head and neck squamous
cell carcinoma in 2003. However, it was not until 2012 and
the European Medicines Agency (EMA) approval of
UniQure’s Glybera, an adeno- associated virus- based therapy designed to treat lipoprotein lipase deficiency, that a
gene therapy treatment strategy was approved in the West.
In 2016 Strimvelis, a lentiviral vector used to treat severe
combined immune deficiency, became the second gene
therapy approved in Europe. In August 2017, the U.S. Food
and Drug Administration (FDA) approved Kymriah
Adeno- associated virus gene transfer, 333
Herpes simplex virus gene transfer, 334
Genetic immunotherapy, 334
Methods to improve gene therapy safety and suicide gene therapy, 337
Conclusions, 339
Further reading, 339
(CTL019, tisagenlecleucel), a chimeric antigen receptor
T-
cell (CAR- T) therapy targeting CD19 for treatment of
pediatric and young adult patients with relapsed/refractory B- cell acute lymphoblastic leukemia (ALL). Several
other CAR- T therapies have followed close behind in what
has become a fast- evolving field in modern medicine.
Since hematology has contributed so much to the genesis
and progression of human gene therapy, it is the purpose of
this chapter to reiterate both the inherent promise and revisit
some of the remaining obstacles posed by the application of
gene transfer into humans employing hematopoietic cells.
While some definitive successes have been obtained; important issues still remain.
Pluripotent hematopoietic stem cells (HSCs) are attractive
targets for gene therapy in humans because of their capacity
for self- renewal and the systemic multilineage distribution of
their progeny (Figure 22.1). Sustained expression of
transgenes at clinically relevant levels in the progeny of HSCs
would result in novel and potentially curative treatments for
a wide range of blood diseases, including, for example,
hemophilia A and B, hemoglobinopathies, hereditary
immune deficiencies, and some lysosomal storage disorders.
Even the partial correction of such blood disorders would
have a substantial impact on the transfusion needs of the
affected populations. Other hematopoietic cell subpopulations are also important targets for gene therapy. This discussion examines some of the targets of gene therapy involving
the hematopoietic system and outcomes mediated by a variety of gene transfer mechanisms.
2
Molecular Hematology, Fifth Edition. Edited by Drew Provan and Hillard M. Lazarus.
© 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.
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321
322 Molecular Hematology
Add genetically
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Remove
hematopoietic
stem cells
Figure22.1 Ex vivo transduction of hematopoietic stem cells (HSCs). HSCs can be harvested from patients and vector transduced. The
transduced cells are returned to the patient, where all blood cells maturing from the gene- modified hematopoietic stem cells retain a copy of the
transgene. In theory, this gene transfer method could help distribute the gene product throughout the body at clinically relevant levels.
Gene therapy has the potential to revolutionize medical treatment by selectively repairing or augmenting the expression of
defective genes by the insertion of new genetic material. To
date, selective repair of genetic defects within the host genome
has proven to be a very difficult endpoint; however, genome
editing technologies capable of such repair are now being
investigated. Targetable DNA cleavage reagents including
zinceffector nucleases (TALEN) cut specific sequences of DNA
allowing for homologous recombination with recombinant
exogenous DNA and the introduction of an edited sequence
at the target site. However, ZFN- based strategies appear to
suffer from context- dependent recognition site binding.
There is also some degeneracy in the TALEN- DNA binding
specificity, both nucleases are highly sensitive to DNA methylation, and they both require very specific protein- DNA
interactions. A third nuclease- based strategy dependent
modied virus
Harvest and return
to patient
General comments ongene transfer/
therapy
finger nucleases (ZFN) and transcription activator- like
Stem cells proliferate
and gene is distributed
solely on nucleic acid base pairing is the clustered regularly
interspaced short palindromic repeats/CRISPR- associated
protein 9 (CRISPR/Cas9) system. CRISPR/Cas9 offers an
easy- to- engineer and particularly efficient system for gene
editing, but off- target effects are still possible as the short recognition sequences used in the system are rarely unique in the
genome. Although tremendously promising, protocols using
these gene editing strategies are still relatively new in the field.
To date, only 15 ZFN- based, 14 TALEN- based, and 67
CRISPR/Cas- based trials have been registered with regulatory agencies around the world. Of these, the gene editing
study furthest through the regulatory pathway is the Vertex
and CRISPR Therapeutics collaboration using CRISPR to
inactivate BCL11A, a repressor of fetal hemoglobin, to treat
beta- thalassemia and sickle cell disease. They have now
reached their Phase I/II/III trial goals of treating more than
70 patients. Of the 44 patients with transfusion- dependent
beta- thalassemia, 42 were transfusion- free with follow- up
ranging from 1.2 to 37.2 months after treatment. These
patients demonstrated substantial mean increases in fetal
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