Introduction mutation involving gain or loss of entire chromosomes,

Introduction

Multiple myeloma is described as
plasma cell malignancy. Plasma cells that are activated B cells, transform into
malignant plasma cells (myeloma cells) following genetic mutation involving
gain or loss of entire chromosomes, translocation, or point mutations (Hideshima et al.).

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As a result of these genetic changes, myeloma cells will have continuous
replication, bone marrow infiltration, and production of excessive quantities
of monoclonal antibodies (M protein) (Hideshima et al.).

The accumulation of M protein can be detected in the blood and urine of
patients with MM and could lead to several complications including
hyper-viscosity, blood clots and renal failure. This review will discuss the
pathogenesis of multiple myeloma and immunotherapy approaches to treat this
disease.

 

Multiple Myeloma Pathogenesis

The infiltration of myeloma cells
in the bone marrow will have two main impacts on the disease progression. It
will alter the microenvironment of bone marrow to facilitate the growth and
migration of malignant cells. In addition, the proliferation of myeloma cells disturbs
the immune system by preventing the activation of tumor-specific immune
response and triggering immune suppressive cells in the microenvironment. Escaping
the immune response is a major hallmark of the disease progression from
asymptomatic pre-malignant stage to the malignant multiple myeloma.

 

Bone marrow microenvironment
alteration

The bone marrow microenvironment
comprises  several components including
extracellular matrix proteins such as laminin, fibronectin, and collagen; stem
cells; immune cells; osteoblast and osteoclast; endothelial cells, and bone
marrow stromal cells (BMSCs). Binding of myeloma cells to the BMSCs via
adhesion molecules triggers further production of adhesion proteins that
enhance the binding and signaling between myeloma cells and stromal cells (Hideshima et al.; Damiano et al.).

The adhesion of myeloma cells and homing in the bone marrow is very crucial for
the growth of these cells. Additionally, cytokines signaling pathways are
activated with increase production of certain cytokines and growth factors such
as IL6, IL3,TGFB, VEGF, and IGF (Dankbar et al.; Urashima et al.).

the secretion of these cytokines and growth factors by myeloma and stromal
cells will ensure the survival, proliferation of cells as well as the
development of bone dysregulation, drug resistance and angiogenesis (Hideshima et al.; Roodman).

Other proteins secreted in this
process including receptor activator of NF?B ligand (RANKL) and macrophage
inflammatory protein 1? (MIP1?), produced by stromal cells and myeloma cells
respectively. These proteins are involved in the activation of osteoclast,
cells responsible for bone resorption (Sezer et al.). While the development of
osteoblast, which forms new bone is inhibited by IL3 from myeloma cells (Hideshima et al.; Ehrlich et al.). The development and
differentiation of osteoclast and osteoblast is activated or inhibited
respectively via the activation of several pathways that produce cytokines and
ligands from myeloma and stromal cells(Hideshima et al.). The outcomes of this is
the development of bone lytic disease and bone destruction that characterized
by bone pain, pathological fractures, and hypercalcemia and subsequently renal
disease and failure.    

 

Immune system dysfunction

The progression of MM is dependent
on the alteration of bone marrow microenvironment and immune system defect. The
defect in immune response in MM patients is the hallmark of progression of the
disease from pre-malignant to the malignant stage of MM particularly the loss
of tumor-specific CD4+ T cells and natural killer cells (Kocoglu and Badros).

Additionally, there is inhibition of the regulatory T cells that have crucial
role in the regulation of immune response against foreign cells. Many other aspects
of the immune system are affected including down-regulation of tumor surface
antigen and upregulation of suppressive antigens to escape the immune reaction (Kocoglu and Badros).

 

Current Treatment

Treating MM usually start by
determining the eligibility for stem cell transplantation that is based on age
and comorbidities (Kumar).

Autologous stem cell transplantation is very effective in treating and
improving the outcome of MM. The process involves isolation of stem cells from
the patient’s own bone marrow, concentration of the stem cells in vitro, then
re-introduce them to the patient after receiving high-dose chemotherapy that
destroy cells of bone marrow. Re-infusion of the stem cells will restore the
bone marrow function, however, there is always the risk of re-infusing myeloma
cells back to the patient. While, allogenic transplantation is an option that
eliminate the risk of re-infusing myeloma cells, the risk of this treatment
itself is high and may leads to life-threatening complications(Kumar).

 

The standard approved treatment for
MM for both transplant and non-transplant patients is combination of
conventional chemotherapy, proteasome inhibitor (e.g. Velcade), and
immunomodulatory agent. Immunomodulatory agents such as thalidomide and
lenalidomide, have multiple effects on myeloma cells growth and bone marrow
microenvironment, which make them very potent and effective in fighting MM.

these agents could induce direct cytotoxicity of myeloma cells, inhibit the
adhesion molecules therefore affecting the interaction with other cells that is
crucial for myeloma cells growth and survival, and can inhibit the production
of certain cytokines secreted by myeloma or stromal cells. In addition to that,
they can activate the immune system, particularly T cells and natural killer cells
against myeloma cells. These mechanisms of action of this class of treatment
have significant effect on the disease history and outcome (Hideshima and Anderson).

 

The introduction of autonomous stem
cells transplantation and immunomodulation agents has improved the outcome in
MM patients significantly. However, majority of patients develop relapse and
refractory disease after the standard treatment. There is no agreed plan for
managing this group of patients with rapid disease progression.

Relapse stages of MM can result
from remnant myeloma cells after the treatment or clonal evolution of the tumor
cells that results in rapid growth of myeloma cells and progression of the
disease. The relapsed patients could present with rapid deterioration of their symptoms
and increase in M proteins level with risk of developing end stage renal
failure. The occurrence of relapse and its severity and duration differ from
individual to another and cannot be predicted. Development of a second relapse
event have a very poor prognosis and usually associated with more severe
symptoms and progression (figure1) (Sandra Kurtin)  

 

New Immunotherapies

Although conventional treatment
have improve the survival and outcome of multiple myeloma, it is still
incurable with majority of patients having relapse and refractory disease (Nooka et al.).

Thus the development of novel therapy is critical to cure the disease and
improve the outcome in relapsed patients.

Many immunotherapies have been
developed and currently tested in clinical trials including monoclonal antibodies,
adoptive T cell therapies, and check-point inhibitors. These immunotherapies
can be utilized to directly target the tumor cells, reverse the tumor-mediated
immune suppression or/and activate tumor specific immune response (Kocoglu and Badros).

 

Monoclonal antibodies

Myeloma cells express multiple
surface antigens, some of them can be also found on normal cells such as CD138
and some are more specific for the myeloma cells such as CD38 (van de Donk et al.).

Monoclonal antibodies can target these antigens specifically to kill the tumor
cells. Binding of the antibodies to the tumor marker induces direct
cytotoxicity and apoptosis (Kocoglu and Badros).

Additionally, these monoclonal antibodies can activate complement-mediated
cytotoxicity and antibody-dependent cytotoxicity and phagocytosis. Combination of
more than one monoclonal antibodies or combination with an immunomodulatory
agent enhance their effect significantly in fighting MM (van de Donk et al.). 

 

Check-points inhibitors

Tumor cells can escape the immune
response and suppress the activated immune cells via binding to programmed
death (PD1) receptor on immune cells using programmed death ligand. The check-point
inhibitors are molecules that can bind the PD1 receptor and prevent its
inhibition by the ligand on tumor cells. Thus the immune cells will remain
active and able to kill the myeloma cells (Kocoglu and Badros).

 

 

Adoptive T cell therapies

Advances in immunotherapy have extremely
encouraging results on the outcome of relapsed MM. Adoptive T cells therapies
are the most effective so far in clinical trials. Combination with monoclonal
antibodies will further enhance their effect. Many approaches involve the use
of T cells as targeted therapy; including the use of lymphokine-activated
killer cells, marrow-infiltrating T cells, Chimeric antigen receptor T cells,
and engineered T cell receptors(Kocoglu and Badros).

Chimeric antigen receptor T cells are
T cells with constructed receptor that contains monoclonal antibody specific
for tumor antigen as one part and the other segment is intracellular domain
responsible for activation of the immune cells against tumor cells. The main limitation
of this approach is the off-target effect possibility and side effect such as
tumor lysis syndrome and cytokine associated syndrome (Kocoglu and Badros).

Engineered T cell receptors is the
most potent and effective approach of T cell therapies in addition to lower
risk for severe side effects and non-specific activity (Kocoglu and Badros).

Biphasic T cell engager (BiTE) is the engineered receptor that has one segment specific
for T cell receptor and the other is specific for tumor cell antigen. Therefore,
BiTE will specifally binds to both T cells and tumor cells at the same time and
activate the specific immune response. BiTE  has higher efficiency and potency in the
treatment of MM than other agents, which gives a great promise to manage and
cure this disease (Kocoglu and Badros).

 

Oncolytic virotherapy

Oncolytic virotherapy is a targeted
tumor therapy, where oncolytic viruses can specifically target, infect and kill
tumor cells without harming the normal cells. The viruses will enter the tumor
cells, replicate in them resulting in cell lysis and release of viral particles
and tumor specific antigens. The release of these markers attract immune cells
to attack infected and non-infected tumor cells.  Several viruses with oncolytic activity are
recognized (Stief and McCart).

Anti-viral immune response is one of the major challenges facing this therapy,
however, patients with MM have dysfunctional immune system which make them the
ideal patients for oncolytic virotherapy (Kreitman et al.).

 

Many tumor markers (e.g. CD38 and
CD46) and signaling pathways (e.g. ras-raf1 pathway) that are involved in MM,
can be targeted by several oncolytic viruses (Stief and McCart).

Preclinical studies are utilizing several oncolytic viruses for the treatment
of MM. these include replicating adenovirus, vaccinia virus, measles virus, and
vesicular stomatitis virus.

 

Replicating adenovirus

Adenovirus is double stranded DNA
virus and widely used for gene therapy and oncolytic virotherapy. Unlike the
non-replicating adenovirus that is used for gene therapy, the replicating
adenovirus is modified and engineered to be used as cancer therapy by deleting
the virus’s critical genes, inserting tumor-specific promoters and genes that
improve virus cell entry (Stief and McCart).

Gene modification of this virus can allow selective targeting of tumors with
specific mutation or promoters such as P53 mutation, Rb mutation or tyrosinase (Cascallo et al.; McCart et al.; Post et al.).

The ability of this virus to be modified and retargeted to specific cell marker
could be useful in targeting myeloma cells with CD38 or CD46 surface proteins (Stief and McCart).

 

Vaccinia virus

Vaccinia virus is large double
stranded DNA, member of the poxviridae family. The WR strain of vaccinia virus is highly potent in its
oncolytic activity compared to the vaccine strain of vaccinia virus that is
attenuated (Zeh
and Bartlett; Kim et al.). Modification of WR strain by
deleting the Thymidine kinase gene make it more specific for tumor cells as
they have high cell division rate. WR strain can efficiently infect myeloma
cells like other viruses.

 

Measles
virus

Measles
virus is a single-stranded RNA virus, it is the most common virus used for MM. Although
it is unable to relpicate in normal cells in the attenuated vaccine strain ( Edmonston
B), however, it is highly potent as oncolytic virus. It selectivly targets
CD46, and found to relpicate and infect best when CD46 is highly expressed in
tumor cells as in myeloma cells. The ability to modify the measles virus with
reverse genetic system will facilitate the production of more potent and more
specific measles oncolytic virus.

 

Vesicular
stomatitis virus (VSV)

VSV
is a double-stranded RNA virus that has wid tissue tropism. It target tumors
with actvated ras-raf1 signalling pathways. The use of this virus is found to
be effecitive and safe in patient with MM (Stief and McCart).

 

Improving virotherapy

Modifying oncolytic viruses and retargeting them to specific
markers expressed on tumor cells will improve both the efficacy and the safety
of the therapy.

Antiviral immune response is a great barrier against the
oncolytic activity. Using cell carriers is one way to avoid this barrier. T
cells can be infected with the oncolytic virus and then administered to the
patient. Fusion between the T cells and the tumor cell will allow the transfer
of the virus and escape the pre-existing antiviral antibodies(Ong
et al.). The other method to overcome
antiviral immune response is to combine the oncolytic virotherapy with other
immunomodulatory agents that could enhance the activation of anti-tumor immune
response.

 

Conclusion

Multiple
myeloma is incurable malignancy that associated with immune suppression. The current
approved treatment have improve the survival of this disease, however, the
development of relapse and refractory disease remain a huge barrier to cure
this disease. The use of different immunotherapies in clinical trials shown a
lot of promises for patients with relapses. Oncolytic virotherapy while it is
still experimental, it has a lot of promises especially if used in combination
with other treatment such as immunomodulatory agents.