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European Biopharmaceutical Review
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In the fight against cancer, the greatest weapon we have is our body,
with Biological Response Modifiers moving us one step further in the
future of therapeutic medicine
Modulating our immune system response to tumours through so-called
Biological Response Modifiers (BRMs) is a powerful approach in the
cancer treatment landscape. There are excellent reasons for the current
excitement, since molecules such as monoclonal antibodies or vaccines
confer specificity when attacking the tumour cells. In addition, BRMs
have the ability to create an anti-tumour immunological memory, and to
stimulate our body to fight against the malignancy that emerged from it
in the first place.
The National Cancer Institute from the National Institutes of Health
defines biological cancer therapies as ones that modulate the body’s
immune system to fight cancer. This modulation is performed by BRMs that
include molecules naturally produced by our own body, such as
interferons, interleukins or monoclonal antibodies. Several other
therapeutic approaches – such as vaccines, gene therapy or cell therapy –
could also be considered as BRMs.
Anti-tumour effects of BRMs can be both direct, when BRMs either have
direct cytotoxic effects on tumour cells or directly impede tumour
proliferation and survival; and indirect, when BRMs either influence the
immune response to eliminate cancer cells or alter essential processes
for cancer progression such as tumour angiogenesis.
Monoclonal Antibodies
Monoclonal antibodies (mAbs) are large proteins produced by the immune
system to identify and label foreign invaders. Since tumour cells show a
different phenotype compared to normal healthy cells, antibody-based
therapy relies on the ability of mAbs to recognise these subtle
differences.
mAbs are designed to detect and bind to a specific antigen of the tumour
cell. Once the target cell is labelled, the mAbs can trigger a variety
of mechanisms to destroy the malignant cell. On the one hand, mAbs can
directly modulate the immune response. mAbs such as Rituximab can
provoke the elimination of tumour cells by triggering immune system
mediated mechanisms like B cell activation; another example of direct
modulation of the immune response is the mAb Ipilimumab, which by
blocking the CTL-4-mediated T-cell repressing signal, enhances the
immunological anti-tumour response (1).
On the other hand, mAbs are also able to directly block survival
signalling cascades, as well as to induce apoptotic pathways in the
tumour cells. Some examples of therapeutic mAbs using these mechanisms
are Cetuximab or Trastuzumab (2). In addition, mAbs such as Gemtuzumab
are used as carriers of cytotoxic molecules that are specifically
delivered to tumour cells to eliminate them (3). Finally, mAbs like
Bevacizumab can block biological processes that are essential for cancer
progression, such as the induction of vascularisation (inhibiting the
VEGF signalling) or the attachment to distant tissues and metastasis
(4).
There are currently over 15 mAbs approved for cancer therapy by the
various regulation authorities around the world. Furthermore, hundreds
of clinical studies are currently under way trying to develop the next
generation of specific mAbs that will lead the fight against cancer (5).
Interleukins
Interleukins (ILs) are a group of over 30 cytokines that are key
signalling molecules to modulate inflammation and immunity. They induce
proliferation, activation, migration and differentiation of immune
cells. Contrary to mAbs, the anti-tumour effect of cytokines is
non-specific.
The most significant case is interleukin-2 (IL-2), the first-ever
immunotherapy approved by the Food and Drug Administration and nowadays
indicated for the treatment of several malignancies including melanoma,
kidney cancer and leukemia. By modulating the homeostasis of T cells,
IL-2 is essential in the establishment of the immunologic memory, as
well as in the identification by the immune system of self and non-self
(6).
Various ILs are currently being tested for cancer treatment in a variety
of clinical assays both alone or in combinational therapies as
adjuvants, including in the brain, prostate and colorectal cancers,
leukaemia and lymphoma (5).
Interferons
Interferons are another group of cytokines produced by cells in response
to pathogen infection and malignant transformation. Their anti-tumour
effects are either direct on the target cells, by reducing protein
synthesis and blocking its cellular proliferation; or indirect, by
enhancing the response of the immune system against the transformed cell
and its elimination, as well as by blocking tumour angiogenesis.
Interferon-alpha is the only interferon type approved for cancer
treatment. It is being used for the treatment of several cancers
including: renal cell carcinoma; multiple myeloma; and some types of
leukemia (7). In addition to the many ongoing clinical trials testing
interferonalpha as the therapeutic agent (alone or in combination) in
various cancers including kidney, lung or bladder, there are several
other studies now testing interferon-beta, including one protocol of
gene therapy in liver cancer (5). Finally, the recently described
interferon lambda has shown a significant anti-tumour activity in
preclinical studies, envisioning a promising future in cancer therapy
since it only acts in a small fraction of cells potentially, showing
fewer sideeffects than current interferon-based therapy (7).
Colony-Stimulating Factors
A third group of cytokines – colonystimulating factors (CSFs) – are
produced and secreted to stimulate the division of bone marrow stem
cells and their differentiation into specific blood cells (platelets,
white cells or red cells). Their administration induces blood cell
production, which in turn is highly beneficial for cancer patients since
their blood cell count is severely damaged by most current cancer
therapies. Therefore, CSFs are prescribed mainly as adjuvants to reduce
the side-effects associated to cancer treatment toxicity.
Several CSFs are currently being used in cancer therapeutic protocols
tumours of the uterus, lung, esophagus and many others. Some highlighted
examples of used CSFs are: the granulocyte CSF, filgrastim, and the
granulocyte macrophage CSF, sargrasmostin, which stimulate the formation
of white blood cells and significantly reduce the risk of infection and
sepsis for cancer patients; the erythropoietin known as epoetin, which
increases the number of red cells, consequently reducing the incidence
of anemia; and interleukin 11 that stimulates megakaryocyte maturation
and platelets production, reducing the need of platelets transfusions
(8-10).
Cancer Vaccines
Following the same biological principles used by anti-pathogens
vaccines, the aim of cancer vaccines is to educate the immune system
into the recognition of tumour cells for their elimination. The ultimate
goal is to develop vaccines that are able to induce long-lasting and
powerful T-cell responses with the capacity of generating immunological
memory.
Most of the cancer vaccines are administered after the tumour is
diagnosed. There are only two preventive cancer vaccines currently
available: the vaccine that prevents the infection of the hepatitis B
virus, which causes 80 per cent of all primary liver cancers (11); and
the vaccine that blocks the appearance of cervical cancer provoked by
the infection of human papilloma virus (12).
The only approved therapeutic vaccine is Sipuleucel-T, which is based on
the use of the patient’s own white blood cells and is designed for
prostate cancer (13). Although no antigen-based therapeutic vaccine has
reached the market yet, various approaches are being developed by
investigators. There are several clinical trials showing success in late
clinical phases for the treatment of several tumour malignancies
including follicular lymphoma, non-small cell lung cancer and prostate
cancer (5).
Cellular Immunotherapy
Dendritic Cells
Dendritic cells (DCs) have the main function of processing and
presenting antigens to lymphocytes. DCs play a crucial role in
presenting tumour antigens to T-cells, in this way initiating the immune
response against cancer. The usage of DCs as anti-cancer treatment is
based on the development of cancer vaccines. The haematopoietic
progenitors of DCs are extracted from the patient and cultured ex vivo
in the presence of cytokines and tumour-specific antigens. Cultured
matured DCs are re-injected into the patient and will migrate to the
lymphnodes to present the tumourantigen to T-cells to trigger the
antitumour immune response (14). There has been over 200 clinical trials
with DC vaccines, and many trials are currently being opened to develop
DC-based vaccines to treat various indications, including colorectal,
kidney or head and neck cancers (5).
T-Cells
Antigen presentation by specialised cells, including DCs, activate the T
lymphocytes which will mediate the tumour-specific immune response to
eradicate the malignant cells. T-cells can be used in cancer
immunotherapy following two main approaches. On one side, T-cells
residing in the tumour can be isolated from a biopsy and expanded ex
vivo. Once grown, these tumour-specific T-cells are infused into
patients in a therapeutic regime accompanied with immunodepletion of the
patient. This approach has been shown to be effective in clinical
studies in the treatment of metastatic melanoma (15).
An additional approach is based on the genetic engineering of T-cells
prior to patient infusion so they overexpress a specific T-cell receptor
(TCR) with high affinity and specificity to a given tumour target
antigen. There are several ways to accomplish the overexpression of a
specific TCR in the lab. The most common consists of isolating T-cells
residing in the tumour and infecting them ex vivo with a lab-generated
vector virus encoding the desired TCR. Once these activated T-cells
expressing the TCR are expanded, they can be infused into the patient to
potentiate the specific anti-tumour immune response (15).
T-cell based immunotherapy – in particular, the genetic engineering
approach – is one of the most promising biological therapies for cancer
as a subtype of the promising field of gene therapy. In accordance to
its relevance and potentiality, many clinical trials are using this
approach to evaluate its anti-tumour effects including prostate, breast
and liver cancers as well as leukemia and lymphoma (5).
Natural Killer Cells
Similarly to T-cells, the natural killer (NK) cells and the natural
killer T (NKT) cells are able to identify tumour cells and target them
for elimination. Their killing capacity is kept under control through a
delicate balance between a complex network of repressive and activating
signals that normal cells are able to regulate with perfection. However,
tumour cells tilt the balance by either losing the repressing
signalling or upregulating the activating cascades.
They are currently being applied in cell therapy protocols in which
either the whole haematopoietic stem cell population or
laboratory-expanded populations of isolated NK/NKT cells are
transplanted from a matching donor to the cancer patient (16).
Conclusion
The field of biological therapies is one of the most active and
promising in cancer treatment. Both the tumour specificity and its
capacity to generate anti-tumour memory are powerful presentation
credentials for a therapeutic approach that possesses the solid
foundation of decades of clinical studies behind it. It has the
potential to become a reference in the future of medicine comprising
gene and cell therapies, as well as personalised medicine.
References
1. Scott AMK et al, Antibody therapy of cancer, Nat Rev Cancer 278,12: pp278-287, 2012
2. Hudis CA, Trastuzumab-mechanism of action and use in clinical practice, N Engl J Med, 357: pp39-51, 2007
3. Niculescu-Duvaz I, Technology evaluation: gemtuzumab ozogamicin, Celltech Group, Curr Opin Mol Ther, 2(6): pp691-696, 2000
4. Ferrara N et al, Discovery and development of bevacizumab, an
anti-VEGF antibody for treating cancer, Nat Rev Drug Discov 3(5):
pp391-400, 2004
5. Visit: www.clinicaltrials.gov
6. Smith KA, Interleukin-2: inception, impact, and implications, Science 240(4856): pp1,169-1,176, 1988
7. Lasfar A et al, Interferon Lambda: A new sword in cancer immunotherapy, Clin Dev Immun: pp1-11, 2011
8. Crawford J et al, Final results of a placebocontrolled study of
filgrastim in small-cell lung cancer: Exploration of risk factors for
febrile neutropenia, Sup Cancer Ther 3(1): pp36-46, 2005
9. Fisher JW et al, Erythropoietin production by interstitial cells of
hypoxic monkey kidneys, Brit Jou Hem 95(1): pp27-32, 1995
10. Paul SR et al, Molecular cloning of a cDNA encoding interleukin 11, a
stromal cell-derived lymphopoietic and hematopoietic cytokine, Proc
Natl Acad Sci 87(19): pp7,512-7,516, 1990
11. King T et al, Comparison of the immunogenicity of hepatitis B
vaccine administered intradermally and intramuscularly, Rev Infect Dis
12(6): pp1,035-1,043, 1990
12. Harper DM et al, Sustained efficacy up to 4.5 years of a bivalent L1
viruslike particle vaccine against human papillomavirus types 16 and
18: Follow up from a randomized control trial, Lancet 367:
pp1,247-1,255, 2006
13. Plosker GL, Sipuleucel-T: in metastatic castration-resistant prostate cancer, Drugs 71(1): pp101-108, 2011
14. Palucka K and Banchereau J, Cancer immunotherapy via dendritic cells, Nat Rev Cancer 12: pp265-277, 2012
15. Restifo NP et al, Adoptive immunotherapy for cancer: harnessing the T cell response, Nat Rev Immunology 12: pp269-281, 2012
16. Vivier E et al, Targeting natural killer cells and natural killer T cells in cancer, Nat Rev Immunology 12: pp239-252, 2012
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