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Revista Colombia Médica
Universidad del Valle - Facultad de Salud
ISSN: 0120-8322 EISSN: 1657-9534
Vol. 42, Num. 2, 2011, pp. 134-135
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NEW CANCER THERAPIES BASED ON THE IMMUNE SYSTEM
Colombia Médica, Vol. 42, No. 1, April - June, 2011, pp. 134-135
EDITORIAL
New Cancer Therapies Based On The Immune System
Pedro Romero, MD
Ludwig Center for Cancer Research,
University of Lausanne, Lausanne, Switzerland,
e-mail: pedro.romero@unil.ch
Code Number: rc11018
In the 1890s, William Coley, a New York City surgeon, obtained
spectacular results in some patients with sarcoma after inoculating
their tumors with the erysipelas-causing bacteria. Since then, many
cancer researchers have dreamt of developing therapies based on the
exquisite specificity of the immune system to eliminate tumors without
the toxicity associated with chemo and/or radiation therapy.
Currently, 120 years later, the list of accomplishments in this area begins to grow:
- Three cytokines are used in anticancer therapies:
high dose IL-2 in advanced melanoma and metastatic renal cancer,
Interferon-α for hairy cell leukemia and as adjuvant therapy in
melanoma in high risk of relapse, and the TNF-a for treatment of
loco-regional disease, via extracorporeal perfusion, in melanoma and
sarcoma.
- It has been shown that Bacille
Calmette-Guérin (BCG) instillation is an efficient treatment in
recurrent superficial bladder carcinoma.
- There are over a dozen monoclonal antibodies that
are used in treating diverse types of tumors; of these, rituximab is
considered an example of immune therapy because it targets the CD20
molecule expressed in the B lymphocytes and is useful in treating
B-cell lymphoma.
- The first therapeutic-cancer vaccine was approved
in the United States by the Food and Drug Administration (FDA) in 2009.
It is a recombinant protein representing a prostate-associat antigen
Prostate Acid Phosphatase, (PAP) that must be loaded onto autologous
dendritic cells prior to their infusion into the bloodstream.
- Finally, in March 2011, the FDA approved the
monoclonal antibody that blocks the CTLA-4 inhibitory receptor, which,
when repeatedly administered, duplicates the median survival time of
patients with advanced metastatic melanoma. It is the first treatment
in many decades that manages to prolong survival rates in a type of
cancer like malignant melanoma.
Hence, the study of the interactions between the immune system and
cancer has been a continuous source of new anti-cancer therapies. The
rate of discoveries has accelerated considerably over the last 15
years, as well as the rate of clinical trials to test new concepts and
new immunotherapeutic products. Scientists, important sectors of big
pharma and, most importantly, cancer patients, share great optimism on
the prospects for new promising therapies based on the immune system.
Conceptually, cancer immunotherapy rests on the postulate of the immune
surveillance of tumors. This was clearly formulated in the 1950s by M.
Burnet. This theory has been received with a variety of attitudes
ranging from extreme enthusiasm to extreme skepticism. Nevertheless, a
considerable amount of experimental results obtained from models of
spontaneous tumors of growing sophistication has come to conclusively
test this hypothesis. Currently, it is perfectly clear that the immune
system specifically recognizes tumors and the outcome of this event is
variable. In some cases, the immune system is capable of suppressing
the tumoral progression, resulting in hidden, clinically silent tumors.
In other cases, the tumoral progression coincides with the induction of
specific immunological tolerance even during early stages of
carcinogenesis. In humans, numerous studies have established the
favorable prognosis associated with an infiltration of primary tumors
by abundant memory T lymphocytes, particularly CD8 T lymphocytes. The
likely meaning of this strong correlation is that the T lymphocytes
that infiltrate the tumors represent a line of defense against tumoral
progression that can protect the patient from a relapse during
prolonged periods after surgical excision of the tumoral mass.
Recent progress in immunology is shedding light on the cellular and
molecular mechanisms governing the initiation and maintenance of T
lymphocyte responses, which protect the host from infections from
viruses, intracellular bacteria, and metazoan parasites, as well as
from tumors. A general model has gained wide acceptance according
to which the immune system has developed mechanisms that permit it to
recognize molecular patterns specifically associated with pathogenic
microorganisms, as well as cell and tissue damage. It has also
generated extremely specific systems allowing efficient discrimination
between autologous and foreign components at the level of each cell of
the economy. The specific recognition systems are the antibodies,
capable of recognizing antigens in solution and the T lymphocytes
equipped with T-cell antigen receptors (TCR) capable of recognizing
internal antigens associated with the antigens of the major
histocompatibility complex. According to this model, the expectation
was that tumor antigens recognized by the lymphocytes infiltrating the
tumors should be derived from oncogenic viruses or from somatically
mutated genes generated during the processes of carcinogenesis.
For this reason, there was general surprise when it became evident that
most tumor antigens are actually self-antigens, derived from normal
proteins. There are currently hundreds of tumor antigens identified,
which are none other than combinations of short peptides derived
generally from non-mutated proteins (10-25 amino acids) and class I HLA
molecules (-A,- B, or -C) or class II (-DR, -DP, or -DQ). The former
are recognized by CD8 T lymphocytes with cytolytic capacity and the
latter by CD4 T lymphocytes capable of multiple immunoregulatory
functions.
Knowledge on the identity of tumor antigens
has opened new avenues of research. First, it has enabled monitoring of
the anti-tumoral responses of T lymphocytes in cancer patients. A
considerable wealth of information has been accumulated, which allows
understanding the dynamics of these responses and understanding the
reasons why tumors progress in spite of the presence of anti-tumoral
immune responses. Second, the scientific community has embarked on the
vigorous search for therapeutic vaccines against cancer. In this case,
certain tumor antigens are selected as targets in the design of
anticancer vaccine candidates. Until now, hundreds of phase I and II
clinical trials have been conducted to test the safety and tolerance of
new therapeutic vaccines. Two promising vaccines (MAGE-A3 and MUC-1)
are being currently evaluated in terms of their clinical efficiency in
treating lung cancer and metastatic melanoma, in randomized, double
blind, placebo controlled phase III clinical trials. Third, this
information has also inspired the optimization of novel cellular
therapies consisting of ex vivo expansion of tumor-infiltrating T
lymphocytes for a subsequent reinfusion of massive numbers (billions)
of these cells. It is also possible to «reprogram»
autologous T lymphocytes via transduction with a retroviral vector that
carries TCRs specific for defined tumor antigens.
At the forefront of basic research, interest centers on understanding
the multiple mechanisms operating inside the tumors and which impede an
efficient anti-tumoral immune response. New targets have been
identified for future therapies that should neutralize these
immune-suppressing circuits and, thus, enhance the anti-tumoral
response. Among these, there are inhibiting receptors such as CTLA-4,
PD-1, Tim-3, BTLA, CD4 regulatory T lymphocytes, or myeloid derived
suppressor cells.
Certain enzymes are expressed at excessively high levels in the tumor
microenvironment like Cox-2, IDO, INOS, and arginase. Their activity
suppresses (for different reasons) the anti-tumoral immune response.
Their inhibition in experimental tumor models has revealed a clear
therapeutic potential. Finally, components of tumor stroma such as
activated fibroblasts or blood neovessels are also valuable therapeutic
targets.
In conclusion, cancer immunotherapy is an area undergoing remarkable
developments. Recently, new therapies have come about based on
harnessing the immune system and it should be expected that in the
future the number and efficiency of the new anti-cancer
immune-therapies will continue to expand significantly.
In light of this, it is worth wondering how to prepare the medical and
cancer patient communities for the new realities associated with the
surge of these new therapies at the national level. It would also be
worthwhile to address the Colombian scientific community about their
attitude and willingness to participate in these latest developments.
Copyright 2011 - Colombia Médica
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