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Cancer Immunotherapy:
It is a well-known fact that chemotherapy kills cancer cells however, in the case
of colorectal cancer it was found that it
can also stimulate cancer cell growth by
activating cells called fibroblast present
in connective tissue. Matthew Kalady
and Jeremy Rich at the Cleveland Clinic
in Ohio and their colleagues analyzed tumors from patients with colorectal cancer
before and after chemotherapy. These researchers found that proliferation of cancer-associated fibroblasts increased significantly after treatment, and that these
cells enhanced the ability of a subset of
cancer cells to initiate tumor growth. The
fibroblasts seem to do this by secreting
signaling proteins, called IL-17A or interleukin 17A. The findings suggest that chemotherapy can trigger drug resistance by
changing the tumors microenvironment.
In the future, cancer therapies can be improved by disrupting this mechanism.
A fourth form of cancer treatment called
cancer immunotherapy has emerged and
developed over the last decade. This form
of biotechnology-enabled treatment involves utilizing the bodys own immune
system to treat cancers. Cancer immunotherapy is a two-way learning process: while the immune system teaches
us about its intricacies, researchers can
in turn teach immune cells how to use
those abilities to target cancer cells. After
gaining this knowledge of the immune
system researchers can create synthetic
molecules to attack a tumor, or can help
the immune system to function more effectively (2). Cancer immunotherapy can
be divided into four major types: non specific therapies, monoclonal antibodies,
vaccines (Figure 1) and T-cell activation
therapy (Figure 2). Non-specific immunotherapy includes the use of cytokines
and chemicals that can stimulate an immune response. The second type uses a
monoclonal antibody, which are antibodies that are specific to a particular antigen
and does not exhibit any cross reactivity.
The third form, called cancer vaccine
therapy, stimulates the bodys immune
system to fight cancer. These vaccines are
derived from cancer cell antigens that are
in turn recognized by cells of the immune
system (Figure 1).
Figure 3. TIL (Tumor infiltrating lymphocyte) based immunotherapy [Credit: Restifo NP et. al
2012 (8)].
CAR grafted T-cells are specific to certain antigens and can recognize MHC
non-restricted structures present in tumor
cells and can be directly given to patients
for treating cancer. (c) The third process
involves isolating T-cell receptors from
humanized mice. These transgenic mice
expressing human MHC class I or MHC
class II molecules can be treated with human tumor antigens. The T-cells generated in this manner can be isolated from the
mice and their TCR genes can be cloned
into retroviral vectors. These vectors can
then be used to generate tumor specific
T-cell receptors compatible to the patients immune system and then used for
treating cancer (Figure 4) (8).
The advantages of using genetically engineered T-cells include the ability by the
researcher to develop T-cells against various types of cancer. The T-cells with high
affinity and high selectivity can be identified to treat patients and then produced
by genetic engineering. In addition, the
Figure 4. Three ways to generate genetically engineered T-cells specific to tumor antigens [Credit: Restifo NP et. al 2012 (8)].
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Figure 5. Development of chimeric antigen receptor (CAR). Part of the monoclonal antibody
shown in circle that recognizes the cancer antigen is combined together to form a single chain via
a linker which is then combined to the signaling portion of the T-cell receptor. These genetically
engineered T-cells can then recognize the tumor cell effectively. [Credit: Ramos et. al 2011 (9)].
a single chain also known as scFv or single-chain fragment variable. This single
chain derivative has high affinity for cancer antigens. Using genetic engineering
techniques, the single chain antibody is
combined with the cytoplasmic domain of
immune receptors that can initiate signal
transduction thereby activating the T-cell
response (Figure 5) (9).
Treatment of tumors using genetically
engineered T-cells also has certain disadvantages. Often times mispairing of and
TCR chains can occur which leads to
reactivity against unintended antigens. Instead of recognizing tumor antigens other
unintended healthy cells can be attacked
due to antigen mimicry. This process
can lead to unnecessary side effects like
inflammation and release of cytokines.
Clinically this can lead to various side
effects like poor pulmonary function, renal failure and even death. However, the
side effects can be brought under control
by rapidly eliminating these T-cells from
the patients body. One such process involves the use of T-cells which are able to
express caspase 9 and are capable of killing toxic T-cells when activated by a small
molecule or drug.
Currently, there are over 1000 clinical
trials to evaluate immunotherapy for the
treatment of a variety of cancers, including prostate cancer and malignant melanoma. Several of the clinical trials will
test currently approved therapies (radiation; chemotherapy) combined with im-
Contributing Editors
Dr. Shyamasri Biswas received her Ph.D.
in Biotechnology jointly from Banaras
Hindu University, India and the University
of Potsdam in Germany in 2003. She was
awarded the prestigious German Academic Exchange Service (DAAD) sandwich
model international scholarship and carried out her Ph.D. thesis work in the Department of Physical Biochemistry at the
University of Potsdam, Germany. She also
received the Council for Scientific and
Industrial Research fellowship in India.
Dr. Biswas has held research positions in
protein biochemistry, structural biology,
biotechnology and molecular biology at
top-tier US institutions. Her most recent
affiliation has been with the University of
Florida where she has worked as a postdoctoral scientist in the Department of
Biochemistry and Molecular Biology. Dr.
Biswas has published over twenty peer-reviewed research papers in prestigious
international journals in the field of biotechnology that include Nature Structural
Biology, Journal of Biological Chemistry,
Structure and Biochemistry. She has also
given several talks at national and international meetings and has been an invited reviewer for a number of international
journals. Dr. Biswas can be contacted at
shyabiswas@gmail.com.
Dr. Megha Agrawal received her Ph.D.
in Biotechnology in 2010 from the Indian Institute of Technology Roorkee,
which is one of the premier institutions
in India with an outstanding reputation
across the globe. She was awarded the
prestigious National Fellowship of Council of Scientific and Industrial Research
to carry out her Ph.D. work. Her research
interests lie predominantly in the area of
Neuroscience with emphasis on neurodegenerative disorders. Her initial research
involved determining the role of various
herbal compounds and trace elements in
neuroprotection within rodent models of
neurodegeneration. During an active research career of more than eight years,
Dr. Agrawal has made significant contributions to develop a rapid, cost effective
and more sensitive mechanism based
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