A tremendous amount of research is being done in an attempt to find a cure for
the many types of cancer. This paper presents background information on cancer as well
as the normal immune system response to cancer cells. The main focus of the paper is to
characterize and introduce the two main goals of cancer immunotherapy: the attempts at
making a cancer vaccine and the attempt to provide an in vivo immunological
environment that is more conducive to the identification and destruction of cancerous
cells. Both types of immunotherapy have been shown to cause the regression of cancer
cells but no technique has been able to provide a clear cure for the disease. Recent
advances and topics of importance to cancer immunotherapy are discussed in detail in an
effort to explain how these techniques work in aiding the immune system and
augmenting the anti-tumor immune response.
According to the American Cancer Society, this year in the United States one in
every four deaths will be caused by some form of cancer (Statistics, 04/02/00). Cancer
presents a unique problem for the immune system because unlike an infection involving
foreign cells, the problematic cells originate from within the organisms’ own body thus
the cell has a similar composition as normal somatic cells. The immune system does
have the means to identify and destroy cancerous cells, but often these cells are able to
avoid identification by various mechanisms such as low Class I MHC expression or by
inhibiting costimulatory signal production or expression (Goldsby et al., 1999).
Costimulatory signals are just as important as MHC expression because antigen
presentation cannot occur without them. A key focus in cancer immunotherapy is to
elucidate the manner in which certain types of cancers are able to avoid or weaken
identification by the cells of the immune system and to find a procedure that will aid in
evoking an immune response capable of the destruction of the cancerous cells.
Cancer cells are the result of a disruption of the cell renewal and death cycle, most
likely as a result of a series of somatic DNA mutations (Goldsby et al., 1999). In general,
the mutation results in a slowing or elimination of apoptosis while colony expansion
increases. Once a cancer cell has formed, it often undergoes mitosis at a very high rate
expanding into a colony of genetic clones. There are many types of cancers originating
within different organs and systems. Some cancer causing mutations have been linked to
genetic factors while others are linked to environmental factors such as certain chemicals
from cigarette smoke and from UV light.
Overview of the Immune Response to Cancer Cells
If cancer cells do form in an organism, the immune system does have a variety of
different ways that the unwanted cells can be eradicated. Research has shown that both
the cell mediated and humoral immune response can play a role in the destruction of
tumor cells (Goldsby et al., 1999). As part of the cell mediated response, T cytotoxic
lymphocytes can recognize altered self-antigen as presented by class I MHC. Once self-
antigen has been recognized, a T cytotoxic lymphocyte divides into effector cells known
as cytotoxic T lymphocytes (CTLs) which can then destroy the cell that the antigen came
from by cytotoxic activity (Goldsby et al., 1999). As mentioned earlier, some cancers
can avoid being recognized in this manner by having a low expression of class I MHC or
by removing co-stimulatory signals that are crucial to the presentation of antigen. In both
cases, this limits the presentation and resulting recognition of self-antigen.
Fortunately, another type of lymphocyte known as the natural killer cells (NK)
specifically targets cells with low expression of class I MHC. The NKs can then destroy
the cell by way of cytotoxic activity (Goldsby et al., 1999). NKs can also destroy tumor
cells after being stimulated by the presence of antibodies that have recognized antigen on
the surface of tumor cells. NKs have CD16 receptors on the cell membrane that bind to
the Fc region of immunoglobulin. Immunoglobulin is secreted by B-lymphocytes as part
of the humoral response. Immunoglobulins have antigen binding sites and an Fc region.
The antigen-binding sites bind to antigen and the Fc region is what is recognized by a
variety of cells such as NKs and Macrophages as well as other cells, which can then
destroy the cell from which the antigen came.
The Need for Immunotherapy
Even though the immune response to cancer is very broad and very specialized it
is obvious due to the high incidence of death of people with cancer that the immune
system still has a difficult time copping with the disease. In an effort to increase the
survivability for those with cancer, a large amount of research has been done and is
continuing to be done with the hope of finding a cure. Immunotherapies of many
varieties have been tested and are now used to aid the immune system in the
identification of cancer cells and their subsequent destruction. Cancer immunotherapy
can be divided into two categories: cancer vaccines and induction of immune response
against specific antigens. The cancer vaccine focus has to do with stimulating immunity
through the use of an outside source of antigens that are analogous with certain cancer
cell antigens, while the immune response to specific antigens has to do with providing an
environment that is conducive to the recognition, presentation, and the destruction of
specific antigens and the tumor cells from which they came. Though no total cure for
cancer has been discovered at this point, many immunotherapeutic techniques are being
practiced that greatly increase the survival rates of cancer patients. Combinations of
different techniques such as administering a vaccine as well as creating a more favorable
immunological environment also have resulted in tumor regression.
One idea behind cancer vaccines is that by creating and injecting an antigen that is
immunogenic and is at the same time identical to an antigen on or within tumor cells, an
immune response will be created that will not only remove the injected antigen, but will
also create enough antigen specific antibodies, B cells, and T cells that are capable of
destroying the cancer cells. Often the source of antigen is the patient’s own cancer cells.
Another focus behind cancer vaccines is the use of a recombinant virus that when
introduced into cancer cells causes them to express antigens and various costimulitory
signals. In both cases the idea is to create antigens that would elicit an immune response
that would create memory B and T cells that would be specific for the antigens thus
thwarting any future re-growth. Many different prototypes of cancer vaccines have been
created. Some use the patient’s own cancer cells while others use recombinant viruses.
Researchers from Hadassah University Hospital in Israel used irradiated mouse
tumor cells as a source of antigen, as well as indomethacin injections which resulted in an
anti-tumor response and protection from a normally deadly dose of murine mammary and
lung carcinoma cells in syngeneic mice (Henderson., 2000). The investigators found that
continuous injections of indomethacin throughout the immunization period as well as
during the injection of the carcinoma cells was pivotal to the destruction of the cancer
cells (Henderson, 2000). This demonstrates the usefulness of combining a cancer vaccine
with an immune system stimulant. The researchers also found a correlation between the
ability of indomethacin to stimulate destruction of the cancer cells and the level of
endogenous prostaglandin within those cells. While anti-tumor immunity was expressed
against murine lung and mammary carcinoma cells which posses high levels of
endogenic prostaglandin, no immunity was shown for other murine tumor cells that
contain low levels (Henderson, 2000). The mice which were injected with indomethacin
remained healthy and displayed no signs of immune system dysfunction such as
increased spleen size or excessive lymphoproliferation (Henderson, 2000).
Dr. David Berd and his team at Thomas Jefferson University created another type
of cancer vaccine (reviewed in Wynn, 1999). Similarly to the experiment discussed by
Henderson, Berd’s experiment used the patients own cancer cells to create a vaccine.
Berd used a patient’s own Melanoma cells but added a hapten to the cell instead of
simply injecting irradiated cells. The hapten solves a common problem that often occurs
when making a cancer vaccine, the problem of antigen tolerance (Wynn, 1999). Because
a cancer cell originates within the organism it often has few molecules that appear as
foreign and as mentioned earlier many cancer cells inhibit antigen presentation so it is
never seen as a foreign or as a threat by the immune system cells. A hapten, which is
antigenic but not immunogenic will be recognized as foreign and will initiate a small
immune reaction. The hapten gets the identification process of the cancer cells going,
hopefully after the cancer cell is processed, other antigens will be found on the cancer
cell that will be recognized as altered-self antigen and will elicit an even more potent
immune response capable of causing tumor regression. In the treatment phase, the
patient's own tumor cells are taken and then the hapten is attached, the complex is then
injected back into the patient also adding the Bacillus Calmette-Geurin adjuvant as well
as a preliminary dose of cyclophosphamide (Wynn, 1999). In clinical studies, this type
of vaccine treatment was able to increase survivability by more than fifty percent. This
technique is being tested on and is showing promise for other types of cancer as well
Another type cancer vaccine involves the use of recombinant viruses to serve as
the vaccine. The virus is designed to target cancer cells and then infiltrate and code for
the production of antigens, most commonly superantigens are chosen because of their
ability to stimulate a large immune response. Construction of viruses that act as a
vaccine for the treatment of murine tumors has been achieved (Carroll, et al., 1998). A
research team in Oxford England created a recombinant virus that as well as coding for
the antigen E. coli Beta-galactosidase, also coded for the cytokine interleukin-12 and the
costimulatory B-7 molecule (Carroll et al., 1998). Interleukin-12 is a cytokine that has
many functions in the immune response, it can induce the immune response from NK’s
as well as being important in the transition of Tc lymphocytes to CTLs (Carroll et al.,
1998). B-7 has a costimulatory effect and is found on most professional antigen
presenting cells. The expression of B-7 is essential for the acceptance of antigen by a Tc
lymphocyte (Carroll et al., 1998). After creating the virus, the virus was injected into
mice that had been previously injected with murine colon carcinoma cells. Varying
viruses were created, some coding only for antigen, some only coding for interleukin-12,
some coding for B-7 only, and then viruses that coded for all three as well as a control
group that received no virus injection (Carroll et al., 1998). Exogenous interleukin-12
also was given to some mice who also received the virus. The mice who received both
the vaccine coding for the antigen and B-7 along with an exogenous supply of
interleukin-12 showed greatest tumor nodule reduction and the greatest survival rate
(Carroll et al., 1998). This is a case when the use of a vaccine as well as an immunolgic-
inducing environment provided the best results in tumor regression. This experiment
demonstrates the importance of the costimulatory molecules and immune system
modulators in the destruction of cancer cells.
Induction of Immune Response
Another key focus in immunotherapy is the attempt to elicit an immune response
by providing more favorable conditions for antigen recognition. This is being done in
various ways from the provision of exogenous cytokines such as interleukin-12,
interleukin-2, or by the growing of tumor antigen specific T lymphocytes in vitro, the use
of other stimulating factors and by direct in vivo transfection of tumors with
Studies have shown that adoptively transferred allogeneic antigen specific T cells
are effective in the treatment of relapsed hematologic malignancies (Schultze et al.,
1997). Efforts are being made to use T cells from the same individual to provide an even
more potent immune response. The idea is to take naïve T cells and “educate” them for
specific cancer antigen in vitro and then reintroduce them to the individual.
Unfortunately, no real grasp of the benefits of therapy involving autologous antigen
specific T cells has been discovered because no one has been capable of isolating and
growing a large amount of antigen-presenting cells for the stimulation of the antigen
specific T cells in vitro (Schultze et al., 1997). Antigen presenting cells are crucial to the
development of antigen specificity in T cells, a process that occurs normally in the
thymus. Attempts had been made using dendritic cells because they are the best antigen
presenting cells, but little success had been found due to little proliferation and loss of
antigen presenting effectiveness outside the body (Schultze et al., 1997). Scientists from
the Dana-Farber Cancer Institute found that autologous B cells are able to act as an
efficient provider for antigen as well as proliferate continually in vitro (Schultze et al.,
1997). B cells, though not as potent of an antigen presenting cell as dendritic cells, were
shown to proliferate and present antigen at a level high enough to allow for a large
number of antigen-specific T cells to be formed (Schultze et al., 1997). This large
number of antigen-specific T cells are then injected back into the patient with the hope of
stimulating a greater degree of effectiveness for the destruction of tumor cells.
The use of cyclophosphamide also has resulted in notable anti tumor activity in
some types of tumor cells (Proietti et al., 1998). Italian researchers explain that the
injection of this widely used chemotherapeutic agent, cyclophosphamide combined with
the use of adoptive immunotherapy dramatically increased the regression of tumor cells
(Proietti et al., 1998). Cyclophosphamide also has a bystander effect on T cytotoxic cells
which helps to facilitate the recognition of cancer cells.
Another approach defined by scientists at the National Jewish Medical and
Research Center was to supply a gene that encoded for a superantigen, which should
elicit a powerful immune response (Dow et al., 1998). The team used dogs with
melanoma tumors and injected plasmid DNA that coded for the superantigen
staphylococcal enterotoxin B to be produced inside the tumor and then expressed (Dow,
Steven R., et all). Expression of the superantigen should evoke a very large immune
response. This technique is similar to the use of the aforementioned virus vaccine
method, but in this case the vector is injected locally. The overall response to the
treatment was a regression of tumor size in 46% of the dogs, with the most regression
seen in dogs with smaller tumors (Dow et al., 1998). The injected tumors showed
increased numbers of both T cytotoxic and T helper cells as well as increased numbers of
macrophages and increased levels of T cytotoxic lymphocytes were found in blood (Dow,
et al., 1998) Dogs who received this treatment had a longer survival time as compared
with those who only had a surgical excision of the cancer (Dow et al., 1998)
A group of researchers from the University of California Los Angeles designed
an experiment to elucidate the mechanism by which adoptive immunotherapy with tumor
infiltrating lymphocytes (TILs) and interleukin-2 works in vivo (Economou et al., 1996).
This therapy appears to provide dramatic shrinkage in metastic melanoma patients as well
as renal cancer patients, however the mechanism by which this happens is unknown
(Economou et al., 1996). In this experiment, nine patients, six with melanoma and three
with renal cancer were injected with DNA marked TILs and also with marked non-tumor
infiltrating lymphocytes. At certain intervals samples of tumor as well as other tissues
were removed and analyzed but unfortunately the results did not show any difference
between TILs and the non-TILs. (Economou et al., 1996). The experiment did provide
insight into the life span of the different lymphocytes and the patterns of movement
throughout the body (Economou et al., 1996). The hypothesis that the TILs are attracted
specifically to tumor cells was left unsupported and the mechanism by which TILs reduce
cancer cells was left unknown (Economou, James S. et al. 1996).
Even though the immune system does have mechanisms to identify and destroy
cancerous cells, often these mechanisms fail or are not expressed in a manner that is
strong enough to prevent the spread of the disease. Cancer is one example of how a
system as broad and specialized as the mammalian immune system can be evaded.
Different types of immunotherapeutic techniques have been tested and are now in use to
aid the immune system in recognizing and destroying cancer cells. The search for a
cancer vaccine and a variety of methods for manipulating the environment of the inner
body to allow for better antigen recognition are two of the focuses of immunotherapy.
Cancers exhibit many properties that make them very difficult to recognize as well as kill
and the many diverse types of cancer makes one single unifying cure for cancer a very
idealistic thought. In spite of its elusive nature, much has been learned about cancer and
survival rates of those with the disease are increasing.
1) Carroll, Miles W., Willem W. Overwijk, Deborah R. Surman, Kangla Tsung, Bernard
Moss, and Nicholas P. Restifo. “Construction and Characterization Of a
Triple-Recombinant Vaccinia Virus Encoding B7-1, Interleukin12, and a Model
Tumor Antigen” Journal of the National Cancer Institute. Vol. 90 Issue 24. 7p.
December 16, 1998. Academic Search Elite.
2) Dow, Steven W., Robyn E. Elmslie, Andrew P. Willson, Lisa Roche, Cori Gorman,
and Terry A. Potter. “In Vivo Tumor Transfection with Superantigen plus Cytokine
Genes Induces Tumor Regression and Prolongs Survival in Dogs with Malignant
Melanoma.” The Journal of Clinical Investigations. Vol.101 Number 11. 20p. June
3) Economou, James S., Arie S. Belldegrun, John Glaspy, Eric M. Toloza, Robert Figlin,
Jane Hobbs, Nancy Meldon, Randhir Kaboo, Cho-Lea Tso, Alexander Miller,
Roy Lau, William McBride, and Robert C. Moon. “In Vivo Trafficking of
Adoptively Transferred Interlukin-2 Expanded Tumor-infiltrating Lymphocytes
and peripheral Blood Lymphocytes.” The Journal of Clinical Investigations. Vol.
97 Number 2. January 1996. www.jci.org.
4) Goldsby, Richard A., Thomas J. Kindt, and Barbara Osborne. Kuby Immunology.
New York: W.H. Freeman Company, 1999.
5) Henderson, C.W. “Anti-tumor Immunity Induced by Indomethacin and Cancer
Vaccine.” Cancer Weekly. March 21, 2000. P. 9. 2 P. Academic Search Elite.
6) Proietti, Enrico, Giampaolo Greco, Beatrice Gerrone, Sara Baccarini, Claudia Mauri,
Massimo Venditti, Davide Carlei, and Filippo Belardelli. “Importance of
Cyclophosphamide-induced Bystander Effect on T Cells for Successful Tumor
Eradication in Response to Adoptive Immunotherapy in Mice.” The Journal of
Clinical Investigation Vol. 101 Number 2. 24p. January 1998. www.jci.org.
7) Schultze, Joachman L., Sabine Michalak, Mark J. Seamon, Glenn Dranoff, Ken Jung,
John Daley, Julio C. Delgado, John G. Gribben, and Lee M. Nadler. “CD40-
activated Human B Cells: An Alternative Source of Highly Efficient Antigen
Presenting Cells to Generate Autologous Antigen-specific T Cells for Adoptive
Immunotherapy.” The Journal of Clinical Investigation Vol. 100. Number 11.
17p. December 1997. www.jci.org.
8) “Statistics” The American Cancer Society Homepage. April 2, 2000
9) Wynn, Paul. “Melanoma Vaccine Doubles Survival Rate, Nears Market.”
Dermatology Times. Vol. 20 Issue 11, 3p. November 1999.