CANCER
VACCINES
INDEX
SL.NO CHAPTER PAGE
NO
1.
INTRODUCTION 2
1.1. CANCER
VACCINES 3
1.2. MANAGEMENT 3
2.
OBJECTIVE 7
3.
DISCRIPTION 9
3.1. TYPES
OF CANCER 9
3.2. THE
IMMUNE SYSTEM AND CANCER 10
3.3. MICROBIAL
AGENTS THAT CAUSE CANCER 12
3.4. AVAILABLE
DRUGS 13
3.5.
CANCER TREATMENT VACCINES - DESIGN
AND WORK 14
3.6. DEVELOPMENT
OF CANCER TREATMENT VACCINES 16
3.7. ADJUVANTS
OF CANCER VACCINES 17
3.8. COMBINATION
IN THERAPY 21
3.9. LIMITATIONS
OF CANCER VACCINES 22
3.10. ADDITIONAL
RESEARCHES 26
4.
CONCLUTION 31
5.
REFERENCE 33
ABBREVIATION
BCG : Bacillus
Calmette-Guerin
CSF : Colony Stimulating Factor
CTL : Cytotoxic T Lymphocyte
DC : Donor Cell
FDA : Food
and Drug Administration
GM : Granulocyte Macrophage
IFN : Interferon
TAA : Tumor
Associated Antigen
TCR : T-Cell
Receptor
IARC : International
Agency for Research on Cancer
HPV : Human
Papilloma Virus
HCV : Hepatitis
C Virus
HBV : Hepatitis
B Virus
HHV8 :
Human Herpes Virus 8
KSHV :
Kaposi Sarcoma -
associated Herpes Virus
HTLV1 : Human
T- cell Lymphotropic Virus type1
KLH : Keyhole
Limpet Hemocyanin
FCA : Freud’s
Complete Adjuvant
IL
: Interleukin
CHAPTER 1
INTRODUCTION
|
INTRODUCTION
Cancer known
medically as a malignant neoplasm,
is a broad group of various diseases, all involving unregulated cell growth. In
cancer, cells divide
and grow uncontrollably, forming malignant tumors, and invade nearby parts of
the body. The cancer may also spread to more
distant parts of the body through the lymphatic system or bloodstream. Not
all tumors are cancerous. Benign
tumors do not grow uncontrollably, do not
invade neighboring tissues, and do not spread throughout the body.
Determining what causes cancer is complex. Many things
are known to increase the risk of cancer, including tobacco use,
certain infections, radiation,
lack of physical activity, poor diet and obesity,
and environmental pollutants. (1) These
can directly damage genes or combine with existing genetic faults within cells
to cause the disease.(2) Approximately
five to ten percent of cancers are entirely hereditary.
Cancer
can affect people of all ages, and a few types of cancer are more common in
children, the risk of developing cancer generally increases with age. In 2007,
cancer caused about 13% of all human deaths worldwide
(7.9 million).
Worldwide
approximately 18% of cancers are related to infectious diseases.(1) This
proportion varies in different regions of the world from a high of 25% in
Africa to less than 10% in the developed world.(1)Viruses are the usual infectious agents that
cause cancer but bacteria and parasites may also have an effect.
A virus that can
cause cancer is called an oncovirus. These include human papilloma virus (cervical carcinoma), Epstein-Barr virus (B-cell lymphoproliferative disease and
nasopharyngeal carcinoma),Kaposi's sarcoma herpesvirus (Kaposi's Sarcoma and primary effusion lymphomas), hepatitis B and hepatitis C viruses (hepatocellular carcinoma),
and Human T-cell leukemia virus-1 (T-cell leukemias). Bacterial
infection may also increase the risk of cancer, as seen in Helicobacter pylori-induced gastric carcinoma.(3) Parasitic infections strongly
associated with cancer include Schistosomahaematobium(squamous cell
carcinoma of thebladder) and the liver
flukes, Opisthorchisviverrini and Clonorchissinensis (cholangio carcinoma).(4)
1.1.
CANCER VACCINES
Cancer vaccines are
designed to boost the body’s natural ability to protect itself, through the
immune system, dangers posed by damaged or abnormal cells such as cancer cells.
Vaccines have been developed that prevent some
infection by some viruses.(5) Human papillomavirus vaccine decreases the risk of developing cervical
cancer.(5) The hepatitis B vaccine prevents infection with hepatitis B
virus and thus decreases the risk of liver cancer.(5)
Cancer vaccines are
medicines that belong to a class of substances known as biological response
modifiers. Biological response modifiers work by stimulating
or restoring the immune system’s ability to fight infections and disease. There
are two broad types of cancer vaccines:
·
Preventive ( prophylactic) vaccines,
which are intended to prevent cancer from developing in healthy people; and
·
Treatment (therapeutic) vaccines,
which are intended to treat an existing cancer by strengthening the body’s
natural defenses against the cancer (20).
1.2.
MANAGEMENT OF CANCER
Many management
options for cancer exist with the primary ones including: surgery, chemotherapy, radiation therapy, and palliative
care. Which treatments are used depends upon the type, location and grade
of the cancer as well as the person's health and wishes.
· Surgery
Surgery is the
primary method of treatment of most isolated solid cancers and may play a role
in palliation and prolongation of survival. It is typically an important part
of making the definitive diagnosis and staging
the tumor as biopsies are usually
required. In localized cancer surgery typically attempts to remove the entire
mass along with, in certain cases, the lymph nodes in the area. For some types of cancer
this is all that is needed for a good outcome.(6)
· Chemotherapy
Chemotherapy in addition to surgery has proven
useful in a number of different cancer types including breast, colorectal
cancer, pancreatic
cancer, osteogenic sarcoma, testicular
cancer, ovarian cancer, and certain lung cancers.(6) The effectiveness of chemotherapy is
often limited by toxicity to other tissues in the body.
· Radiation
Radiation
therapy involves the use of ionizing radiation in an attempt to either cure or
improve the symptoms of cancer. It is used in about half of all cases and the
radiation can be from either internal sources in the form of brachytherapy or external sources. Radiation is
typically used in addition to surgery and or chemotherapy but for certain types
of cancer such as early head and neck cancer may be used alone. For painful bone
metastasis it has been found
to be effective in about 70% of people. (7)
· Alternative treatments
Complementary and alternative cancer
treatments are a diverse
group of health care systems, practices, and products that are not part of
conventional medicine and have not been shown to be effective. (8) "Complementary medicine"
refers to methods and substances used along with conventional medicine, while
"alternative medicine" refers to compounds used instead of
conventional medicine.(38) Most
complementary and alternative medicines for cancer have not been rigorously
studied or tested. Some alternative treatments have been investigated and shown
to be ineffective but still continue to be marketed and promoted. (10)
· Palliative care
Palliative
care is an approach to symptom management that aims to reduce the
physical, emotional, spiritual, and psycho-social distress experienced by
people with cancer. Unlike treatment that is aimed at directly killing cancer
cells, the primary goal of palliative care is to make the person feel better.
Palliative care
attempts to help the person cope with the immediate needs and to increase the
person's comfort. It does not require people to stop treatment aimed at
prolonging their lives or curing the cancer.
Multiple national medical
guidelines recommend early
palliative care for people whose cancer has produced distressing symptoms
(pain, shortness of breath, fatigue, nausea) or who need help coping with their
illness. An oncologist should consider a palliative care consult in any patient
they feel has a prognosis of less than 12 months even if continuing aggressive
treatment.(11)(12)(13)
CHAPTER 2
OBJECTIVES
|
OBJECTIVE
To study about cancer and cancer vaccine
therapy.
CHAPTER 3
DESCRIPTION
|
DESCRIPTION
3.1
TYPES OF CANCER
Cancers are classified by the type
of cell that resembles the tumor and, therefore, the tissue presumed to be the
origin of the tumor. These are the histology and the location, respectively.
Examples of general categories include:
Ø Carcinoma: Malignant tumors derived from epithelial
cells. This group represents the most common cancers, including the common
forms of breast, prostate, lung and colon cancer.
Ø Sarcoma: Malignant tumors derived from connective
tissue, or mesenchymal cells.
Ø Lymphoma and leukemia: Malignancies derived from
hematopoietic (blood-forming) cells
Ø Germ cell tumor: Tumors derived from totipotent cells.
In adults most often found in the testicle and ovary; in fetuses, babies, and
young children most often found on the body midline, particularly at the tip of
the tailbone; in horses most often found at the poll (base of the skull).
Ø Blastic tumor or blastoma: A tumor (usually
malignant) which resembles an immature or embryonic tissue. Many of these
tumors are most common in children.
Malignant tumors (cancers) are usually named using -carcinoma, -sarcoma
or -blastoma as a suffix, with the Latin or Greek word for the organ of origin
as the root. For instance, a cancer of the liver is called ''hepatocarcinoma'';
a cancer of the fat cells is called ''liposarcoma''. For common cancers, the
English organ name is used. For instance, the most common type of breast cancer
is called ''ductal carcinoma of the breast'' or ''mammary ductal carcinoma''.
Here, the adjective ''ductal'' refers to the appearance of the cancer under the
microscope, resembling normal breast ducts.
Benign tumors (which are not cancers) are named using -oma as a suffix
with the organ name as the root. For instance, a benign tumor of the smooth
muscle of the uterus is called ''leiomyoma'' (the common name of this frequent
tumor is ''fibroid''). Unfortunately, some cancers also use the -oma suffix,
examples being melanoma and seminoma.
3.2
THE IMMUNE SYSTEM AND CANCER
To the immune system, cancer cells
differ from normal cells in very small, ways. Therefore, the immune system
largely tolerates cancer cells rather than attacking them. Although tolerance
is essential to keep the immune system from attacking normal cells, tolerance
of cancer cells is a problem. Therapeutic cancer vaccines must not only provoke
an immune response but stimulate the immune system strongly enough to overcome
its usual tolerance of cancer cells.
Another reason cancer cells may not
stimulate a strong immune response is that they have developed ways to evade
the immune system. Scientists now understand some of the ways in which cancer
cells do this. For example, they may shed certain types of molecules that
inhibit the ability of the body to attack cancer cells. As a result, cancers
become less "visible" to the immune system.
Researchers are now using these advances
in knowledge in their efforts to design more effective cancer vaccines. They
have developed several strategies for stimulating immune responses against
cancers, including the following:
Ø Identify
unusual or unique cancer-related molecules that are rarely present on normal
cells and use these so-called “tumor antigens” as vaccines.
Ø Intervene
to make tumor antigens more visible to the immune system. This can be done in
several ways:
Ø Alter
the structure of a tumor antigen slightly (that is, make it look more foreign)
and give the altered antigen as a vaccine. One way to alter an antigen is
modify the gene needed to make it. This can be done in the laboratory.
Ø Put
the gene for a tumor antigen into a viral vector (a harmless virus) and use the
virus as a vehicle to deliver the gene to cancer cells or to normal cells.
Cells infected with the viral vector will make much more tumor antigen than
uninfected cancer cells and may be more visible to the immune system. Cells can
also be infected with the viral vector in the laboratory and then given to
patients as a vaccine. In addition, patients can be infected (that is,
vaccinated) with the viral vector as another way to get virus-infected cells
inside the body.
Ø Put
genes for other molecules that normally help stimulate the immune system into a
viral vector along with a tumor antigen gene.
Ø Use
“primed” dendritic cells or other APCs as a vaccine. There are three ways to
prime a dendritic cell.
Ø APCs
can be fed tumor antigens in the laboratory and then injected into a patient.
The injected cells are primed to activate T cells.
Ø Alternatively,
APCs can be infected with a viral vector that contains the gene for a tumor
antigen.
Ø A
third way to make primed APCs is to feed the cell’s DNA or RNA that contains
genetic instructions for the antigen. The APCs will then make the tumor antigen
and present it on their surface.
Ø Use
antibodies that have antigen-binding sites that mimic, or look like, a tumor
antigen. These antibodies are called anti-idiotype antibodies. They can
stimulate B cells to make to make antibodies against tumor antigens. Anti-idiotype
antibodies present tumor antigens in a different way to the immune system
3.3
MICROBIAL
AGENTS THAT CAUSE CANCER
Microbes cause or contribute to between 15 percent and 25 percent of all
cancers diagnosed worldwide each year, with the percentage being lower in
developed than developing countries (4, 8, 13).
The International
Agency for Research on Cancer (IARC) has classified several microbes as carcinogenic
(causing or contributing to the development of cancer in people), including HPV
and HBV (14). These infectious agents—bacteria, viruses, and parasites—and the
cancer types with which they are most strongly associated are listed in the
table below.
|
Infectious Agents
|
Type of
Organism |
Associated Cancers
|
|
Hepatitis
B virus (HBV)
|
Virus
|
Hepatocellular carcinoma (a type of liver cancer)
|
|
Hepatitis C virus (HCV)
|
Virus
|
Hepatocellular
carcinoma (a type of liver cancer)
|
|
Human
papilloma virus (HPV) types 16 and 18, as well as other HPV types
|
Virus
|
Cervical
cancer; vaginal cancer; vulvar cancer; oropharyngeal cancer (cancers of the
base of the tongue, tonsils, or upper throat); anal cancer; penile cancer;
squamous cell carcinoma of the skin
|
|
Epstein-Barr virus
|
Virus
|
Burkitt lymphoma; non-Hodgkin lymphoma; Hodgkin lymphoma; nasopharyngeal carcinoma (cancer of the upper part of the
throat behind the nose)
|
|
Kaposi sarcoma-associated herpes virus (KSHV), also known
as human herpes virus 8(HHV8)
|
Virus
|
Kaposi
sarcoma
|
|
Human T-cell lymphotropic virus type 1 (HTLV1)
|
Virus
|
Adult
T-cell leukemia/lymphoma
|
|
Helicobacter pylori
|
Bacterium
|
Stomach cancer; mucosa-associated lymphoid tissue (MALT)
lymphoma
|
|
Schistosomes
(Schistosomahematobium)
|
Parasite
|
Bladder cancer
|
|
Liver
flukes (Opisthorchisviverrini)
|
Parasite
|
Cholangiocarcinoma (a type of liver cancer)
|
3.4
AVAILABLE DRUGS
In April 2010, the FDA approved the first
cancer treatment vaccine. This vaccine, sipuleucel-T
(Provenge®,
manufactured by Dendreon), is approved for use in some men with metastatic prostate cancer.
It is designed to stimulate an immune response to prostatic acid
phosphatase (PAP), an antigen that is found on
most prostate cancer cells. In a clinical trial, sipuleucel-T increased the
survival of men with a certain type of metastatic prostate cancer by about 4
months (19).
Unlike some other
cancer treatment vaccines under development, sipuleucel-T is customized to each
patient. The vaccine is created by isolating immune system cells called
antigen-presenting cells (APCs) from a patient’s blood through a procedure
called leukapheresis.
The APCs are sent to Dendreon, where they are cultured with a protein called
PAP-GM-CSF. This protein consists of PAP linked to another protein called granulocyte-macrophage
colony-stimulating factor (GM-CSF). The latter protein
stimulates the immune system and enhances antigen presentation.
APC cells cultured with
PAP-GM-CSF constitute the active component of sipuleucel-T. Each patient’s
cells are returned to the patient’s treating physician and infused into the
patient. Patients receive three treatments, usually 2 weeks apart, with each
round of treatment requiring the same manufacturing process. Although the
precise mechanism of action of sipuleucel-T is not known, it appears that the
APCs that have taken up PAP-GM-CSF stimulate T cells of the immune system to
kill tumor cells that express PAP.
The U.S. Food and Drug
Administration (FDA) has approved two vaccines, Gardasil®
and Cervarix®,
that protect against infection by the two types of HPV—types 16 and 18—that
cause approximately 70 percent of all cases of cervical cancer worldwide.
At least 17 other types of HPV are responsible for the remaining 30 percent of
cervical cancer cases (22). HPV types 16 and/or 18 also cause
some vaginal,vulvar, anal, penile,
and oropharyngeal
cancers (23).
In addition, Gardasil protects
against infection by two additional HPV types, 6 and 11, which are responsible
for about 90 percent of all cases of genital warts in males and females but do
not cause cervical cancer.
Gardasil, manufactured by Merck
& Company, is based on HPV antigens that are proteins. These proteins are
used in the laboratory to make four different types of “virus-like particles,”
or VLPs, that correspond to HPV types 6, 11, 16, and 18. The four types of VLPs
are then combined to make the vaccine. Because Gardasil targets four HPV types,
it is called a quadrivalentvaccine (24). In contrast with
traditional vaccines, which are often composed of weakened whole microbes, VLPs
are not infectious. However, the VLPs in Gardasil are still able to stimulate
the production of antibodies against HPV types 6, 11, 16, and 18.
Cervarix, manufactured
by GlaxoSmithKline, is a bivalent vaccine. It is composed of VLPs made with
proteins from HPV types 16 and 18. In addition, there is some initial evidence
that Cervarix provides partial protection against a few additional HPV types
that can cause cancer. However, more studies will be needed to understand the
magnitude and impact of this effect.
Gardasil is approved for use in
females to prevent cervical cancer and some vulvar and vaginal cancers caused
by HPV types 16 and 18, and for use in males and females to prevent anal cancer
andprecancerous anal
lesions caused by these HPV types. Gardasil is also approved for use in males
and females to prevent genital warts caused by HPV types 6 and 11. The vaccine
is approved for these uses in females and males ages 9 to 26. Cervarix is
approved for use in females ages 10 to 25 to prevent cervical cancer caused by
HPV types 16 and 18.
The FDA has also approved a
cancer preventive vaccine that protects against HBV infection. Chronic HBV
infection can lead to liver cancer. The original HBV vaccine was approved
in 1981, making it the first cancer preventive vaccine to be successfully
developed and marketed. Today, most children in the United States are
vaccinated against HBV shortly after birth (25).
3.5
CANCER TREATMENT VACCINES - DESIGN AND WORK
Cancer treatment
vaccines are designed to treat cancers that have already developed. They are
intended to delay or stop cancer cell growth; to cause tumor shrinkage;
to prevent cancer from coming back; or to eliminate cancer cells that have not
been killed by other forms of treatment.
Developing effective
cancer treatment vaccines requires a detailed understanding of how immune
system cells and cancer cells interact. The immune system often does not “see”
cancer cells as dangerous or foreign, as it generally does with microbes.
Therefore, the immune system does not mount a strong attack against the cancer
cells.
Several factors may
make it difficult for the immune system to target growing cancers for
destruction. Most important, cancer cells carry normal self-antigens in
addition to specific cancer-associated antigens. Furthermore, cancer cells
sometimes undergo genetic changes that may lead to the loss of
cancer-associated antigens. Finally, cancer cells can produce chemical messages
that suppress anticancer immune responses by killer T cells. As a result, even
when the immune system recognizes a growing cancer as a threat, the cancer may
still escape a strong attack by the immune system (28).
Producing effective
treatment vaccines has proven much more difficult and challenging than
developing cancer preventive vaccines(29). To be effective, cancer
treatment vaccines must achieve two goals. First, like traditional vaccines and
cancer preventive vaccines, cancer treatment vaccines must stimulate specific
immune responses against the correct target. Second, the immune responses must
be powerful enough to overcome the barriers that cancer cells use to protect
themselves from attack by B cells and killer T cells. Recent advances in
understanding how cancer cells escape recognition and attack by the immune
system are now giving researchers the knowledge required to design cancer
treatment vaccines that can accomplish both goals (30, 31).
Cancer
preventive vaccines target infectious agents that cause or contribute to the
development of cancer (21). They are similar to traditional
vaccines, which help prevent infectious diseases, such as measles or polio, by
protecting the body against infection. Both cancer preventive vaccines and
traditional vaccines are based on antigens that are carried by infectious agents
and that are relatively easy for the immune system to recognize as foreign.
3.6
DEVELOPMENT
OF CANCER TREATMENT VACCINES
Cancer treatment vaccines are made using antigens
from cancer cells or modified versions of them. Antigens that have been used thus
far include proteins, carbohydrates (sugars), glycoproteins or glycopeptides
(carbohydrate-protein combinations), and gangliosides (carbohydrate-lipid combinations).
Cancer
treatment vaccines are also being developed using weakened or killed cancer cells
that carry a specific cancer-associated antigen or immune cells that are
modified to express such an antigen. These cells can come from a patient
himself or herself (called an autologous vaccine,
such as sipuleucel-T) or from another patient (called an allogeneic vaccine).
Other types of cancer treatment vaccines are
made using molecules of deoxyribonucleic
acid (DNA)
or ribonucleic acid (RNA)
that contain the genetic instructions for cancer-associated antigens. The DNA
or RNA can be injected alone into a patient as a “naked nucleic acid” vaccine,
or researchers can insert the DNA or RNA into a harmless virus. After the naked
nucleic acid or virus is injected into the body, the DNA or RNA is taken up by
cells, which begin to manufacture the tumor-associated antigens. This cell will
make enough of the tumor-associated antigens to stimulate a strong immune
response.
Scientists have
identified a large number of cancer-associated antigens, several of which are
now being used to make experimental cancer treatment vaccines. Some of these
antigens are found on or in many or most types of cancer cells. Others are
unique to specific cancer types (14, 18, 19, 31–35).
3.7
ADJUVANTS
OF CANCER VACCINES
·
Adjuvants
Adjuvants
are compounds that enhance the specific immune response against co-inoculated
antigens. The word adjuvant comes from the Latin word adjuvare, which means to help or to enhance. The concept of
adjuvants arose in the 1920s from observations such as those of Ramon, who
noted that horses that developed an abscess at the inoculation site of diphtheria
toxoid generated higher specific antibody titres. They subsequently found that
an abscess generated by the injection of unrelated substances along with the
diphtheria toxoid increased the immune response against the toxoid. The
adjuvant activity of aluminium compounds was demonstrated by Glenny, in
1926 with diphtheria toxoid absorbed to alum. To this day, aluminium-based
compounds (principally aluminium phosphate or hydroxide) remain the predominant
human adjuvants. In 1936, Freund developed an emulsion of water and mineral oil
containing killed mycobacteria, thereby creating one of the most potent known
adjuvants, Freund's complete adjuvant (FCA). Despite being the gold standard
adjuvant, FCA causes severe local reactions and is considered too toxic for
human use. The oil in water emulsion without added mycobacteria is known as
Freund's incomplete adjuvant (FIA) and, being less toxic, has been used in
human vaccine formulations. In the 1950s, Johnson et al. found that
lipopolysaccharides (LPS) from Gram-negative bacteria exhibited adjuvant
activity and detoxified LPS or related compounds such as lipid A have since
been used as adjuvants in human studies. In 1974, Lederer. identified
muramyldipeptide (MDP) as a mycobacterial component with adjuvant activity
contained in FCA. Bacterial components are often potent immune activators
although commonly associated with toxicity, for example, bacterial DNA with
immunostimulatory CpG motifs is one of the most potent cellular adjuvants.
Immunostimulatory CpG are unmethylated cytosine-guanine dinucleotides found in
bacterial DNA but absent in mammalian DNA. Overall, several hundred natural and
synthetic compounds have been identified to have adjuvant activity. Although a
significant number are clearly more potent than alum, toxicity is perhaps the
single most important impediment in introducing most such adjuvants to human
use.
·
Adjuvant roles
Adjuvants
can be used for various purposes: (i) to enhance the immunogenicity of highly
purified or recombinant antigens; (ii) to reduce the amount of antigen or the
number of immunizations needed for protective immunity; (iii) to improve the
efficacy of vaccines in newborns, the elderly or immuno-compromised persons; or
(iv) as antigen delivery systems for the uptake of antigens by the mucosa.
·
Adjuvant selection
Some
of the features involved in adjuvant selection are: the antigen, the species to
be vaccinated, the route of administration and the likelihood of side-effects.
Ideally, adjuvants should be stable with long shelf life, biodegradable, cheap
to produce, not induce immune responses against themselves and promote an
appropriate immune response (i.e. cellular or antibody immunity depending on
requirements for protection). There are marked differences in the efficacy of
adjuvants depending on the administration route (e.g. between mucosal and
parenteral routes). Hence new vectors, antigen delivery systems or adjuvant
compounds need to take into account the characteristics of the proposed
administration route.
·
Adjuvant safety issues
The
benefits flowing from adjuvant incorporation into any vaccine formulation have
to be balanced with the risk of adverse reactions. Adverse reactions to
adjuvants can be classified as local or systemic. Important local reactions
include pain, local inflammation, swelling, injection site necrosis,
lymphadenopathy, granulomas, ulcers and the generation of sterile abscesses.
Systemic reactions include nausea, fever, adjuvant arthritis, uveitis,
eosinophilia, allergy, anaphylaxis, organ specific toxicity and immunotoxicity
(i.e. the liberation of cytokines, immunosuppression or autoimmune diseases).
Unfortunately, potent adjuvant action is often correlated with increased
toxicity, as exemplified by the case of FCA which although potent is too toxic
for human use. Thus, one of the major challenges in adjuvant research is to
gain potency while minimizing toxicity. The difficulty of achieving this
objective is reflected in the fact that alum, despite being initially
discovered over 80 years ago, remains the dominant human adjuvant in use today.
·
Adjuvant regulatory requirements
Regulations
for the human use of adjuvants are far more rigorous than those applied to
veterinary vaccines. In addition to preclinical studies on the adjuvant itself,
the combined antigen-adjuvant formulation also needs to be subjected to
toxicology prior to commencement of phase 1 clinical trials. The toxicological
evaluation is normally conducted in small animal species such as mice, rats or
rabbits and should use the same administration route proposed for human use.
The dose and frequency of vaccination for preclinical toxicology should be
similar to or higher than the proposed human dose to maximize the ability to
identify potential safety problems. Preclinical studies may also help in
selecting the optimum vaccine dose (26).
·
Adjuvant classification
Adjuvants
can be classified according to their source, mechanism of action or
physicochemical properties. Edelman classified adjuvants into three groups: (i)
active immunostimulants, being substances that increase the immune response to
the antigen; (ii) carriers, being immunogenic proteins that provide T-cell
help; and (iii) vehicle adjuvants, being oil emulsions or liposomes that serve
as a matrix for antigens as well as stimulating the immune response. An
alternative adjuvant classification divides adjuvants according to
administration route, namely mucosal or parenteral. A third classification divides
adjuvants into alum salts and other mineral adjuvants; tensoactive agents;
bacterial derivatives; vehicles and slow release materials or cytokines. A
fourth more recently proposed system of classification divides adjuvants into
the following groups: gel-based adjuvants, tensoactive agents, bacterial
products, oil emulsions, particulated adjuvants, fusion proteins or
lipopeptides
·
Adjuvant limitations
In
spite of progress in the identification of mechanisms of adjuvant action, alum
remains the dominant adjuvant for human vaccines. Although many other adjuvants
have been proposed over the years, these have failed to be successful in humans
largely because of toxicity, stability, bioavailability and cost. Because of
effects of size, electric charge and hydrophobicity which regulate the
incorporation of proteins into the adjuvant formulation, it is difficult to
predict on an empirical basis which adjuvant will work most effectively with a
particular protein or peptide. Moreover, epitope modifications may occur during
formulation or conjugation. In the case of carrier proteins, a pre-existing
immunity to the carrier protein is a major limitation. Furthermore, each
adjuvant generates a characteristic immune response profile. For example, the
inability of alum-based adjuvants to induce Th1 antibody isotypes or cellular
immune responses, and their poor adjuvant effect on polysaccharide antigens
limit their applicability to many vaccines.
· Cancer vaccine adjuvants
There is
increasing excitement regarding the potential for anticancer vaccines to slow
or even eradicate some tumours. These vaccines utilize either complete tumour
cells, tumour antigens or tumour growth factor receptors combined with powerful
adjuvants. These vaccines, being based on self molecules are generally of very
low immunogenicity thereby leading to the requirement for potent adjuvants for
effect. Approaches taken include the use of Montanide adjuvants, very small
size proteoliposomes (VSSP) obtained from the external membrane of Neisseria meningitidis or the use of
peptides adjuvated with GM-CSF.
Cancer vaccines often have added
ingredients, called adjuvants, which help boost the immune response. These
substances may also be given separately to increase a vaccine’s effectiveness.
Many different kinds of substances have been used as adjuvants, including
cytokines, proteins, bacteria, viruses, and certain chemicals.
Researchers often add
extra ingredients, known as adjuvants, to treatment vaccines. These substances
serve to boost immune responses that have been set in motion by exposure to
antigens or other means. Patients undergoing experimental treatment with a
cancer vaccine sometimes receive adjuvants separately from the vaccine itself (36).
Adjuvants used for
cancer vaccines come from many different sources. Some microbes, such as the
bacterium Bacillus
Calmette-Guérin (BCG) originally used as a vaccine
against tuberculosis,
can serve as adjuvants (37).Substances
produced by bacteria, such as Detox B, are also frequently used. Biological
products derived from nonmicrobial organisms can be used as adjuvants, too. One
example is keyhole limpet
hemocyanin (KLH), which is a large protein produced by a
sea animal. Attaching antigens to KLH has been shown to increase their ability
to stimulate immune responses. Even some nonbiological substances, such as
emulsified oil known as montanide ISA–51, can be used as adjuvants.
Natural
or synthetic cytokines can
also be used as adjuvants. Cytokines are substances that are naturally produced
by white blood cells to regulate and fine-tune immune responses. Some cytokines
increase the activity of B cells and killer T cells, whereas other cytokines
suppress the activities of these cells. Cytokines frequently used in cancer
treatment vaccines or given together with them include interleukin 2
(IL2, also known as aldesleukin), interferon alpha (INF–a),
and GM–CSF, also known assargramostim.
3.8.
COMBINATION IN THERAPY
In many of the clinical
trials of cancer treatment vaccines that are now under way, vaccines are being
given with other forms of cancer therapy. Therapies that have been combined
with cancer treatment vaccines include surgery, chemotherapy, radiation
therapy, and some forms of targeted therapy,
including therapies that are intended to boost immune system responses against
cancer.
Several studies have
suggested that cancer treatment vaccines may be most effective when given in
combination with other forms of cancer therapy (34, 38). In
addition, in some clinical trials, cancer treatment vaccines have appeared to
increase the effectiveness of other cancer therapies (34, 38).
Additional evidence
suggests that surgical removal of large tumors may enhance the effectiveness of
cancer treatment vaccines (38)..In patients with extensive disease,
the immune system may be overwhelmed by the cancer. Surgical removal of the
tumor may make it easier for the body to develop an effective immune response.
Researchers are also
designing clinical trials to answer questions such as whether a specific cancer
treatment vaccine works best when it is administered before chemotherapy, after
chemotherapy, or at the same time as chemotherapy. Answers to such questions
may not only provide information about how best to use a specific cancer
treatment vaccine but also reveal additional basic principles to guide the
future development of combination therapies involving vaccines.
3.9.
LIMITATIONS OF CANCER VACCINES
Vaccines intended to
prevent or treat cancer appear to have safety profiles comparable to those of
traditional vaccines (32). However, the side effects of cancer
vaccines can vary among vaccine formulations and from one person to another.
The most commonly
reported side effect of cancer vaccines is inflammation at the site of
injection, including redness, pain, swelling, warming of the skin, itchiness,
and occasionally a rash.
People sometimes
experience flu-like symptoms after receiving a cancer vaccine, including fever,
chills, weakness, dizziness, nausea or vomiting, muscle ache, fatigue,
headache, and occasional breathing difficulties. Blood pressure may also be
affected.
Other, more serious
health problems have been reported in smaller numbers of people after receiving
a cancer vaccine. These problems may or may not have been caused by the
vaccine. The reported problems have included asthma, appendicitis, pelvic
inflammatory disease, and certain autoimmune diseases, including arthritis
and systemic lupus erythematosus.
Vaccines, like any
other medication affecting the immune system, can cause adverse effects that
may prove life threatening. For example, severe hypersensitivity (allergic)
reactions to specific vaccine ingredients have occurred following vaccination.
However, such severe reactions are quite rare.
v Side effects of HPV vaccination
· Yellow Card Scheme
The Yellow Card
Scheme allows you to report suspected side effects from any type of medicine
that you are taking. It is run by a medicines safety watchdog: Medicines and
Healthcare Products Regulatory Agency (MHRA). Following clinical trials, the
vaccine used in the UK human papilloma virus (HPV) vaccination programme
(Cervarix) was shown to cause side effects in some people.
Immediately after
having the injection, you may experience a stinging sensation or slight pain
that lasts for a short time. Other side effects may take longer to appear.
· Very common side effects of HPV vaccine
Very common side effects of the HPV
vaccine include:
Ø Pain
at the injection site
Ø Redness
or swelling at the injection site
Ø Headaches
Ø Muscle
pain
Ø Tiredness.
Ø Nausea
(feeling sick)
Ø Vomiting
Ø Diarrhea
Ø Abdominal
(tummy) pain
Ø Itchy
skin
Ø A
red skin rash
Ø Hives (urticarial –
an itchy, red rash)
Ø Joint
pain
Ø A
high temperature (fever) of 38C (100.4F) or over.
Ø upper respiratory
tract infection (infection of the nose, throat or windpipe)
Ø Dizziness.
Ø Other
reactions at the injection site, such as a hard lump, tingling or numbness
Ø Breathing
difficulties and wheezing.
Ø Swollen
eyes, lips, genitals, hands, feet and other areas (this is called angioedema)
Ø Itching
Ø A
strange metallic taste in the mouth
Ø Sore,
red, itchy eyes
Ø Changes
in heart rate
Ø Loss
of consciousness
In very rare cases, it
is possible for someone who has had the HPV vaccine to experience a more severe
allergic reaction, known as an anaphylactic reaction (anaphylaxis or
anaphylactic shock).
·
Quadrivalent Human Papillomavirus [Types
6, 11, 16, and 18] Recombinant Vaccine side effects
As
with any medicine, there are possible side effects withQuadrivalent Human
Papillomavirus [Types 6, 11, 16, and 18] Recombinant Vaccine;everyone will not
experience side effects. In fact, most people tolerate Gardasil well. When side
effects do occur, in most cases they are minor, meaning they require no
treatment or are easily treated by you or your healthcare provider.
·
Common Side Effects
Quadrivalent Human Papillomavirus [Types
6, 11, 16, and 18] Recombinant Vaccine hasbeen studied thoroughly in clinical
trials, with many people having been evaluated. In these studies, side effects
are always documented and compared to side effects that occur in a similar
group of people not taking the medicine. Based on these studies, the most
commonQuadrivalent Human Papillomavirus [Types 6, 11, 16, and 18] Recombinant
Vaccine side effects include:
Ø Pain
in the area of the injection -- occurring in up to 83.9 percent of people
Ø Swelling in the area of the injection -- up to
25.4 percent
Ø Redness in the area of the injection -- up to
24.6 percent
Ø Fever -- up to 13 percent
Ø Headache
-- up to 12.3 percent
Ø Nausea -- up to 6.7 percent
Ø Dizziness
-- up to 4 percent
Ø Diarrhea -- up to 3.6 percent.
Ø Vomiting
Ø Cough
Ø Toothache
Ø General
ill feeling
Ø Joint
pain
Ø Trouble
sleeping (insomnia)
Ø Stuffy
or runny nose
Ø Sore
throat
Ø Upper
respiratory tract infection (such as the common cold)
Ø Muscle
pain
Ø Dizziness.
Ø Very
high fever
Ø Weakness,
tingling, or paralysis (which may be signs of Guillain-Barré syndrome)
Ø Signs
of an allergic reaction, including difficulty breathing, wheezing, an unusual
skin rash, itching, or hives.
Ø Gastroenteritis,
which is an inflammation of the stomach and intestines, usually involving
vomiting or diarrhea
Ø Appendicitis,
which is an infection or inflammation of the appendix
Ø Pelvic
inflammatory disease (PID), which is an infection or inflammation in the pelvic
area that can lead to infertility and other problems
Ø Asthma
or bronchospasms (airway spasms)
Ø Blood
clots in the legs or lungs.
Ø Seizures.
Ø Guillain-Barré
syndrome.
This most of side effects will be able
to diagnose and treat the problem.
3.9.
ADDITIONAL
RESEARCHES
Although researchers
have identified many cancer-associated antigens, these molecules vary widely in
their capacity to stimulate a strong anticancer immune response. Two major
areas of research aimed at developing better cancer treatment vaccines involve
the identification of novel cancer-associated antigens that may prove more
effective in stimulating immune responses than the already known antigens and
the development of methods to enhance the ability of cancer-associated antigens
to stimulate the immune system. Research is also under way to determine how to
combine multiple antigens within a single cancer treatment vaccine to produce
optimal anticancer immune responses (39).
Perhaps the most
promising avenue of cancer vaccine research is aimed at better understanding
the basic biology underlying how immune system cells and cancer cells interact.
New technologies are being created as part of this effort. For example, a new
type of imaging technology allows researchers to observe killer T cells and
cancer cells interacting inside the body (40).
Researchers are also
trying to identify the mechanisms by which cancer cells evade or suppress
anticancer immune responses. A better understanding of how cancer cells
manipulate the immune system could lead to the development of new drugs that
block those processes and thereby improve the effectiveness of cancer treatment
vaccines (41). For example, some cancer cells produce chemical
signals that attract white blood cells known as regulatory T cells, or Tregs,
to a tumor site. Tregs often release cytokines that suppress the activity of
nearby killer T cells (34, 42). The combination of a cancer
treatment vaccine with a drug that would block the negative effects of one or
more of these suppressive cytokines on killer T cells might improve the
vaccine’s effectiveness in generating potent killer T cell antitumor responses.
·
KILLER
T CELL
A cytotoxic T cell (also known as TC, Cytotoxic T Lymphocyte, CTL, T-Killer cell,
cytolytic T cell, CD8+ T-cells or killer
T cell) belongs to a sub-group of T lymphocytes (a
type of white blood cell) that are capable of inducing the
death of infected
somatic or tumor cells; they
kill cells that are infected with viruses (or other pathogens),
or are otherwise damaged or dysfunctional. Most cytotoxic T cells express T-cell
receptors (TCRs) that can recognize a specific antigenic peptide bound to Class I MHC molecules, present on
all nucleated cells, and a glycoprotein called CD8, which is attracted
to non-variable portions of the Class I MHC molecule. The affinity between CD8 and the MHC molecule
keeps the TC cell and the target cell bound closely together during
antigen-specific activation. CD8+ T
cells are recognized as TC cells once they become activated
and are generally classified as having a pre-defined cytotoxic role within the
immune system. However, CD8+ T cells also have the ability to make some cytokines
Tumor immunotherapy with T lymphocytes,
which can recognize and destroy malignant cells, has been limited by the
ability to isolate and expand T cells restricted to tumor-associated antigens.
Chimeric antigen receptors (CARs) composed of antibody binding domains
connected to domains that activate T cells could overcome tolerance by allowing
T cells to respond to cell surface antigens; however, to date, lymphocytes
engineered to express CARs have demonstrated minimal in vivo expansion and
antitumor effects in clinical trials. We report that CAR T cells that target
CD19 and contain a costimulatory domain from CD137 and the T cell receptor ζ
chain have potent non–cross-resistant clinical activity after infusion in three
of three patients treated with advanced chronic lymphocytic leukemia (CLL). The
engineered T cells expanded >1000-fold in vivo, trafficked to bone marrow,
and continued to express functional CARs at high levels for at least 6 months.
Evidence for on-target toxicity included B cell aplasia as well as decreased
numbers of plasma cells and hypogammaglobulinemia. On average, each infused
CAR-expressing T cell was calculated to eradicate at least 1000 CLL cells.
Furthermore, a CD19-specific immune response was demonstrated in the blood and
bone marrow, accompanied by complete remission, in two of three patients.
Moreover, a portion of these cells persisted as memory CAR+ T cells
and retained anti-CD19 effector functionality, indicating the potential of this
major histocompatibility complex–independent approach for the effective
treatment of B cell malignancies.
CHAPTER 4
CONCLUSION
|
CONCLUSION
Vaccines are used to treat various types
of cancer. Even though it has some adverse effects, it is very effective in
prevention and treatment of cancer. Various developments have paved way to
enhance the therapeutic effect of cancer vaccines and minimize its adverse
effect and also combination therapy of vaccines.
Pharmacist as a health care professional
can play an inevitable role to here, educating people with proper information
about cancer, its treatment and the details about the treatment of cancer vaccines.
CHAPTER 5
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