cancer immune therapy

8/7/2019 cancer immune therapy

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Submitted To: Dr. Abhay Kumar

Submitted By: Mudaser Ahmad lone

Section : P7905

Roll no : A16

Registration no: 10907230


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Cancer biology

Cancer is a class of diseases in which a group of cells display uncontrolled growth (division

beyond the normal limits), invasion (intrusion on and destruction of adjacent tissues), and

sometimes metastasis (spread to other locations in the body via lymph or blood). Cancer harms

the body when damaged cells divide uncontrollably to form lumps or masses of tissue called

tumors (except in the case of leukemia where cancer prohibits normal blood function by

abnormal cell division in the blood stream). Tumors can grow and interfere with the digestive,

nervous, and circulatory systems, and they can release hormones that alter body function.

Tumors that stay in one spot and demonstrate limited growth are generally considered to be

benigMore dangerous, or malignant, tumors form when two things occur: A cancerous cell

manages to move throughout the body using the blood or lymph systems, destroying healthy

tissue in a process called invasion. That cell manages to divide and grow, making new blood

vessels to feed itself in a process called angiogenesis. When a tumor successfully spreads to

other parts of the body and grows, invading and destroying other healthy tissues, it is said tohave metastasized. This process itself is called metastasis, and the result is a serious condition

that is very difficult to treat .Physicians and researchers who specialize in the study, diagnosis,

treatment, and prevention of cancer are called oncologists. The branch of medicine concerned

with the study, diagnosis, treatment, and prevention of cancer is oncology. Cancers are caused by

abnormalities in the genetic material of the transformed cells.

These abnormalities may be due to the effects ofcarcinogens, such as tobacco smoke, radiation,

chemicals, or infectious agents. Other cancer-promoting genetic abnormalities may randomly

occur through errors in DNA replication, or are inherited, and thus present in all cells from

birth. The heritability of cancers is usually affected by complex interactions between carcinogens

and the host's genome. Genetic abnormalities found in cancer typically affect two general

classes of genes. Cancer-promoting oncogenes are typically activated in cancer cells, giving

those cells new properties, such as hyperactive growth and division, protection against

programmed cell death, loss of respect for normal tissue boundaries, and the ability to become

established in diverse tissue environments. Tumor suppressor genes are then inactivated in

cancer cells, resulting in the loss of normal functions in those cells, such as accurate DNA

replication, control over the cell cycle, orientation and adhesion within tissues, and interaction

with protective cells of the immune system.

Immune system dysfunction

HIV is associated with a number of malignancies, including Kaposi's sarcoma, non-Hodgkin's

lymphoma, and HPV- associated malignancies such as anal cancer and cervical cancer involves

breakdown of immune surveillance as a possibility of cancer. Excepting the rare transmissions

that occur with pregnancies and only a marginal few organ donors, cancer is generally not a

transmissible disease. The main reason for this is tissue graft rejection caused by MHC


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incompatibility. In humans and other vertebrates, the immune system uses MHC antigens to

differentiate between "self" and "non-self" cells because these antigens are different from person

to person. When non-self antigens are encountered, the immune system reacts against the

appropriate cell. Such reactions may protect against tumour cell engraftment by eliminating

implanted cells. In the United States, approximately 3,500 pregnant women have a malignancy

annually, and transplacental transmission of acute leukaemia, lymphoma, melanoma and

carcinoma from mother to fetus has been observed .

Cancer immunotherapy

Cancer immunotherapy is the use of the immune system to reject cancer. The main premise is

stimulating the patient's immune system to attack the malignant tumor cells that are responsible

for the disease. This can be either through immunization of the patient (e.g. by administering a

cancer vaccine, in which case the patient's own immune system is trained to recognize tumor

cells as targets to be destroyed, or through the administration of therapeutic antibodies as drugs,

in which case the patient's immune system is recruited to destroy tumor cells by the therapeutic

antibodies. Since the immune system responds to the environmental factors it encounters on the

basis of discrimination between self and non-self, many kinds of tumor cells that arise as a result

of the onset of cancer are more or less tolerated by the patient's own immune system since the

tumor cells are essentially the patient's own cells that are growing, dividing and spreading

without proper regulatory control.

Anti-Tumor Antibodies Can Enhance Tumor Growth

Following the discovery that antibodies could be produced to tumor-specific antigens, attemptswere made to protect animals against tumor growth by active immunization with tumor antigens

or by passive immunization with antitumor antibodies. Much to the surprise of the researchers,

these immunizations did not protect against tumor growth; in many cases, they actually enhanced

growth of the tumor. The tumor-enhancing ability of immune sera subsequently was studied in

cell-mediated lympholysis (CML) reactions invitro. Serum taken from animals with progressive

tumor growth was found to block the CML reaction, whereas serum taken from animals with

regressing tumors had little or no blocking activity. K. E. and I. Hellstrom extended these

findings by showing that children with progressive neuroblastoma had high levels of some kind

of blocking factor in their sera and that children with regressive neuroblastoma did not have such

factors. Since these first reports, blocking factors have been found to be associated with anumber of human tumors. In some cases, antitumor antibody itself acts as a blocking factor.

Presumably the antibody binds to tumor-specific antigens and masks the antigens from cytotoxic

T cells. In many cases, the blocking factors are not antibodies alone but rather antibodies

complexed with tumor antigens. Although these immune complexes have been shown to block

the CTL response, the mechanism of this inhibition is not known. The complexes also may

inhibit ADCC by binding to Fc receptors on NK cells or macrophages and blocking their activity


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Vaccine Therapy and Antibody Therapy

Cancer cells have substances on their outer surfaces that can act as antigens and thus mark the

cells as different or abnormal. Viruses, bacteria, and parasites have cells that are substantially

different from normal human cells because they are truly foreign to the body and are detected by

the immune system. However, the differences between cancer cells and normal human cells may

be more difficult for the immune system to detect. Cancer immunotherapies are designed to

help the immune system recognize cancer cells and/or to strengthen the immune response to the

cancer cells and thus destroy the cancer. The cancer cells antigens may not be different enough

from those of normal cells to cause an immune reaction; thus, the immune system may not

recognize the cancer cells as foreign. The immune system may recognize the cancer cells

antigens, but the immune response may not be strong enough to destroy the cancer. Additionally,

some cancer cells themselves may also give off substances that prevent the immune system from

responding properly. There are two broad classes of immunotherapies, active immunotherapy

and passive immunotherapy. Active immunotherapies stimulate the bodys own immunesystem to fight the disease. Passive immunotherapies do not rely on the immune system to attack

the disease; instead, they use immune system components (such as antibodies) that are created

outside of the body to fight the disease. These two approaches are also called vaccine therapy

and antibody therapy respectively. In vaccine therapy, or active therapy, the patient is given a

vaccine that should stimulate the immune system to attack the cancer. In antibody therapy, or

passive therapy, the patient is given antibodies that will hopefully target the cancer but leave the

non-cancerous cells alone. The problem with both approaches is finding substances that the

immune system can target (antigens) which are only present on the cancer cells and not on

normal cells. Sometimes vaccines combined with nonspecific immunotherapy, using additional

substances or cells called adjuvants in order to boost the immune systems response.

Vaccine Therapy

Cancer vaccines contain cancer cells, parts of cells, or pure antigens that increase the immune

response against cancer cells that are already present in the body. They are considered active

immunotherapies since they are meant to trigger your own immune system to respond. They are

considered specific because they do not result in a generalized immune system response. They

cause the immune system to produce antibodies to one or several specific antigens, and/or to

produce Killer T cells to attack cancer cells that have specific antigens. There are several

different types of vaccines; among them are tumor cell vaccines, dendritic cell vaccines,

antigen vaccines, anti-idiotype vaccines, and DNA vaccines. Tumor cell vaccines use cancer

cells that are removed from the patient during surgery. The tumor cells are then killed so they

cannot form more tumors. The tumor cells may be modified with chemicals or genes, or mixed

with other substances known to increase the immune response in an attempt to improve the

effectiveness of the vaccine. The tumor cells are the injected back into the patient. The antigens


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on the cells are recognized and attacked by the immune system. The two basic types of tumor

cell vaccines are autologous and allogeneic. An autologous vaccine is made from tumor cells

taken from the patient that will receive them. An allogeneic vaccine uses cells of a particular

cancer type that originally came from someone other than the patient that will receive them. The

cells are often grown in a lab from a stock of cancer cells kept for this purpose.

Antibody Therapy

Monoclonal antibodies are laboratory-produced antibodies that can locate and bind to specific

cancer cells anywhere in the body. Each monoclonal antibody recognizes a different protein on

specific cancer cells. Monoclonal antibodies are used in cancer detection as well as in cancer

therapy. They can be used alone or to deliver drugs, toxins, or radioactive material directly to a

tumor. Monoclonal antibodies have been used in various ways as experimental

immunotherapeutic agents for cancer. For example, anti-idiotype monoclonal antibodies have

been used with some success in treating human B-cell lymphomas and T-cell leukemias. In oneremarkable study, R. Levy and his colleagues successfully treated a 64-year-old man with

terminal B-cell lymphoma. At the time of treatment, the lymphoma had metastasized to the liver,

spleen, bone marrow, and peripheral blood. Because this was a B-cell cancer, the membrane-

bound antibody on all the cancerous cells had the same idiotype. These researchers produced

mouse monoclonal antibody specific for the B-lymphoma idiotype. When this mouse

monoclonal anti-idiotype antibody was injected into the patient, it bound specifically to the B-

lymphoma cells, because these cells expressed that particular idiotype. Since B-lymphoma cells

are susceptible to complement-mediated lysis, the monoclonal antibody activated the

complement system and lysed the lymphoma cells without harming other cells. After four

injections with this anti-idiotype monoclonal antibody, the tumors began to shrink, and thispatient entered an unusually long period of complete remission. However, this approach requires

that a custom monoclonal antibody be raised for each lymphoma patient. This is prohibitively

expensive and cannot be used as a general therapeutic approach for the thousands of patients

diagnosed each year with B lymphoma. Recently, Levy and his colleagues have used direct

immunization to recruit the immune systems of patients to an attack against their B lymphoma.

In a clinical trial with 41 B-cell lymphoma patients, the genes encoding the rearranged

immunoglobulin genes of the lymphomas of each patient were isolated and used to encode the

synthesis of recombinant immunoglobulin that bore the idiotype typical of the patients tumor.

Each of these Igs was coupled to keyhole limpet hemocyanin (KLH), a mollusk protein that is

often used as a carrier protein because of its efficient recruitment of T-cell help. The patients

were immunized with their own tumor-specific antigens, the idiotypically unique

immunoglobulins produced by their own lymphomas. The anti-idiotypic approach is by its very

nature patient-specific. A more general monoclonal antibody therapy for B-cell lymphoma is

based on the fact that most B cells, whether normal or cancerous, bear lineage distinctive

antigens. One such determinant, CD20, has been the target of intensive efforts; a monoclonal


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antibody to it, raised in mice and engineered to contain mostly human sequences, has been useful

in the treatment of B-cell lymphoma .Aside from CD20, a number of tumor-associated antigens

are being tested in clinical trials for their suitability as targets for antibody- mediated anti-tumor

therapy. A variety of tumors express significantly increased levels of growth-factor receptors,

which are promising targets for anti-tumor monoclonal antibodies. For example, in 25 to 30

percent of women with metastatic breast cancer, a genetic alteration of the tumor cells results in

the increased expression of HER2, an epidermal-growth-factorlike receptor. An anti-HER2

monoclonal antibody was raised in mice and the genes encoding it were isolated. Except for the

sequences encoding the antibodys CDRs, the mouse Ig sequences were replaced with human Ig

counterparts. This prevents the generation of human anti-mouse antibodies (HAMAs) and allows

the patient to receive repeated doses of the humanizedanti-HER2 in large amounts (100

milligrams or more). Preparations of this antibody, called Herceptin, are now commercially

available for the treatment of HER2-receptorbearing breast cancers. Monoclonal antibodies also

have been used to prepare tumor-therapy specific anti-tumor agents. In this approach, antibodies

to tumor-specific or tumor- associated antigens are coupled with radioactive isotopes,chemotherapy drugs, or potent toxins of biological origin. In such guided missile therapies, the

toxic agents are delivered specifically to tumor cells. This focuses the toxic effects on the tumor

and spares normal tissues. Reagents known as immunotoxins have been constructed by coupling

the inhibitor chain of a toxin (e.g.,diphtheriatoxin) to an antibody against a tumor-specific or

tumor-associated antigen . In vitro studies have demonstrated that these magic bullets can kill

tumor cells without harming normal cells. Immunotoxins specific for tumor antigens in a variety

of cancers (e.g., melanoma, colorectal carcinoma, metastatic breast carcinoma, and various

lymphomas and leukemias) have been evaluated in phase I or phase II clinical trials. Ina number

of trials, significant numbers of leukemia and lymphoma patients exhibited partial or complete

remission. However in a number of cases, the clinical responses in patients with larger tumormasses were disappointing .In some of these patients, the sheer size of the tumor may render

most of its cells inaccessible to the immunotoxin.

Interferons and cytokinesis therapy

Interferons belong to a group of proteins known as cytokines. They are produced naturally by

white blood cells in the body (or in the laboratory) in response to infection, inflammation, or

stimulation. They have been used as a treatment for certain viral diseases, including hepatitis B.

Interferon-alpha was one of the first cytokines to show an antitumor effect, and it is able to

slow tumor growth directly, as well as help to activate the immune system. Interferon-alpha has

been approved by the FDA and is now commonly used for the treatment of a number of cancers,

including multiple myeloma, chronic myelogenous leukemia, hairy cell leukemia, and

malignant melanoma. Interferon-beta and interferon-gamma are other types of interferons that

have been investigated. Other cytokines with antitumor activity include the interleukins (e.g., IL-

2) and tumor necrosis factor. IL-2 is frequently used to treat kindey cancer and melanoma. Some


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of the problems with these cytokines, including many of the interferons and interleukins, are

their side effects, which include malaise and flu-like syndromes. When given at a high dose, the

side effets can be greatly magnified

Cytokinesis therapy

Cytokines may also be administered systemically for the treatment of various human tumours.

The largest clinical experience is with IL-2 administered in high doses alone or in conjunction

with lymphokine-activated killer (LAK)cells. After the administration of IL-2, numbers of blood

T and B lymphocytes, NK cells are increased with increase in serum TNF, IL-1 and IFN-g

concentrations. The severe toxicities associated with high dose IL-2 andIL-2 + LAK cells include

fever, pulmonary oedema and capillary leak syndrome. IL-2 has been effective in inducing

measurable tumour regression in patients with advanced melanoma, and renal cell carcinoma.

Currently the potential of IL-12 to enhance anti-tumour effect via T cells and NK cells has

aroused great interest and phase I and II trials are being conducted on patients with advancedcancer. Hematopoietic growth factors, including GM-CSF, G-CSF and IL-11 are used in cancer

treatment protocols to shorten periods of neutropenia and thromocytopenia after chemotherapy

or autologous bone marrow transplantation.

Some Research papers and journals

Article No.1 Immune Dysfunction in Cancer Patients

Immune deficiency in cancer patients is well documented, and tumor cells have developed a

variety of cellular and molecular mechanisms to avoid antitumor immune responses. These

mechanisms include defective presentation of tumor antigens on the cell surface and/or an

inability of the host to effectively recognize these cells and target them for destruction. Tumor-

induced defects are known to occur in all major branches of the immune system. The continuous

administration of vascular endothelial growth factor (VEGF), a factor produced by most solid

tumors, inhibits the functional maturation of dendritic cells, significantly decreases T-cell to B-

cell ratios in the peripheral lymphoid organs, and induces rapid and dramatic thymic atrophy in

tumor-bearing animals. VEGF is abundantly expressed by a large percentage of solid tumors,

and defective antigen presentation, T-cell defects, and premature thymic atrophy are known to

occur in cancer patients and tumor-bearing animals. This review will encompass the major

mechanisms responsible for tumor evasion of immune surveillance and highlight a role for

VEGF as a principal contributor to tumor-associated immune deficiencies.


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Article no .3 The application of Toll like receptors for cancer therapy.

Abstract

Toll-like receptor (TLR) proteins play key roles in immune responses against infection. UsingTLR proteins, host can recognize the conserved molecular structures found in pathogens called

pathogen-associated molecular patterns (PAMPs). At the same time, some TLRs are able to

detect specific host molecules, such as high-mobility group box protein 1 (HMGB1) and heat

shock proteins (hsp), and lead to inflammatory responses. Thus, it has been suggested that TLRs

are involved in the development of many pathogenic conditions. Recent advances in TLR-related

research not only provide us with scientific information, but also show the therapeutic potential

against diseases, such as autoimmune disease and cancer.

Article no 4 Immunotherapy of Cancer:

Cancer immunotherapy broadly includes active immunization, as in the use of cancer vaccines,

passive immunization, such asthe use of adoptive cell therapy and antibodies that modulate

tumor function, and immuno stimulation, using antibodies and

small molecules to treat

malignancy by activating or destroying an endogenous immune response against tumor cells.

Different monoclonal antibodies are in use or underevaluation for use as therapeutic agents in

various malignancies.

Active stimulation of the host's immune system holds promise

for

Journal of translational medicine

Interleukin-13 receptor alpha2 DNA prime boost vaccine induces tumor immunity in

murine tumor models

Hideyuki Nakashima , Toshio Fujisawa , Syed R Husain and Raj K Puri :Journal of Translational

Medicine 2010 published :08 November 2010

Abstract

DNA vaccines represent an attractive approach for cancer treatment by inducing active T cell

and B cell immune responses to tumor antigens. Previous studies have shown that interleukin-13

receptor alpha2 chain (IL-13Ralpha2), a tumor-associated antigen is a promising target for

cancer immunotherapy as high levels of IL-13Ralpha2 are expressed on a variety of human

tumors. To enhance the effectiveness of DNA vaccine, we used extracellular domain of IL-

13Ralpha2 (EC

Dalpha2) as a protein-boost against murine tumor models.


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achieving durable remission of malignant disease and represents

a nontoxic method of therapy if

tumor-specific effector cellscan be selectively targeted.

Article no 5:

Endothelin B Receptor, a New Target in Cancer ImmuneTherapy

Abstract

The endothelins and their G protein-coupled receptors A and B have been implicated in

numerous diseases and have recently emerged as pivotal players in a variety of malignancies.

Tumors overexpress the endothelin 1 (ET-1) ligand and the endothelin-A-receptor (ETAR). Their

interaction induces tumor growth and metastasis by promoting tumor cell survival and

proliferation, angiogenesis, and tissue remodeling. On the basis of results from xenograft models,drug development efforts have focused on antagonizing the autocrine-paracrine effects mediated

by ET-1/ETAR. In this review, we discuss a novel role of the endothelin-B-receptor (ETBR) in

tumorigenesis and the effect of its blockade during cancer immune therapy. We highlight key

characteristics of the B receptor such as its specific overexpression in the tumor compartment;

and specifically, in the tumor endothelium, where its activation by ET-1 suppresses T-cell

adhesion and homing to tumors. We also review our recent findings on the effects of ET BR-

specific blockade in increasing T-cell homing to tumors and enhancing the efficacy of otherwise

ineffective immunotherapy.

Article no 6 Immune Therapy for Cancer

ABSTRACT

Immune therapy has become a standard treatment for a variety of cancers. Monoclonal

antibodies, immune adjuvants, and vaccines against oncogenic viruses are now well-established

cancer therapies. Immune modulation is a principal element of supportive care for many high-

dose chemotherapy regimens. In addition, immune activation is now appreciated as central to the

therapeutic mechanism of bone marrow transplantation for hematologic malignancies. Advances

in our understanding of the molecular interactions between tumors and the immune system have

led to many novel investigational therapies and continue to inform efforts for devising more

potent therapeutics. Novel approaches to immune-based cancer treatment strive to augment

antitumor immune responses by expanding tumor-reactive T cells, providing exogenous

immune-activating stimuli, and antagonizing regulatory pathways that induce immune tolerance.


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The future of immune therapy for cancer is likely to combine many of these approaches to

generate more effective treatments.

Article no 7

The idiotype (Id) cascade in mice elicited the production of anti-R24 Id and anti-anti-Id

monoclonal antibodies with antitumor and protective activity against human melanoma.

Abstract

Gangliosides have been considered as potential targets for immunotherapy because they are

overexpressed on the surface of melanoma cells. However, immunization with purified

gangliosides results in a very poor immune response, usually mediated by IgM antibodies. To

overcome this limitation, we immunized mice with R24, a monoclonal antibody (mAb) that

recognizes the most tumor-restricted ganglioside (GD3); our goal was to obtain anti-idiotype (Id)

antibodies bearing the internal image of GD3. Animals produced anti-Id and anti-anti-Id

antibodies. Both anti-Id and anti-anti-Id antibodies were able to inhibit mAb R24 binding to

GD3. It was shown to recognize two different GD3-expressing human melanoma cell lines invitro and to mediate tumor cell cytotoxicity by complement activation and antibody-dependent

cellular cytotoxicity. The biological activity of the anti-anti-Id m Ab was also tested in a mouse

tumor model, in which it was shown to be a powerful growth inhibitor of melanoma cells .

Conclusion

Tumor cells differ from normal cells in numerous ways. In particular, changes in the regulation

of growth of tumor

cells allow them to proliferate indefinitely, then invade the underlying tissue, and eventuallymetastasize to other tissues . Normal cells can be transformed in vitro by chemical and physical

carcinogens and by transforming viruses. Transformed cells exhibit altered growth properties and

are sometimes capable of inducing cancer when they are injected into animals.

Proto-oncogenes encode proteins involved in control of normal cellular growth. The

conversion of proto-oncogenes to oncogenes is one of the key steps in the induction of most


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References

Books : Immunology by kuby and Faheem haleem khan

Immunotherapy of Cancer, by Dr. C. Komen Brown and Dr. John Kirkwood,

Horizons in Cancer Therapeutics

Cancer Research UK and American Cancer Society

National Cancer Institute Targeted Cancer Therapies

(http://www.cancer.gov/cancertopics/factsheet/Therapy/targeted)

Ramos AS, Parise CB, Travassos LR, Han SW, Department of Biophysics Experimental

Oncology Unity ,Brazil Laval University Cancer .

Research Center April 2009) Michael Dougan and Glenn Dranoff Department of Medical

Oncology and Harvard Medical School.

So EY, Ouchi T :The University ofChicago

Dominik Rttinger, Laboratory ofClinical and Experimental Tumor Immunology, Department

of Surgery, Grosshadern Medical Center, Ludwig-Maximilians-University

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