Principles of cancer immunotherapy
Clinical oncology for students > Principles of cancer immunotherapy
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Last modified:
29 November 2016 09:57:06
Author(s):
Dr Craig Gedye — Author
Cancer Council Australia Oncology Education Committee — Co-author
Cite this page
Contents
1 Introduction
2 The immune system
3 Controlling the immune system: immune checkpoints
4 Cancer immunosurveillance and immunoevasion
5 Spectrum of cancer immunotherapy
6 Active non-specific cancer immunotherapy
7 Active specific cancer immunotherapy
8 Passive non-specific cancer immunotherapy
9 Passive specific cancer immunotherapy
10 Immune checkpoint inhibitors
11 Mechanism of action of immune checkpoint inhibitors
12 Current examples of immune checkpoint inhibitors
13 Side effects of checkpoint immunotherapy antibodies
14 Managing side-effects of immune checkpoint cancer immunotherapy
15 Managing expectations of immune checkpoint cancer immunotherapy
Introduction
Cancer immunotherapy has a long history, but has rapidly developed since 2010. The goals of cancer immunotherapy are to kill or control cancer cells by activating, or reactivating the immune system.
Back to top
The immune system
Our immune systems have evolved to a complex system involving innate and adaptive immune systems. Innate immunity starts with physical barriers (skin, mucus), and involves non-specific defences from immune cells such as neutrophils and natural killer cells. The adaptive immune system has evolved from innate immune cells, which include B-cells that produce antibodies, and is governed by lymphocytes, primarily alpha/beta, which include CD4+ helper, CD8+ killer and FOXP3+ regulatory T-cells.
The adaptive immune system is most relevant in managing the immune system, addressing viral infections, and has evolved to be the most important part of the immune system in terms of controlling and eliminating cancer.
Adaptive immune cells recognise other cells via antigen presentation. A small peptide fragment of a native, viral or cancer protein (the antigen or epitope) is “presented” on a cell surface complex made of proteins called the major histocompatibility complex (MHC). These epitopes are then recognised by proteins (e.g. the T-cell receptor, TCR) on the surface of individual T- or B-cell lymphocytes (Figure A). The repertoire of human T-cells and B-cells can recognise up to 109 individual patterns. The outcome of antigen presentation and recognition is determined by the balance of interactions between pairs of immune checkpoint costimulatory molecules (e.g. CTLA4-CD80, OX40-OX30L, CD154-CD40, PD1-PDL1; Figure B below).
Figures A and B
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Controlling the immune system: immune checkpoints
Uncontrolled immune activation leads to autoimmune diseases like ulcerative colitis, dermatitis and interstitial pneumonitis. The activity of the immune system is modulated and carefully controlled by costimulatory molecules called immune checkpoints. When antigen recognition occurs, a committee of other molecules interact on the surface of the immune cell and the target cell to determine the balance of the interaction. If the signals are largely positive, the immune cell activates and is primed to attack the antigen presented by the target cell. However if the balance of signals is negative, then the immune cell can become inactivated, sometimes permanently, and the antigen is accepted as a normal/self antigen (Figure B). Immune checkpoints of relevance to cancer include CTLA4, PD1 and PDL1 (see above).
Back to top
Cancer immunosurveillance and immunoevasion
Every cancer that becomes clinically detectable and relevant has survived elimination by the immune system. As soon as tiny cancers form, the aberrant proteins they express from mutated genes generate so-called “neoantigens” that can be recognised by the immune system by antigen presentation, targeting the aberrant cell for destruction.
Cancers are edited by this process, and may be eliminated at this point; so called immunosurveillance. Some cancers can enter a state of equilibrium with the immune system, and though present, remain clinically undetectable and irrelevant. If this balance is then later disturbed, for example by immunosuppression caused by age, illness or iatrogenic causes, the cancer can escape and evade immune control.
Cancer immunotherapies attempt to redress these escape mechanisms at many points, but a key mechanism for cancer cells to evade the immune system seems to be via negative immune checkpoint signalling (Figure C).
Figure C
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Spectrum of cancer immunotherapy
Cancer immunotherapies can be categorised by whether:
they actively stimulate the immune system, or passively alter immune system signalling or cell populations, and,
the treatment is targeted at a specific, known antigenic target, or is non-specifically stimulating the immune system.
Spectrum of cancer immunotherapy
(adapted from Davis et al., 2000)
Back to top
Active non-specific cancer immunotherapy
Bacillus Calmette-Guerin (BCG) is one of the most commonly used and earliest discovered cancer immune therapies. This live attenuated strain of Mycobacterium tuberculosis is instilled intravesically to reduce recurrence of debulked non-muscle invasive bladder cancer. The mechanism of action is a non-specific inflammatory reaction; side effects can include dysuria and other lower urinary tract symptoms.
Immunostimulatory cytokines such as interferon-alpha and interleukin-2 were previously mainstay treatments of metastatic renal-cell carcinoma and melanoma. Interferon-alpha was used as adjuvant therapy in resected high-risk melanoma, though the survival advantage was debatable. Interleukin-2 is still used in some countries in a limited highly restricted patient population. Treatment requires ICU admission due to severe systemic inflammatory responses and hypotension. A proportion of patients who took IL2 have experienced long-term remission of their cancer.
Oncolytic viruses such as T-VEC (talimogene laherparepvec) and CAVATAK® (Coxsackievirus A21) are attenuated or modified viruses that can be injected directly into tumour masses or administered intravenously. Infection of tumour cells is associated with activation of an immune response, that in some patients can even spread to other, uninjected tumour sites (the “abscopal” effect). Many viruses are being explored, but none are yet in routine clinical practice.
Back to top
Active specific cancer immunotherapy
Cancer vaccines have been trialled in many different formats, but all attempt to direct the immune system to recognise particular antigens that are then hoped to cause recognition and elimination of the cancer. Cancer vaccines can target a single peptide, a protein, or autologous or allogenic cancer cells. Unfortunately most of these vaccines have failed to improve patient outcomes. Sipeleucel-T is an allogeneic vaccine using prostate cancer cell lines that has a modest effect in prostate cancer, but is not available in Australia.
Oncogenic virus vaccines are the most common and important form of cancer immunotherapy. Vaccines that prevent infection by the hepatitis B virus (causing hepatocellular carcinoma) or the human papillomavirus (causing cervical, ****, penile and some head and neck cancers) are internationally and numerically the most effective and most cost-effective cancer immunotherapies available.
CAR-T-cells are autologous patient derived T-cells, that have been genetically modified to display cancer cell recognition molecules on their cell surface. In isolated cases these have generated extraordinary responses (e.g. CD19+ paediatric B-ALL) but with considerable toxicity.
Meghna Thapar 5 years ago
Principles of cancer immunotherapy
Clinical oncology for students > Principles of cancer immunotherapy
Export options
Create a book
Export as PDF
Information on authorship and revision
Last modified:
29 November 2016 09:57:06
Author(s):
Dr Craig Gedye — Author
Cancer Council Australia Oncology Education Committee — Co-author
Cite this page
Contents
1 Introduction
2 The immune system
3 Controlling the immune system: immune checkpoints
4 Cancer immunosurveillance and immunoevasion
5 Spectrum of cancer immunotherapy
6 Active non-specific cancer immunotherapy
7 Active specific cancer immunotherapy
8 Passive non-specific cancer immunotherapy
9 Passive specific cancer immunotherapy
10 Immune checkpoint inhibitors
11 Mechanism of action of immune checkpoint inhibitors
12 Current examples of immune checkpoint inhibitors
13 Side effects of checkpoint immunotherapy antibodies
14 Managing side-effects of immune checkpoint cancer immunotherapy
15 Managing expectations of immune checkpoint cancer immunotherapy
Introduction
Cancer immunotherapy has a long history, but has rapidly developed since 2010. The goals of cancer immunotherapy are to kill or control cancer cells by activating, or reactivating the immune system.
Back to top
The immune system
Our immune systems have evolved to a complex system involving innate and adaptive immune systems. Innate immunity starts with physical barriers (skin, mucus), and involves non-specific defences from immune cells such as neutrophils and natural killer cells. The adaptive immune system has evolved from innate immune cells, which include B-cells that produce antibodies, and is governed by lymphocytes, primarily alpha/beta, which include CD4+ helper, CD8+ killer and FOXP3+ regulatory T-cells.
The adaptive immune system is most relevant in managing the immune system, addressing viral infections, and has evolved to be the most important part of the immune system in terms of controlling and eliminating cancer.
Adaptive immune cells recognise other cells via antigen presentation. A small peptide fragment of a native, viral or cancer protein (the antigen or epitope) is “presented” on a cell surface complex made of proteins called the major histocompatibility complex (MHC). These epitopes are then recognised by proteins (e.g. the T-cell receptor, TCR) on the surface of individual T- or B-cell lymphocytes (Figure A). The repertoire of human T-cells and B-cells can recognise up to 109 individual patterns. The outcome of antigen presentation and recognition is determined by the balance of interactions between pairs of immune checkpoint costimulatory molecules (e.g. CTLA4-CD80, OX40-OX30L, CD154-CD40, PD1-PDL1; Figure B below).
Figures A and B
Back to top
Controlling the immune system: immune checkpoints
Uncontrolled immune activation leads to autoimmune diseases like ulcerative colitis, dermatitis and interstitial pneumonitis. The activity of the immune system is modulated and carefully controlled by costimulatory molecules called immune checkpoints. When antigen recognition occurs, a committee of other molecules interact on the surface of the immune cell and the target cell to determine the balance of the interaction. If the signals are largely positive, the immune cell activates and is primed to attack the antigen presented by the target cell. However if the balance of signals is negative, then the immune cell can become inactivated, sometimes permanently, and the antigen is accepted as a normal/self antigen (Figure B). Immune checkpoints of relevance to cancer include CTLA4, PD1 and PDL1 (see above).
Back to top
Cancer immunosurveillance and immunoevasion
Every cancer that becomes clinically detectable and relevant has survived elimination by the immune system. As soon as tiny cancers form, the aberrant proteins they express from mutated genes generate so-called “neoantigens” that can be recognised by the immune system by antigen presentation, targeting the aberrant cell for destruction.
Cancers are edited by this process, and may be eliminated at this point; so called immunosurveillance. Some cancers can enter a state of equilibrium with the immune system, and though present, remain clinically undetectable and irrelevant. If this balance is then later disturbed, for example by immunosuppression caused by age, illness or iatrogenic causes, the cancer can escape and evade immune control.
Cancer immunotherapies attempt to redress these escape mechanisms at many points, but a key mechanism for cancer cells to evade the immune system seems to be via negative immune checkpoint signalling (Figure C).
Figure C
Back to top
Spectrum of cancer immunotherapy
Cancer immunotherapies can be categorised by whether:
they actively stimulate the immune system, or passively alter immune system signalling or cell populations, and,
the treatment is targeted at a specific, known antigenic target, or is non-specifically stimulating the immune system.
Spectrum of cancer immunotherapy
(adapted from Davis et al., 2000)
Back to top
Active non-specific cancer immunotherapy
Bacillus Calmette-Guerin (BCG) is one of the most commonly used and earliest discovered cancer immune therapies. This live attenuated strain of Mycobacterium tuberculosis is instilled intravesically to reduce recurrence of debulked non-muscle invasive bladder cancer. The mechanism of action is a non-specific inflammatory reaction; side effects can include dysuria and other lower urinary tract symptoms.
Immunostimulatory cytokines such as interferon-alpha and interleukin-2 were previously mainstay treatments of metastatic renal-cell carcinoma and melanoma. Interferon-alpha was used as adjuvant therapy in resected high-risk melanoma, though the survival advantage was debatable. Interleukin-2 is still used in some countries in a limited highly restricted patient population. Treatment requires ICU admission due to severe systemic inflammatory responses and hypotension. A proportion of patients who took IL2 have experienced long-term remission of their cancer.
Oncolytic viruses such as T-VEC (talimogene laherparepvec) and CAVATAK® (Coxsackievirus A21) are attenuated or modified viruses that can be injected directly into tumour masses or administered intravenously. Infection of tumour cells is associated with activation of an immune response, that in some patients can even spread to other, uninjected tumour sites (the “abscopal” effect). Many viruses are being explored, but none are yet in routine clinical practice.
Back to top
Active specific cancer immunotherapy
Cancer vaccines have been trialled in many different formats, but all attempt to direct the immune system to recognise particular antigens that are then hoped to cause recognition and elimination of the cancer. Cancer vaccines can target a single peptide, a protein, or autologous or allogenic cancer cells. Unfortunately most of these vaccines have failed to improve patient outcomes. Sipeleucel-T is an allogeneic vaccine using prostate cancer cell lines that has a modest effect in prostate cancer, but is not available in Australia.
Oncogenic virus vaccines are the most common and important form of cancer immunotherapy. Vaccines that prevent infection by the hepatitis B virus (causing hepatocellular carcinoma) or the human papillomavirus (causing cervical, ****, penile and some head and neck cancers) are internationally and numerically the most effective and most cost-effective cancer immunotherapies available.
CAR-T-cells are autologous patient derived T-cells, that have been genetically modified to display cancer cell recognition molecules on their cell surface. In isolated cases these have generated extraordinary responses (e.g. CD19+ paediatric B-ALL) but with considerable toxicity.
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