TUMOUR IMMUNOLOGY AND IMMUNOTHERAPY
It is thought that the immune system can perceive and eliminate some tumors early on their
development. However, the theory of immunoediting, which involves the process of
immunosurveillance, suggests that certain tumors escape from an equilibrium state previously held in
check by the immune system, and become clinically significant.
Approaches to Cancer Immunotherapy:
- Therapeutic cancer vaccines
- Adoptive T cell therapy
- Anti-tumor antibodies
- Immune checkpoint blockade
Innate Immunity and Cancer
Tissue inflammation as part of the innate immune response serves to help eliminate invasive foreign
pathogens, initiate tissue repair, and can serve to stimulate the adaptive immune response through B
and T cells.
However, there is a significant amount of evidence that both acute and chronic inflammation may
promote genetic abnormalities and cancer progression.
In an environment of chronic inflammation, myeloid cell differentiation can occur (myeloid-derived
suppressor cells. These cells can inhibit anti-tumor immune response through suppression of both T
cells and NK cells.
It has been shown that myeloid-derived suppressor cells can promote neoangiogenesis, tumor stromal
remodelling, and even metastasis.
Dendritic Cells and Cancer
A subset of CD8+ DCs in mice and CD141+ DCs in humans have been reported to play a major role
in cross-presentation and priming of anti-tumor immune response.
DC based immunotherapy aims to induce an effective anti-tumor response using externally generated
DCs as antigen presenting cells. The widespread implementation of this approach as been hampered
by logistical challenges and limited clinical success. However, the first FDA approved DC-based
immunotherapy was approved for men with metastatic castrate resistant prostate cancer.
Adaptive Immunity and Cancer
An effective immune response is initiated when a B cell or T cell recognizes antigen in a pro-
stimulatory context and undergoes selective activation and proliferation.
This immune response is tightly regulated by multiple costimulatory and coinhibitory pathways. Full
activation of a T cell also requires the simultaneous engagement of positive costimulatory molecules
present on activated APCs, known as signal 2. These costimulatory molecules are not present on
quiescent APCs, tumor cells or normal host cells.
Compensatory coinhibitors attenuate the immune response and are often co-opted by anti-tumor
immune response.
In cancer immunity, APCs may also play a role in tolerance by presenting antigens in a tolerogenic
environment leading to lack of T cell activation and potential exhaustion.
Adaptive T Cell Therapy
, Adoptive T cell therapy is a promising and rapidly advancing form of immunotherapy that overcomes
tolerance by harnessing the natural ability of immune cells to recognize and eliminate target cells to
generate durable anti-tumor immune responses.
Adoptive T cell therapy involves the infusion of externally manipulated T cells.
The potential to treat metastatic solid tumors via manipulation of endogenous T cells was first
explored with the use of high dose intravenous interleukin-2 (IL-2), a canonical T cell growth factor.
Tumor-infiltrating lymphocytes (TILs) therapy involves extracting lymphocytes from tumor tissue, ex
vivo expansion with IL-2 followed by reinfusion. Although expanded TILs are thought to be one of
the least labour-intensive ACT strategies, several limitations preclude widespread adoption at the
current time. These include the need for appropriate cell processing equipped facilities as well as the
need for patients to have moderately bulky tumors for TIL isolation.
Another approach to adoptive T cell therapy is the use of endogenous peripheral tumor specific T cells
that are specifically expanded and activated ex vivo with reintroduction into the host via adoptive
transfer. This approach is somewhat labor intensive, involving multiple pheresis sessions to isolate
PBMCs followed by the expansion of antigen-specific T cells.
Anti-Tumor Antibodies
- Monoclonal antibodies directed against tumor associated antigens like CD20 and HER-2 are a
standard of care treatment in many malignancies.
- This technology was facilitated by the simultaneous understanding of antibody structure and the
application of hybridoma technology.
- Another technology has been the development of engineered bi-specific antibodies, in which one
fragment arm binds the CD3 portion of the T cell receptor on T lymphocytes, and the other fragment
arm carries specificity for a tumor antigen. These constructs aim to co-localize T lymphocytes to
tumor cells and thus induce anti-tumor immune responses.
Immune Surveillance
It proposes that the immune system is constantly screening and potentially eliminating aberrant or
transformed cancer cells.
The initial phase of immune surveillance where the innate and adaptive immune systems work
together to destroy and control malignant cells. However, there is a proposed state of equilibrium at a
point where cancer cells have accumulated sufficient alterations to resist immune mediated cell death
and survive at a steady state.
At some point after this the cancer cells continue to suppress the immune system to the point of it
becoming refractory and reach the escape phase where they rapidly proliferate and spread.
Cancer Vaccines
Oncogenic viruses are an ideal target for preventative cancer vaccines.
The HPV vaccine has been shown in large clinical trials to drastically reduce the chances of
developing cervical cancer. Additionally, other tissues such as oral and anal mucosa are susceptible to
HPV mediated transformation, and thus the HPV vaccine has the potential to reduce development of
multiple different types of cancer.
Therapeutic cancer vaccines aim to treat cancer after diagnosis. This task can be much more difficult
given the development of immune tolerance mechanisms and the obstacles to immune function.
Several broad categories of therapeutic cancer vaccines include peptide based vaccine, cell-based
vaccines, virus-based vaccine and vaccines based on ex-vivo generated dendritic cells.
CANCER IMMUNOLOGY
It is thought that the immune system can perceive and eliminate some tumors early on their
development. However, the theory of immunoediting, which involves the process of
immunosurveillance, suggests that certain tumors escape from an equilibrium state previously held in
check by the immune system, and become clinically significant.
Approaches to Cancer Immunotherapy:
- Therapeutic cancer vaccines
- Adoptive T cell therapy
- Anti-tumor antibodies
- Immune checkpoint blockade
Innate Immunity and Cancer
Tissue inflammation as part of the innate immune response serves to help eliminate invasive foreign
pathogens, initiate tissue repair, and can serve to stimulate the adaptive immune response through B
and T cells.
However, there is a significant amount of evidence that both acute and chronic inflammation may
promote genetic abnormalities and cancer progression.
In an environment of chronic inflammation, myeloid cell differentiation can occur (myeloid-derived
suppressor cells. These cells can inhibit anti-tumor immune response through suppression of both T
cells and NK cells.
It has been shown that myeloid-derived suppressor cells can promote neoangiogenesis, tumor stromal
remodelling, and even metastasis.
Dendritic Cells and Cancer
A subset of CD8+ DCs in mice and CD141+ DCs in humans have been reported to play a major role
in cross-presentation and priming of anti-tumor immune response.
DC based immunotherapy aims to induce an effective anti-tumor response using externally generated
DCs as antigen presenting cells. The widespread implementation of this approach as been hampered
by logistical challenges and limited clinical success. However, the first FDA approved DC-based
immunotherapy was approved for men with metastatic castrate resistant prostate cancer.
Adaptive Immunity and Cancer
An effective immune response is initiated when a B cell or T cell recognizes antigen in a pro-
stimulatory context and undergoes selective activation and proliferation.
This immune response is tightly regulated by multiple costimulatory and coinhibitory pathways. Full
activation of a T cell also requires the simultaneous engagement of positive costimulatory molecules
present on activated APCs, known as signal 2. These costimulatory molecules are not present on
quiescent APCs, tumor cells or normal host cells.
Compensatory coinhibitors attenuate the immune response and are often co-opted by anti-tumor
immune response.
In cancer immunity, APCs may also play a role in tolerance by presenting antigens in a tolerogenic
environment leading to lack of T cell activation and potential exhaustion.
Adaptive T Cell Therapy
, Adoptive T cell therapy is a promising and rapidly advancing form of immunotherapy that overcomes
tolerance by harnessing the natural ability of immune cells to recognize and eliminate target cells to
generate durable anti-tumor immune responses.
Adoptive T cell therapy involves the infusion of externally manipulated T cells.
The potential to treat metastatic solid tumors via manipulation of endogenous T cells was first
explored with the use of high dose intravenous interleukin-2 (IL-2), a canonical T cell growth factor.
Tumor-infiltrating lymphocytes (TILs) therapy involves extracting lymphocytes from tumor tissue, ex
vivo expansion with IL-2 followed by reinfusion. Although expanded TILs are thought to be one of
the least labour-intensive ACT strategies, several limitations preclude widespread adoption at the
current time. These include the need for appropriate cell processing equipped facilities as well as the
need for patients to have moderately bulky tumors for TIL isolation.
Another approach to adoptive T cell therapy is the use of endogenous peripheral tumor specific T cells
that are specifically expanded and activated ex vivo with reintroduction into the host via adoptive
transfer. This approach is somewhat labor intensive, involving multiple pheresis sessions to isolate
PBMCs followed by the expansion of antigen-specific T cells.
Anti-Tumor Antibodies
- Monoclonal antibodies directed against tumor associated antigens like CD20 and HER-2 are a
standard of care treatment in many malignancies.
- This technology was facilitated by the simultaneous understanding of antibody structure and the
application of hybridoma technology.
- Another technology has been the development of engineered bi-specific antibodies, in which one
fragment arm binds the CD3 portion of the T cell receptor on T lymphocytes, and the other fragment
arm carries specificity for a tumor antigen. These constructs aim to co-localize T lymphocytes to
tumor cells and thus induce anti-tumor immune responses.
Immune Surveillance
It proposes that the immune system is constantly screening and potentially eliminating aberrant or
transformed cancer cells.
The initial phase of immune surveillance where the innate and adaptive immune systems work
together to destroy and control malignant cells. However, there is a proposed state of equilibrium at a
point where cancer cells have accumulated sufficient alterations to resist immune mediated cell death
and survive at a steady state.
At some point after this the cancer cells continue to suppress the immune system to the point of it
becoming refractory and reach the escape phase where they rapidly proliferate and spread.
Cancer Vaccines
Oncogenic viruses are an ideal target for preventative cancer vaccines.
The HPV vaccine has been shown in large clinical trials to drastically reduce the chances of
developing cervical cancer. Additionally, other tissues such as oral and anal mucosa are susceptible to
HPV mediated transformation, and thus the HPV vaccine has the potential to reduce development of
multiple different types of cancer.
Therapeutic cancer vaccines aim to treat cancer after diagnosis. This task can be much more difficult
given the development of immune tolerance mechanisms and the obstacles to immune function.
Several broad categories of therapeutic cancer vaccines include peptide based vaccine, cell-based
vaccines, virus-based vaccine and vaccines based on ex-vivo generated dendritic cells.
CANCER IMMUNOLOGY
