TUMOR IMMUNOLOGY from an ABNORMAL

PROLIFERATION of cells, through

the loss or modification of normal
growth.
 TUMOR IMMUNOLOGY  Cells which normally do not divide
(e.g. muscle or kidney cells) may
 Tumor antigen, response to
start proliferating, or cells which
tumor and evasion of the
normally do proliferate (e.g. basal
immune system, cancer
epithelial cells or hemopoietic cells)
immunotherapy, stem cell
may begin dividing in an
therapy.
uncontrolled fashion.

TUMOR MARKERS – for recurrence

CARCINOGENS
significance and for screening.
 RADIATION: ultraviolet light,
sunshine; X-rays, radioactive
elements induce DNA damage and
chromosome breaks.

 CHEMICAL: smoke and tar,

countless chemicals that damage
DNA (mutagens).
TUMOR MARKERS
 ONCOGENIC VIRUSES: insert DNA
or DNA copies of viral oncogenes
into the genome of host target cells.

 HEREDITARY: certain oncogenes

are inheritable.

CLASSIFICATION OF CANCER

CANCER  CARCINOMAS: epithelial origin

involving the skin, mucous
 Cancer remains one of the leading membranes, epithelial cells in
causes of death globally, with an glands.
estimated 12.7 million cases around
the world affecting both sexes  SARCOMAS: cancer of connective
equally. tissue.
 This number is expected to increase
to 21 million by 2030.
 Appearance of a tumor (from the
Latin word for “swelling”) results
  LYMPHOMAS: T- B-cell, Hodgkin's,  Tumor-Specific Transplantation
Burkitt's lymphomas; solid tumors. Antigens, or TSTA
o Chemical or radiation-
 LEUKEMIAS: disseminated tumors - induced tumors each
may be lymphoid, myeloid, acute generally express a unique
and chronic. neo-antigen, different from
other tumors induced by the
same or different agent.
TUMOR IMMUNOLOGY
 Tumor-Associated
 Tumor antigens
Transplantation Antigens, or TATA
 Tumors induced by the same
 Effectors mechanisms in anti-tumor virus express antigens
immunity. shared between different
tumors.
 Mechanisms of tumor evasion of the  These consist of membrane-
Immune system. expressed virally encoded
antigens and have been
 Immunotherapy for tumors. termed Tumor-Associated
Transplantation Antigens
(since they are not, strictly
speaking, tumor "specific").
TUMOR ANTIGEN
 Oncofetal antigens
 Many tumors can be shown to  These are TATAs which are
express cell surface antigens which more or less selectively
are not expressed in the normal expressed on tumors but are
progenitor cells before the neoplastic also shared with some
transformation event. normal fetal or embryonic
 These antigens have been tissues.
categorized based on their nature  Examples include
and distribution, resulting in a carcinoembryonic antigen
complex collection of acronyms, (CEA, shared with healthy
some of which are defined as: fetal gut tissue), and alpha-
fetoprotein (AFP, also
present in the serum of
 Tumor-Specific Transplantation healthy infants, but
Antigens, or TSTA decreasing by one year of
 Tumor-Associated age).
Transplantation Antigens, or
TATA
 Oncofetal antigens Tumors stimulate an immune response:
  Animals can be immunized against
tumors.
Tumor Surveillance

 Immunity is transferable from  Macrophage/Dendritic cell attack or

immune to naïve animals. antigen presentation.
 CD8 cell-mediated cytotoxicity.
 Tumor specific antibodies and cell  Antibody dependent cell mediated
have been detected in humans with cytotoxicity (ADCC).
some malignancies.  Natural killer cells

 Tumors can both activate and

suppress immunity

Cancer cells are different: - Tumors can activate the immune

response (ex. expression of foreign
 Escape normal intercellular antigen with MHCI) or suppress the
communication immune response (activation of T
 Allow for rapid growth regulatory cells that release IL-10
 Increased mobility of cells and TGFß) - the balance determines
 Invade tissues whether the cancer becomes
 Metastasis clinically relevant or not.
 Evade the immune systems

Immunosurveillance

Basic Tumor Immunosurveillance:

 The presence of tumor cells and

tumor antigens initiates the release
of "danger" cytokines such as IFNa
and heat shock proteins (HSP).

 These cause the activation and

maturation of dendritic cells such
that they present tumor antigens to
 A hypothesis that states that a CD8 and CD4 cells.
physiologic function of the immune
system is to recognize and destroy  Subsequent T cytotoxic destruction
malignantly transformed cells before of the tumor cells occurs.
they grow into tumors.

 Implies that cells of the immune  Helper T cells

system recognize something
 T cells: reacting to class
"foreign" on transformed/tumor cells.
II MHC peptide complex,
 they secret cytokines.  GM-CSF Granulocyte-
cytotoxic T cell response monocyte colony
(Thi helper T cells) stimulating factor) --
antibody response (Th2 reconstituting antigen-
helper T cells) presenting cells.

 Dendritic Cells
Antibody - produced by B cells
 The professional antigen-
presenting cells in the  Direct attack: blocking growth factor
final common pathway for receptors, arresting proliferation of
activating Naïve T-cells. tumor cells, or inducing apoptosis.
 is not usually sufficient to
 Cytotoxic T cells (CTLs)T completely protect the body.
cells(CTLs)  Indirect attack: major protective
 CD8+ T cells: attaching to efforts
class I MHC peptide (1) ADCC (antibody-dependent cell
complex, they destroy mediated cytotoxicity)
cancer cells by  recruiting cells that have
perforating the cytotoxicity, such as monocytes
membrane with enzymes and macrophages.
or by triggering an  (2) CDC (complement
apoptotic pathway. dependent cytotoxicity)
- binding to receptor,
Cytokines
initiating the complement
 Regulating the innate system, 'complement
immune system: NK cascade’, resulting in a
cells, macrophages and membrane attack complex
neutrophils; and the causing cell lysis and death.
adaptive immune system:
T and B cells
 IFN-a -- upregulating
MHC class I tumor
Cancer Immunotherapy
antigens and adhesion
molecules; promoting  Immunotherapy is the most recent
activity of B and T cells, advanced technique in cancer
macrophages, and therapy.
dendritic cells.  Cancer Immunotherapy is the use of
 IL-2 -- T cell growth factor immune system to reject Cancer.
that binds to a specific The main purpose of this premise is
tripartite receptor on T stimulating the patient's immune
cells. system to attack the malignant tumor
 IL-12 -- promoting NK cells that are responsible for the
and T cell activity and a disease.
growth factor for B cells.
  Immunotherapy works to harness  Monoclonal Antibodies
the innate powers of the immune
system to fight cancer.  Cytokines
 It fights cancer more powerfully, to
offer long-term protection, with less  Adoptive cell therapy
side effects.
 It may hold greater potential than  Cancer vaccines
current treatments, due to unique
properties of Immune System. Monoclonal Antibodies

History  Monoclonal antibody (mAbs)

therapy, is most widely used, and a
 Although cancer immunotherapy is form of Passive Immunotherapy.
being touted as a recent  It is a targeted therapy, directed to a
breakthrough in cancer treatment, its single target on a cancer cell,
origins at Memorial Sloan Kettering usually an antigen or a receptor site
go back more than a century. on the cancer cell.
 In the 1890s, William Coley, a  It binds to Cancer cell-surface
surgeon at New York Cancer specific antigens. When it recognize
Hospital (the predecessor to the antigen against which it is
Memorial Sloan Kettering) directed, they fit together like two
discovered cancer patients who pieces of a puzzle, setting of a
suffered from infections after surgery cascade of events leading to tumor
often fared better than those who did cell death.
not.  Examples: Avastin, Erbitux, Rituxan,
 His finding led to the Herceptin, Campath, Zevalin, Bexxar
development of Coley's
toxins; a cocktail of inactive
bacteria injected into tumors
that occasionally resulted in
complete remission.
 But eventually the use of this
Types of Monoclonal Antibodies
treatment fell out of favor.
 In the 1960s, research by Memorial  NAKED MABS
Sloan Kettering investigator Lloyd  Naked mAbs work alone, and
Old led to the discovery of antibody because they are unmodified.
receptors on the surface of cancer  MARK TARGETS FOR IMMUNE
cells, which enabled the SYSTEM - bind to targets and make
development of the first cancer them more visible. The immune
vaccines and led to the system is triggered and then
understanding of how certain white destroys the target.
blood cells, known as T cells or T  Attach to antigens that are
lymphocytes, can be trained to responsible for sending important
recognize cancer. signals that contribute to the target's
reproduction.
Types of Cancer Immunotherapy
  Binding to cell receptors, so that
proteins that trigger growth are
blocked. Usually used in cancer
treatments

 CONJUGATED MABS
 Conjugated mAbs are modified with
additional material.
 Radio immunotherapy (RIT) - These
mAbs have radioactive particles Adoptive Cell Therapy
directly attached and deliver them
directly to cancerous cells to kill  Adoptive cell transfer (ACT) is the
them. transfer of cells into a patient; as a
 Chemo-labeled - these mAbs have a form of cancer immunotherapy.
chemotherapy drug attached to their  It requires the generation of tumor-
structures, which would normally be antigen-reactive-T cells.
too powerful if delivered by itself.  The cells are most derived from the
This drug kills the cancerous cell. immune system, with the goal of
transferring improved immune
Cytokines [Active Immunotherapy functionality and characteristics
along with the cells back to the
 Cytokines are a large group of
patient.
proteins, that function as short range
 Interleukin-2 is normally added to
mediators involved in essentially all
the extracted T cells to boost their
biological processes.
effectiveness, but in high doses it
 Cytokines serve as molecular
can have a toxic effect.
messengers between cells.
 The reduced number of injected T
 They have important rate-limiting
cells is accompanied by reduced IL-
signals.
2, thereby reducing side effects.
 These are chemically made by some
immune system cells.
 They are injected, either under the Limitations of Adoptive Cell Therapy
skin, into a muscle, or into a vein.
 Not all tumor infiltrating lymphocytes
grow well enough in culture to
generate the quantity of cells that
Most common Cytokines are:
would be required to produce a
useful anti-tumor effect when they
are infused into the patient.
 Not all tumor infiltrating lymphocytes
can be made, in culture, to become
more adept at killing the tumor upon
return to the patient.
 Autologous therapy is cumbersome
and does not easily lend itself to the
 commercial scale mass production  Many cancer vaccines are poorly
techniques necessary to reach the immunogenic and require the use of
multitude of cancer patients world- adjuvants to elicit an effective
wide. immune response. The addition of
adjuvants may increase
immunogenicity of vaccine but may
Cancer Vaccines also increase toxicity.

 Unlike other vaccines, which

defends the immune system from
germs, Cancer vaccines make
person's immune system attack
cancer cells.
 There are two Broad Types of
Cancer Vaccines:

 PREVENTATIVE VACCINES: which

are intended to prevent cancer from
developing in healthy people.
 Cancer preventive vaccines target
infectious agent that cause or
contribute to the development of
cancer.

 TREATMENT VACCINES: which are

intended to treat an existing cancer
by strengthening the body's natural
defense against the cancer.

Limitations of Cancer Vaccines

 Today, most cancer vaccines are

targeted: that means it made against
a specific tumor cell antigenic target.
The limitations of targeted vaccines
are very similar to the limitations of
other targeted change, the target
vaccine becomes ineffective.
 Not all antigen are same
 Autologous vaccine therapy
presents many manufacturing
challenges.
 Autologous therapy is costly