CANCER TERMINOLOGY

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CANCER TERMINOLOGY

• Tumor Neoplasm
• BENIGN
• -Slow growing, circumscribed, encapsulated,well
  defined edges
• MALIGNANT
• -Rapidly growing, aggressive, invasive, forms
  metastases

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Drs. Barry Marshall Robin Warren, Univ. of
Western Australia
Medicine 2005
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TUMOR FORMATION IS A MULTI-STEP PROCESS INVOLVING
SEVERAL GENETIC EVENTS
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Chemotherapy and radiotherapy share the following
characteristics

• A. Equally effective for treating metastatic
  disease
• B. May equally destroy normal cells and cancer
  cells
• C. Cause toxicity, nausea and fatigue
• D. Cause suppression of the immune system

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Tumors are infiltrated by various immune cells
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WHY CONSIDER IMMUNOTHERAPY OF CANCER ?

• Observations that support immune response against
  cancer
• i. Spontaneous regression of certain tumors
• ii. Favorable prognosis of certain cancers
  associated with presence of immune cells at the
  tumor site
• iii. Immunocompetence in cancer patients
  correlates with good prognosis
• iv. Presence of tumor-specific immunity based on
  presence of CTLs, antibodies
• v. Augmentation of tumor immunity achieved by
  immunization

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The immune system can distinguish cancer cells
from normal cells because cancer cells

• A. Are larger than normal cells
• B. Reproduce faster than normal cells
• C. Express unique proteins not found on normal
  cells
• D. Express very high levels of proteins found on
  normal cells

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CANCER ANTIGENS

• Tumor Specific Antigens (TSA)
• Expressed ONLY on tumor cells, induced by
  chemicals, radiation or viruses.
• Tumor Associated Antigens (TAA)
• Expressed on BOTH normal cells and tumor cells,
  but usually over-expressed on tumor cells.
• Examples
• A) MAGE-1, tyrosinase (melanoma),
• B) Prostate specific antigen (PSA) (prostate
  cancer),
• C) Her-2/Neu (breast cancer)
• D) Oncofetal antigens
• i) Carcinoembryonic antigen (CEA) (colon
  cancer)
• ii) Alpha fetoprotein (AFP) (liver cancer)

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Dendritic cells (DC) are the most potent
antigen-presenting cells, inducing
both naïve and memory immune responses.
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NON-SPECIFIC IMMUNOTHERAPYBacteria and Bacterial
Products
BCG (Bacille-Calmette Guerin) Effective in
animal models at inhibiting tumor growth or
inducing rejection of established tumors
Regression of cutaneous melanoma metastases
after intralesional injection of BCG.
Intravesicular instillation of BCG effective in
treatment of superficial bladder cancer. Still in
use as adjuvant for treating human cancers
Corynebacterium parvum (C. parvum) Heat killed
organisms prolong disease free interval in
melanoma patients. Mixed results obtained with
breast cancer. Microbial products Developed to
avoid risks associated with use of intact
organisms. Examples include Cell Wall Skeleton
(CWS-polymeric polysaccharide- mucopeptide
complex esterified with mycolic acid) of BCG,
Endotoxin (LPS), Lipid A, Monophosphoryl lipid A
(MPL), Muramyl dipeptide (MDP), CpG
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NON-SPECIFIC IMMUNOTHERAPY Immunomodulators
Interleukins IL-2 Most extensively used.
Stimulates proliferation and activation of T
cells and NK cells. Effective in treatment of
melanoma and renal cancer (10-15 clinical
responses). Caveat most recent study (melanoma)
demonstrates induction of Treg cells after high
dose IL-2 therapy. IL-12 Extensive antitumor
effects demonstrated in pre-clinical animal
models. No significant clinical responses
observed in treatment of solid tumors in humans.
Potentially effective doses are toxic in
humans.Interferons Interferon-alpha most
extensively used in clinical trials. Some success
in treatment of numerous cancers namely, Hairy
cell leukemia, chronic myelogenous leukemia,
lymphomas, AIDS-associated Kaposi's sarcoma,
melanoma
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Antigen-Specific Immunotherapy

• TUMOR VACCINES
• Whole tumor cells BCG or DETOX, e.g. Melacine
  vaccine (cell lysates), CancerVax ( irradiated
  melanoma cell lines), M-Vax (hapten-treated
  autologous cells) and gene-modified, irradiated
  tumor cells (GM-CSF)
• b. Viral oncolysate-viruses used to infect tumor
  cells e.g. vaccinia virus, New Castle disease
  virus, direct intratumoral injection of oncolytic
  viruses (RNA, DNA)
• c. Tumor antigens
• MAGE-1, MART-1/Melan-A, tyrosinase, gp100, MUC-1,
  CEA, etc.
• d. Peptide vaccines mutated ras, mutated p53,
  Her-2/neu, MART -1, gp100, MUC-1
• e. Dendritic cells gene engineered, pulsed with
  peptides/tumor Iysates, DC-tumor cell hybrid
• f. Heat shock proteins
• g. DNA vaccines

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Antigen-Specific Immunotherapy
Adoptive Cellular Therapy 1. Lymphokine
Activated Killer (LAK) cells 2. Tumor
Infiltrating Lymphocytes (TIL) 3. TCR
gene-modified TIL 4. Draining Lymph Node
Cells  
Most of the available data are on melanoma
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Superficial Spreading of Malignant Melanoma
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Metastatic Malignant Melanoma
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PEPTIDE VACCINES

• Melanoma peptides gp100, MART-1, Tyrosinase
• 2. Breast cancer peptides Her-2/Neu
• 3. Adenocarcinoma MUC1, CEA
• Used in conjunction with adjuvants (e.g. IFA,
  DETOX, CpG-ODN, IL-2, GM-CSF)

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Tumor Antigen Loading of DC
X
Tumor lysate pulsing
DC x tumor cell fusions
Tumor antigen peptide pulsing
Tumor antigen gene transduction
(mRNA, virus)
Chaperone/tumor antigen peptide pulsing
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Ridgway, 2003
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Summary of DC Vaccines
First published trial 1995 Since 1995, over 200
studies published, taken place in over 15
countries However, relatively few complete or
partial clinical responses reported Success
Rate Dendritic Cell vaccines 2-10, Other
Vaccines 1-3
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Enhancing Cellular Therapy

• Adoptive cell transfer
• plus
• lymphodepletion

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Fig. 2. Multiple lung metastases (arrows) showed
dramatic shrinkage in computed tomographic scans
of patient 6 who had an overall partial response
to treatment
Rosenberg, Steven A. and Dudley, Mark E. (2004)
Proc. Natl. Acad. Sci. USA 101, 14639-14645
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Mocellin et al. Lancet Oncol. 5 681, 2004
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SUMMARY

• Some Thoughts.

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Why have we not been more successful with
immunotherapy as a strategy for treating cancer?
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Inefficient Immune Response
Lymphocyte Factors
Insufficient of anti-tumor T cells Ineffective
antigen-presenting cells Insufficient avidity of
T cells for tumor T cells tolerized (antigen
weakly immunogenic) Down-regulation T cell
receptor signal transduction Apoptosis of T cells
upon encountering tumor Inadequate T cell
function (cytokines, lysis) Poor T cell
trafficking to tumor site Active suppression by
regulatory lymphocytes
Tumor Factors
Tumor cannot activate quiescent memory T
cells Insufficient tumor antigen expression Lack
of T cell help (i.e. lack of MHC II display by
tumor) Loss of HLA expression by tumor Tumor
produces local immunosuppressive factors (TGF- b,
IL-10, VEGF)
Rosenberg, J Int Med 250 462-74,2001
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Where do we expect the most success given the
present state of affairs?

• Immunotherapy as adjuvant treatment in setting
  of
• Minimal disease
• Non-evident clinical disease to prevent
  recurrence
• Bulky disease (only after improving our knowledge
  of the tumor microenvironment, etc.). This is the
  least likely.