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Immunity and Tumors. Cancer Immunotherapy. Immunity and Tumors. 1890s Coley treats patients with bacterial extracts 1950-1960s Burnet and Thomas - Immune-surveillance Hypothesis “ Major function of the immune system is to recognize and destroy arising malignantly transformed cells ” 1957

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slide1

Immunity and Tumors

  • Cancer Immunotherapy
slide2

Immunity and Tumors

1890s

Coley treats patients with bacterial extracts

1950-1960s

Burnet and Thomas- Immune-surveillance Hypothesis

“Major function of the immune system is to recognize and destroy arising malignantly transformed cells”

1957

Prehn and Main- The origin of modern tumor immunology

slide3

Pathogenesis of neoplasia

Promotion

Normal

Initiation

Progression

Clonal evolution

Additional mutations

DNA damage

(chemical, phisical, biologic)

DNA damage

differentiation

proliferation

proliferation

apoptosis

slide4

I tumori e la risposta immunitaria

I tumori derivano da tessuti normali

I tessuti normali non inducono risposta immunitaria

Esiste una risposta immunitaria contro i tumori?

slide5

L’immunosorveglianza

  • 1959 Thomas e Burnet: l’immunosorveglianza
  • The immune system maintains vigil over both alien microorganisms and altered somatic cells
  • Il tumore è antigenico ed immunogenico
  • Evidenze sperimentali:
  • Il trapianto di tumori in ospiti singenici viene rigettato, mentre il
  • trapianto di tessuti normali viene accettato
  • Il rigetto di tumori spontanei o indotti conferisce protezione
  • 2) Evidenze cliniche:
  • L’insorgenza di tumori è piu’ alta in assenza di competenza
  • immunologica (immunodeficienze congenite o acquisite)
slide6

Evidenze di immunogeneticità dei tumori

Sarcoma

Vaccinazione con cellule tumorali

Resezione chirurgica

Topo naive

Topo vaccinato

Nessuna crescita

Crescita del tumore

Nessuna crescita

slide7

Conclusions from experiments on transplanted tumors

  • - The immune system of inbred mice can recognize antigens expressed
  • by tumor cells induced by chemical carcinogens
  • - Such recognition results in rejection of a subsequent challenge of the
  • same but not a different tumor in previously immunized animals
  • - Specificity and memory
  • The immune cells but not antibodies can mediate this reaction
slide8

Evidenze sperimentali

dell’immunogenicità dei tumori

1. Presenza di cellule mononucleate nel siti di crescita del tumore (linfociti T, natural killer, macrofagi)

2. Iperplasia dei linfonodi drenanti il sito di crescita del tumore

3. Evidenze di effetti dovuti a citochine pro-infiammatorie direttamente sul tumore (indotta espressione di MHC II, ICAM-1)

4. Regressione spontanea di alcuni tumori.

slide9

Evidenze cliniche di immunosorveglianza

  • Inherited Immunodeficiency
  • 2) Organ transplant recipients
  • 3) Patients with auto-immune disorders
  • 4) Second tumors in cancer patients
  • 5) HIV infection
slide10

Evidenze cliniche di immunosorveglianza

1) Inherited Immunodeficiency

slide11

Experiments in gene-knockout mice lacking various components

of the immune system

  • - IFN-g deficient mice have a higher rate of both spontaneous and carcinogen-
  • induced tumors
  • - Double IFN-g and Rag-2 deficient mice
  • Perforin-deficient mice
  • TRAIL-deficient mice

Role for NK cells

slide12

Tumor cell recognition by NK cells

  • Missing self recognition:
  • - Inhibitory receptors (KIR, CD94/NKG2A) bind directly to intact MHC class I
  • molecules

Recognition of induced self ligands as marker of abnormal self:

- Stimulatory receptors (NKG2D) bind to ligands expressed or up-regulated in

tumor cellsand virally infected cells

- Ligands: MICA/B expressed on tumor cells of epithelial origin; Retinoic

acid early inducible protein (Rae1); H60

slide13

L’immunosorveglianza

presuppone l’esistenza di:

1. Antigeni tumore specifici/ tumore associati

2. Cellule effettrici in grado di riconoscere il tumore e mediarne il rigetto

Conoscere l’identità degli antigeni tumorali è fondamentale per sviluppare immuno-terapie antigene/tumore specifiche

Caratterizzare le cellule effettrici è fondamentale per poter intervenire e manipolare la risposta immunitaria

slide14

Elementi critici nello sviluppo di una risposta anti-tumorale

Risposta primaria

Tumore (sorgente di antigene)

Cellule adibite alla presentazione antigenica

Linfociti T e B

Colocalizzazione

Risposta secondaria

Tumore

Cellule adibite alla presentazione antigenica

Linfociti T e B

Macrofagi, cellule NK, NKT

slide15

Primary lymphoid organs:

bone marrow and thymus

Secondary lymphoid organs:

lymph nodes and spleen

Non lymphoid organs:

site of infection

Anatomy of the adaptive immune responses

slide16

Primary lymphoid organs:

bone marrow and thymus

Secondary lymphoid organs:

lymph nodes and spleen

Non lymphoid organs:

site of tumor growth

Anatomy of the adaptive anti-tumor immune responses

slide17

Physiological condition

Tissue antigens

Tissue-specific antigens are ignored

slide18

Lymph

Blood

Transforming event

Tumor antigens

or tumor cells

Blood

Tumor-specific T cells

Patological conditions

Tumor-specific immune responses

slide19

The fine balance between

immune responsiveness and immune resistance

Spontaneous inflammation in the tumor microenvironment

Tumor regression

Immune stimulation or inflammation

Tumor growth

Tumor progression

Antigen-specific immunization

Non specific immune stimulation

slide20

Critical factors in adaptive immune responses

Proper selection of antigen specific progenitors

Secondary lymphoid organs

Appropriate timing

Proinflammatory stimuli

Shaping of the immune response over time and space

slide21

Main lymphocytes subsets

participating to anti-tumor responses

Th-1 CD4 T lymphocytes: helper cell, CD8, APC, killing

Th-2 CD4 T lymphocytes: helper cell, B cells

Tc-1 CD8 T lymphocytes: cytotoxic cell

B cells: Ab production

NK, NKT, gd T cells

slide22

Classification of tumor antigens

- Tumor-specific shared antigens/Cancer-testis antigens

Antigens encoded by genes expressed in variable proportion on

different cancers, but not in normal tissues except testis and placenta

- Differentiation tumor antigens

Antigens encoded by genes expressed in tumor cells and in normal tissue

- Unique tumor antigens

Antigens corresponding to peptides encoded by regions of ubiquitously

expressed proteins that are mutated in tumor cells

- Over-expressed tumor antigens

Antigens encoded by non-mutated genes that are expressed at different level

in neoplastic and normal tissue

- Viral antigens

Antigens derived from oncogenic viruses

slide23

Fong, L and Engleman, EG

Annu Rev Immunol, 18:217,

2000

slide24

CD4+ T cells are important for tumor rejection

- In vivo depletion experiments with antibody recognizing

different lymphocytes population

- Experiments using CD4-knockout mice

- Adoptive transfer of tumor-specific CD8+ and CD4+ T

lymphocytes

slide25

CD4+ T cells

in anti-tumor immune response

Lymphoid

organs

Peripheral

tissues

slide26

Priming phase

Tumor cell

Mature

dendritic cell

Tumor antigens

Draining

Lymph node

Immature

dendritic cell

MHC

Class I

MHC

Class II

Tumor

peptides

CD40

CD8+

T cell

CD40L

Th2

CD4+

T cell

B cell

Th1

Effector phase

Th1/Th2

CD4+

CTL

Th1

Killing

Reactive oxigen

intermediates

Release of

granule contents

Macrophage

Tumorcell

Killing

CD8+

CTL

slide27

Effector mechanisms in cancer immunity

  • - Antibodies
  • - Coating with antigen, opsonization and phagocytosis by macrophages
  • - Crosspriming
  • - NK cells
  • -Lyse MHC mismatched cells, cells having low level of or lacking
  • MHC class I expression, cells expressing ligands of stimulatory receptors
  • NKT cells
  • - Recognize glycolipid antigens by non-classical MHC molecules and
  • produce large amounts of type 1 or type 2 cytokines
  • - Macrophages and neutrophils
  • - Activated by tumor microenvironment, and CD4+ T cells
  • - Release of tumoricidal factors (TNF, nitrogen oxides), endocytosis of
  • malignant cells
  • - Cytokines
  • - T cells
slide28

Different mechanisms may be responsible for failure

to develop effective anti-tumor immunity in vivo

- Failure to develop immunity

Ignorance

-Tolerance induction

Anergy/Deletion

- Mechanisms of immune escape

slide29

Failure to develop efficient anti-tumor immunity

Tumor cell

Antigen uptake by

tolerance-inducing APC

T cell

APC

T cell

TCR

MHC-peptide

Tolerance

Receptor for

costimulatory

signals

slide30

Mechanisms of tumor immune escape

- Loss of MHC expression

- Down-regulation of antigen processing machinery

- Antigen loss variants

- Expression of local inhibitory molecules (FasL)

- Secretion of immunosuppressive cytokines

- IL-10, TGF-b

slide32

Strategies of antitumor immunotherapy

- Adoptive immunotherapy

- Active vaccination

  • Monoclonal antibodies
  • Vaccination against tumor
  • neovascularization
slide33

Strategies of antitumor immunotherapy

- Adoptive immunotherapy

- LAK

- TIL

- DLI

- CD8 clones

- Cell cloning technique

- TCR transfection

slide34

Adoptive transfer of IL-2 activated tumor

infiltrating lymphocytes (TILs)

Adoptive transfer of TILs expanded in vitro and high dose IL-2 following a non-myeloablative conditioning regimen

Dudley ME et al. Science, 2002

slide37

Adoptive transfer of antigen-specific CD8+ T cell clones

In vivo persistence, migration and antitumor effect of transferred

MART-1/Melan-A specific T cell

Yee, C. et al. PNAS 99: 16168, 2002

slide39

Monoclonal antibodies

Mechanisms of action:

- antibody-dependent cell-mediated cytotoxicity

- cross-presentation by immune complexes

Clinical studies

- anti-CD20 (B-cell lymphomas)

slide42

Goal of cancer vaccines

- To identify ways to break tolerance

- To identify resistance mechanisms

and ways to circumvent them

slide43

Vaccine design

- Targeting CTL responses

- Targeting CD4+ T cell responses

- Targeting multiple antigens and epitopes that cover a broad repertoire

of T cells

Undefined (cancer cell extracts, mRNA)

- Choice of the antigen

Defined

- Adjuvant

- Dose

- Route of injection

- Schedule

slide44

Different forms of cancer vaccines

u

- Cell based cancer vaccines

- Antigen specific cancer vaccines

- Dendritic cells vaccines

- Heat shock proteins vaccines

slide45

Cell-based cancer vaccines

Tumor cell as a source of antigen (autologous or allogenic)

Early generation:

- Killed tumor cells or tumor cell lysate mixed with adjuvants

such as BCG

Genetically modified tumor cells:

- Immunologically active genes

- MHC genes

- genes encoding membrane associated costimulatory molecules

(B7-1, B7-2)

- cytokines genes (IL-2, IL-4, GM-CSF)

Clinical trials:

- Several with limited success

slide46

Antigen-specific cancer vaccines

- Peptide vaccine

- Protein vaccine

- Recombinant viral vaccine

- Recombinant bacteria vaccine

- Nucleic acid vaccine

slide47

Peptide vaccine

Depends on loading of empty MHC class I molecules in vivo

Advantages

- Easy to manufacture in GMP conditions

Disadvantages

- May results in tolerance induction

Clinical trials:

- MAGE-3 presented by HLA-A1

Marchand M, et al. Int J Cancer 80:219, 1999

- gp100 presented by HLA-A2

Rosenberg SA, et al. Nat Med 4:321, 1998

slide48

Protein vaccine

Depends on cross-priming on autologous MHC molecules

Advantages

- non HLA restriction

- activation of both CD8+ and CD4+ T cells

Disadvantages

- Difficulty and expenses of generating recombinant proteins suitable

for human administration

slide49

Recombinant viral vaccines

Adenovirus, vaccinia virus, avipox

Mechanisms of action:

- Cellular damage, danger signals, cross-priming

- Direct infection of bone marrow derived APC

Disadvantages

- Neutralizing antibodies

- Previous exposure to cross-reacting viruses

- Previous immunization

  • Clinical trials
  • Weak generation of anti-tumor T cells
  • Rosenberg SA, et al. J Natl Cancer Inst 90:1894, 1998 (Melanoma, MART-1 or gp100)
  • Marshall JL, et al. J clin Oncol 23: 3963, 2000 (CEA)
  • - Eder JP, et al. Clin Cancer Res 5: 1632, 2000 (Prostate cancer, PSA)
slide50

Nucleic acid vaccines

Advantages

- easy to construct

- chemical stability

- inherently immunogenic, do not need adjuvants

- broad range of specific immune responses

- no presence of neutralizing antibodies

- less risk of insertional mutagenesis

- do not down-regulate MHC

Disadvantages

- Much less potent

- No replicative amplification

- Smaller inflammation

- No danger response

slide51

Heat shock proteins

gp96 and hsp70 purified from tumor cells

Mechanisms of action:

- Bind a wide array of peptides

- They introduce bound peptide into the MHC class I and II processing

pathways

- Binding of gp96 to macrophages induces secretion of proinflammatory

cytokines

Disadvantages

- Tumor tissue required

Clinical trials

- Belli, F. et al. J Clin Oncol 20:4169, 2002

slide52

A

A

A

A

A

A

A

A

A

A

A

A

Dendritic cells vaccines

Virus

Gene

Vector

Apoptotic bodies

Bacteria

Lysates

mRNA

Natural or

Synthetic peptides

Non genetic delivery

Genetic delivery

slide53

CD34 derived mature DC pulsed with several MHC class I

tumor peptides plus KLH and Flu-MP

Banchereau J, et al. Cancer Res. 61:6451, 2001

slide54

Mature monocyte-derived DC pulsed with several MHC class I

and class II tumor peptides plus TT

Schuler-Thurner, B et al. J Exp Med 10:1279, 2002

Thurner, B et al. J Exp Med 11:1669, 1999

slide61

What we have learn from clinical trials so far

  • - Vaccinations are safe and well tolerated
  • - No or transient major side effect (autoimmunity phenomena)
  • Patients are immunized, with tumor specific T cell induction
  • or expansion
  • - Memory induction?
  • - Limited clinical benefits in heavily affected patients
slide62

Factors limiting the therapeutic impact of anti-tumor T cells

Tumor factors

Lymphocytes factors

- Production of immunosuppressive

cytokines

- Loss of MHC molecules or tumor

antigens

- CD4+ and CD8+ subsets

- Insufficient numbers, avidity

- Secretion of non appropriate

cytokines or not sufficient

lytic activity

- Regulatory T cells

slide63

Future challenges

- Best DC culture methods (maturation stage)

- Optimum antigen loading

- Most important TAA

- Vaccination schedule

- Dosages

- Route of injection

- Improvements/standardization of immunomonitoring

- Combination therapy

slide64

Strategies of antitumor immunotherapy

  • Vaccination against tumor
  • neovascularization
slide65

Vaccination against tumor neovascularization

Preclinical studies

- DC pulsed with soluble VEGF-R2

- neutralizing antibodies

- CD8+ CTL

- Attenuated salmonella engineered

to express VEGF-R2

- CD8+ CTL