경희대학교 의과대학·의학전문대학원

전체 글

(1)

종양 면역학

Tumor Immunology

경희의대 종양혈액내과

조 경 삼

(2)

Immune System

• Complex network of molecules, cells and

organs

• Defend against pathogenic microorganisms

and noninfectious foreign substances

• Regulate tissue homeostasis and tissue

repair

• Cells of immune system identify and

(3)

Evidence for the Immune

Response

• Spontaneous regression : 1 - 2 % of

melanoma and renal cell Ca

• Tumor regression during acute

bacterial infection

• Autologous serologic activity

(4)

Tumor Antigens

• Tumor-specific antigens

• Tumor-associated antigens

• Chemical or physical carcinogens :

– products of unique mutations of normal cellular genes – little or no immunologic cross-reactivity

• Virus :

– viral antigen

– extensive immunologic cross-reactivity

(5)

Tumor Antigens

• Nonmutated self-antigens recognized by CD8+

and CD4+ T cells

– Cancer/Testis Antigens : MAGE-1, NY-ESO-1 – Melanocyte differentiation Ag : MART-1, gp100 – Overexpressed gene products : FGF5, PLAME – Oncofetal antigens : CEA, AFP

• Mutated gene products recognized by CD8+ and

CD4+ T cells

(6)
(7)

Limitations of the Immune Response

• Tumor resides in immunologically

privileged site

• Antigenic modulation

• Blocking factors

• Suppressor T lymphocytes

• Immune suppression by tumor cell

products

(8)

Tumor and Immune system

• Elimination of the cancer

• Cancer equilibrium, in which there is immune

selection of less immunogenic tumors during an

antitumor immune response

• Tumor escape, the growth of tumor variants that

resist immune destruction

(9)

Cancer Treatment

Surgery (

수술 )

Chemotherapy (

항암화학요법 )

Radiotherapy (

방사선치료 )

Biologic therapy (

생물학적치료 )

Others : Tumor embolization,

Hyperthermia etc.

(10)

Biologic Therapy

Through the action of natural host

defense mechanisms or by the

(11)

Biologic Therapy

BRM (biologic response modifiers) :

Function by altering the host response

to cancer, however, some causes

direct cytotoxicity

Immunotherapy

Differentiating agents

Antiangiogenic therapy

Targeted therapy

(12)

Principles of Immunotherapy

• Most applications of biologic therapy for cancer

have attempted to stimulate immune defense

mechanisms.

• The immune system evolved as a means to detect

and eliminate molecules or pathogens that are recognized as "nonself" but not react to host (self) tissues.

• Many immunotherapies attempted to cause the

tumor to appear more "foreign” compared with

normal tissues or tried to magnify relatively weak host immune reactions to growing tumors.

(13)

Immunotherapy

Classification Examples

Active immunotherapy

Nonspecific Immune adjuvants (BCG, C. parvum,

levamisole) INFs, IL-2

Specific Immunization with tumor Ag

vaccines Passive

immunotherapy Antibodies

Monoclonal or polyclonal Ab alone or conjugated with toxins or

radio-labels Cells TIL, LAK Indirect

Removal of blocking factors, inhibition of growth factors or angiogenic

(14)

Active Nonspecific Immunotherapy

1800s: tumors sometimes regress in cancer

patients who contracted bacterial infection

1892-1936: William B. Coley (MSKCC) Infect

cancer patient with bacteria,

vaccine consisting of killed bacteria

1970s: BCG (Bacillus Calmette-Guerin)

(15)

Interferons (I)

Property IFN-alpha IFN-beta IFN-gamma Synonyms Type I Type I Type II

Leukocyte Fibroblast Immune

Lymphoblastoid Cells Leukocytes Fibroblasts T cells

Macrophages epithelial cells NK cells

Biological properties

A Antiviral Yes Yes 10- to 100-fold less

(16)

Interferons (II)

Immunomodulatory activities

Antiviral activities

Antiproliferative activities

Inhibition of angiogenesis

Regulation of differentiation

Enhancement of the expression of a variety

of cell-surface antigens

hairy cell leukemia, CML, cutaneous T-cell

lymphoma, Kaposi’s sarcoma

(17)

Interferon (III)

Tumors RR (%)

Cervical intraepithelial neoplasia 80-90

Basal cell cancer 90

Superficial bladder cancer 60-70 Malignant neuroendocrine tumors 30-80

Kaposi’s sarcoma 35

Hairy cell leukemia 80-90

CML 70-80

CMPD (ET, PV) 75

Cutaneous T-cell lymphoma 55-80

NHL low grade 40-50

(18)

IL-2

• Immunomodulatory cytokine

• Produce LAK cell

• Renal cell Ca, melanoma

• Capillary leak syndrome

(19)

Toxicity of high dose IL-2

Systemic: malaise, chills, pruritus, weight gain, edema

Hemodynamic: hypotension

Cardiac: arrhythmia, angina, MI

Pulmonary: respiratory distress, pleural effusion

Renal: oliguria, elevated creatinine

GI: mucositis, nausea/vomiting, diarrhea

Hepatic: hyperbilirubinemia

Neurologic: disorientation, somnolence, coma

Hematologic: anemia, thrombocytopenia

Infection: infection, line sepsis

Death: treatment related (0.7%)

(20)

Active Specific Immunotherapy

Tumor vaccine: autologous or allogeneic tumor cells using living cells, inactivated cells, or cell

fragments alone or in conjunction with immune adjuvants, such as BCG, or with viruses

Local production of suppressor factors

The modulation of tumor antigens or MHC antigens on tumors The lack of appropriate costimulatory molecules

(21)

Cancer vaccines (I)

Whole cancer cells:

Inactivated cancer cells and their extracts can jump-start the immune system.

Cancer cells engineered to secrete cytokines, such as IL-2 or GM-CSF, similarly highten antitumor immunity.

Cells designed to express co-stimulatory molecules, such as B-7, enhance the ability of T cells to recognize tumor cells

Peptides:

Tumor peptides, fragments of tumor proteins recognizes by T cells, are injected alone or with immune boosting adjuvants

(22)

Cancer vaccines (II)

Proteins:

Antigen-presenting cells take up injected tumor proteins and break them down into a range of peptide fragments recognized by T cells

Dendritic cells:

These antigen-presenting cells are isolated from the blood, exposed to tumor peptides or engineered to produce tumor proteins and then reinjected

Gangliosides:

Human can produce Abs to these molecules, such as GM2, found on the surface of tumor cells.

Clinical studies have shown that melanoma patients with GM2 Abs have a better prognosis

(23)

Cancer vaccines (III)

Heat-shock proteins:

These cellular constituents ordinarily bind peptides.

Injecting heat-shock proteins isolated from tumors rouses antitumor immunity in mice

Viral and bacterial vectors:

Genes coding for tumor Ags are incorporated into viral or bacterial genomes.

When injected, these altered infectious agents draw immunity against themselves and the encoded antigens

Nucleic acids:

DNA and RNA coding for tumor Ags prompt normal cells to begin producing these Ags

(24)

Cancer vaccines

• Vaccines against

– Breast cancer :

HER2 antigen

– B-cell lymphoma :

tumor Ig idiotype

– Lung cancer :

MUC1 antigen)

– Melanoma : dendritic cells loaded with tumor

peptides or killed tumor cells

– Pancreatic cancer : telomerase peptides

– Prostate cancer : dendritic cells loaded with

prostatic acid phosphatase

(25)

Active Specific Immunotherapy

• Allogenic T cells : graft-versus-tumor effects

– Allogenic stem cell transplantation

– Donor lymphocyte infusion

– Nonmyeloablative stem cell transplantation

• Autologous T cell : sensitized ex vivo, and

expanded with cytokines

(26)

Passive immunotherapy

• Antibodies :

monoclonal antibody alone

or conjugated with toxins or radio-labels

• Cells : TIL, LAK

• Indirect : removal of blocking factors,

inhibition of growth factors or

angiogenic factors

(27)

Monoclonal antibodies

• - a -

Rat

• - e -

Hamster

• - i -

Primate

• - o -

Mouse

• - xi -

Chimeric

• - zu -

Humanized

• - u -

Human

(28)

Monoclonal antibodies (III)

Treatment : FDA approved

• MAb unconjugated

– Rituximab (Mabthera) : CD20 NHL 1997

– Trastzumab (Herceptin) : HER-2R breast 1998 – Alemtuzumab (Campayh): CD52 CLL 2001

– Cetuximab (Erbitux): EGFR CRC, H&N 2004 – Bevacizumab (Avastin): VEGF CRC, lung 2004 – Panitumumab (Vectibix): EGFR CRC 2006

– Ofatumumab ( Arzerra): CD20 CLL 2009

• MAb conjugated

– Gemtuzumab ozogamicin : CD33 AML 2000 – Ibritumomab tiuxetan(90Y): CD20 NHL 2002

(29)

Adoptive immunotherapy

LAK (lymphokine activated killer) cells:

colon, melanoma, renal cell Ca

TIL (tumor infiltrating lymphocytes)

DLI (donor lymphocyte infusion):

CML after allogeneic BMT

(30)

Figure 62-1

Adoptive cell transfer therapy for patients with cancer involves (1) the generation and selection of lymphocyte cultures with desired

characteristics, (2) the in vitro expansion and activation of the T cells, and (3) the conditioning of the patient for optimum treatment efficacy before infusion of the cells and interleukin-2 (IL-2) support.

(31)

Escape from immune attack

by tumor cells

Altering characteristics:

immunoselection --- loss of tumor Ag or MHC

molecules, or costimulator

Suppressing the immune response:

specific --- inappropriate or ineffective signal to

T cells

nonspecific --- TGF-beta, CT, RT

Hiding from the IR: brain, dense tumor stroma

Exploiting the immune system’s ignorance: tolerance

Outpacing the IR: rapid growth

(32)

HGF

GM-CSF, G-CSF, IL-3, TPO, Epo, SCF

Neutropenic patients

High dose chemotherapy

PBSCT (peripheral stem cell

transplantation) for mobilization

Ex vivo expansion of stem cells

(33)

Others

• Differentiating treatment

– ATRA for APL

• Antiangiogenic treatment

– Thalidomide, lenalidomide

• Targeted therapy

– Gleevec : tyrosine kinase (CML) inhibitor

– Iressa : EGFR tyrosine kinase inhibitor

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