Cellular & Molecular Cellular & Molecular ImmunologyImmunology

Cancer and the Immune SystemCancer and the Immune System

Nicholas M. Ponzio, Ph.D.Nicholas M. Ponzio, Ph.D.Department of Pathology & Laboratory MedicineDepartment of Pathology & Laboratory Medicine

May 4, 2009May 4, 2009

Lecture Overview• Tumor “antigens” as targets of immune attack

• Potential host immune mechanisms that protect against development and growth of cancer cells

• Ways in which tumor cells circumvent or neutralize host immune mechanisms

• Immunotherapeutic strategies for treatment of cancer patients

a group of diseases characterized by uncontrolled growth and spread of abnormal cells

What is Cancer?What is Cancer?

Cancer FactoidsCancer Factoids

• Since 2000, nearly 10 million new cancer cases have been diagnosed

• More than 1.2 million Americans develop cancer each year

• A new cancer is diagnosed every 30 seconds in the United States

• Cancer is the second leading cause of death after heart disease in the United States

What causes cancer?What causes cancer?

DonDon’’t know the exact causes, but evidence t know the exact causes, but evidence suggests contributing factors include:suggests contributing factors include:

Genetic influences Genetic influences –– oncogenesoncogenes

Environmental influences Environmental influences –– (carcinogens) (carcinogens) found in tobacco products, industrial found in tobacco products, industrial pollutants, pesticides, fertilizers, etc.pollutants, pesticides, fertilizers, etc.

Infectious organisms Infectious organisms –– some viruses and some viruses and bacteria may be bacteria may be oncogeniconcogenic

Suppression of immune protective mechanismsSuppression of immune protective mechanisms

How do cancer cells differ from normal How do cancer cells differ from normal cells?cells?

Autonomous growth Autonomous growth –– failure to respond to failure to respond to regulatory growth controlsregulatory growth controls

Ability to break away from the original tumor mass Ability to break away from the original tumor mass and migrate/grow in other tissues and migrate/grow in other tissues –– Metastasis Metastasis

Expression of Expression of ““newnew”” molecules (cell surface or molecules (cell surface or intracellular) that are not present on normal cellsintracellular) that are not present on normal cells

These new molecules (antigens) are potential These new molecules (antigens) are potential targets for the immune responsetargets for the immune response

TumorTumor rejection is an immune responserejection is an immune response

Remove tumor

Fig 17Fig 17--22

Tumor Antigens

Table 17-1: Tumor Antigens

PSA; CD10 (ALL); Ig idiotypes (B lymphomas)

Differentiation Ag

Papilloma viruses (cervical Ca); EBNA-1 (EBV-assoc lymphomas); SV40 T antigen (rodent tumors)

MART (melanomas; normally expressed in melanocytes)

CEA (GI and other Ca; normal in liver & during inflammation); AFP (Alpha-fetoprotein)

Oncofetal antigens

Oncogenic viruses

Overexpressed normal genes

Ras mutations (~10% human Ca); Her2/neu (breast & other Ca)

Oncogenes & tumor suppressor genes

Examples of Human Tumor AgsAntigens From

Oncofetal Antigens

Carcinoembryonic Antigen; Alpha fetoprotein

Normal vs. malignant B cells

• Malignant transformation can occur at any stage of development

• Daughter cells within the malignant clone express many of the same surface molecules as their normal counterparts

• Malignant cells exhibit unregulated growth

CD10 on normal and malignant B cells

<10% of PBMC are CD10+

100% of cells within the malignant clone

are CD10+

MHC IMHC II

Flow cytometry and Fluorescence-Activated Cell Sorting (FACS)

Immunophenotype of a patient with ???Chronic Lymphocytic (B cell) LymphomaCLL

Positive for:

CD5, CD20, CD19, CD23 (FcR);

kappa light chain

Negative for:

CD3; lambda light chain

Ig expression during B lymphocyte maturation

Electrophoresis patterns

Normal

Multiple Myeloma

Concept of Immunosurveillance(Lewis Thomas & McFarland Burnet; 1959)

Immune system functions to recognize and destroy clones of malignant cells before they develop into clinically relevant tumors. (T cells)

Based on this concept, one would expect a higher incidence of cancer in people who manifest T cell immunodeficiencies.

However, there is not an inordinately higher frequency of common cancers (breast, prostate, colon, lung) associated with T cell immunodeficiency states

Immunodeficiency (ID) and Cancer

KSHV-8Kaposi’s Sarcoma

Hepatitis BLiver

PapillomaCervical EBVB cell lymphoma

EBVB cell (Burkitt’s)lymphoma

Infectious Disease; Malaria

PapillomaSkin

Immuno-suppression for transplants or due to AIDS

EBVB cell lymphomaInherited Virus involvedType of CancerCause of ID

CR2 (CD21) = EBV Receptor

Potential Host Immune Mechanisms Against the Development of Cancer

• Anti-tumor antibodies

• Tumor-specific Cytotoxic T Lymphocytes (CTL)

• Natural Killer (NK) cells (resting or activated)

• Activated Macrophages

Potential Host Immune Mechanisms: Antibody response against tumor antigens

Potential Host Immune Mechanisms: Stimulation of tumor specific Cytotoxic T Lymphocytes (CTL)

Fig 17Fig 17--33

Potential Host Immune Mechanisms: Resting and cytokine activated NK cells

MHC I

MHC II

Potential Host Immune Mechanisms: Resting and cytokine activated macrophages

ADCC Effector Cells = NK cells, macrophages, eosinophils

Antibody Dependent Cell-mediated Cytotoxicity (ADCC)

Paradox: Tumor growth can occur in spite of immune reactivity

Genetic FactorsInnate & Adaptive

Immunity

Tumor

Escape

Mechanisms

Tumor escape mechanisms:Location Location Location

Tumor escape mechanisms:

Not all tumor antigens are created equal

(i.e., equally immunogenic)

Tumor Cell

MHC molecules present peptide antigens

Fig 17Fig 17--4: Tumor Escape 4: Tumor Escape MechanismsMechanisms

Tumor escape mechanisms:Failure to express co-stimulatory molecules

The most common cancers (breast, prostate, lung, colon) do not express co-stimulatory

molecules

The major goals of immunotherapy:The major goals of immunotherapy:

•• to identify tumor antigensto identify tumor antigens

•• to stimulate the patientto stimulate the patient’’s own immune system s own immune system to recognize antigens on tumor cells and mount to recognize antigens on tumor cells and mount effective mechanisms to destroy the tumor cells effective mechanisms to destroy the tumor cells

•• to be used with other forms of treatment to seekto be used with other forms of treatment to seekout and destroy tumor cells at metastatic sitesout and destroy tumor cells at metastatic sites

•• to be effective with minimal side effectsto be effective with minimal side effects

Immunotherapy Against Cancer

Antibodies coupled to drugs, toxins, radioisotopes; CTL

Specific

CytokinesNon-specificPassive

Tumor vaccinesSpecificBCG; C. parvumNon-specific

Active

Active immunotherapy requires the recipient to respond to the agent being administered

Table 17-2: Tumor Vaccines

Various carcinomasDC + tumor Ag gene

Melanoma; Renal CaHeat Shock Protein

MelanomaLysates

MelanomaAdeno or Vacciniawith tumor Ag

Viral Vectors

MelanomaImm w tumor Ag encoding plasmids

DNA Vaccines

Melanoma; NHL; ProstateDC + tumor AgAPC-based Vaccines

MelanomaMelanoma AntigenPurified tumor antigen

Melanoma; Colon CaCells Killed tumor vaccine

Clinical TrialsPreparationType

Fig 17Fig 17--5: Tumor Vaccines5: Tumor Vaccines

Table 17-4: Systemic Cytokine Therapy for Tumors

Abnormal liver functionPhase I Toxicity; Melanoma and others

Septic Shock Syndrome

Melanoma; Sarcoma

Bone painRoutine use to promote BM recovery in patients

GM-CSF

Fever; abnormal liver; CNS toxicicty; hypotension

Renal (no benefit seen)

IL-6

IL-12

TNF

Vascular leak; shock; pulmonary edema

Melanoma; Renal; Colon (<15% response)

IL-2ToxicityClinical TrialsCytokine

Fig 17Fig 17--6: Cytokine Gene6: Cytokine Gene--transfected Tumor Cellstransfected Tumor Cells

Table 17-5: mAbs for Cancer Therapy

Ovarian cancerMouse mAbCA-125

B cell lymphomaHumanized mouse mAb

B cell lymphomaHumanized mouse mAb

MelanomaHumanized mouse mAb

GD3 Ganglioside

GI and lung cancers

Humanized mouse mAb

CEA

CD10

CD20

Breast Ca (approved for clinical use)

Humanized mouse mAb

Her-2/NeuClinical TrialsForm of mAb usedSpecificity

B-Cell Lymphomas Express Several Antigens That Can Be Targeted

Adapted from Press. Semin Oncol. 1999;26:5(suppl 14):58.

HLA-DR (MHC II)

sIg

CD19

CD22

CD23

CD40CD80

CD20

CD20 Is Not Expressed on Stem Cells or Plasma Cells

Pluripotent stem cell

Lymphoid stem cell

Pre-B cell B cell Activated B cell

Plasma cell

Bone Marrow Blood, Lymph

Press. Semin Oncol. 1999;26:5(suppl 14):58.

CD20

BEXXAR: Characteristics

131131II

Tyrosine Tyrosine labellabel

TositumomabTositumomab(Murine IgG2a) (Murine IgG2a)

CD20 BindingCD20 Binding

γγ and and ββ--radiationradiation

Tumors can develop resistance to treatment

Adapted from Press. Semin Oncol. 1999;26:5(suppl 14):58.

HLA-DR (MHC II)

sIg

CD19

CD22

CD23

CD40CD80

CD20

Resistance to continued treatment

Downregulation or mutation of

surface molecules

Anti-CD20 mAb

Generation of tumor-specific CTL clones