Tumor Immunology (II): Cancer Immunotherapy

Tumor Immunology (II):

Cancer Immunotherapy

Masoud H. ManjiliDepartment of Microbiology &

ImmunologyGoodwin Research Building-286

(804) 828-8779

Learning Objective

Learn how to harness the immune system to kill tumors: immunotherapy

Cancer Immunotherapy

How to kill tumors without killing normal cells?

To induce an immune response against the tumor that would

discriminate between the tumor and normal cells:

Adaptive immunity

Tumor Specific Antigens (TSA) Are only found on tumors As a result of point mutations or gene rearrangement derive from viral antigens

Tumor Associated Antigens (TAA) Found on both normal and tumor cells, but are overexpressed

on cancer cells Developmental antigens which become derepressed. (CEA) Differentiation antigens are tissue specific Altered modification of a protein could be an antigen

Tumor antigens

Tumor antigens

Tumor antigens

Immunotherapy

Adoptive T cell therapy (AIT)

Passive immunotherapy using antibodies

Active-specific immunotherapy by using vaccines

AIT + IL-2 against

melanoma

AIT + IL-2 against melanoma

Before After

Transfer tumor-specific T cell receptor genes using

retroviral vectors into patients’ T cell before AIT

AIT for B cell lymphoma

Passive immunotherapy

Passive immunotherapy

Passive immunotherapy: mAbs

Herceptin: anti-HER-2/neu in breast cancer patients

Rituximab: anti-CD20 in patients with non-Hodgkin’s lymphoma

Bevacizumab: anti-VEGF in patients with advanced colorectal cancer

Limitations: clearance by soluble Ags, antigenic variation of the tumor, inefficient killing or penetration into the tumor mass

Passive immunotherapy: immunotoxins

Anti-CD22 Ab fused to a fragment of Pseudomonas toxin in patients with B-cell leukemia (hairy-cell leukemia)

Passive immunotherapy: drug-linked antibodies

Anti-CD20 antibodies linked to a radioisotope yttrium-90 in patients with refractory B-cell lymphoma

Antibody-directed enzyme/pro-drug therapy (ADEPT): Antibodies linked to an enzyme that metabolizes a nontoxic pro-drug to the active cytotoxic drug

Signal I

Signal II

T cells

Tumor

Vaccination: cross presentation of

tumor antigens by APCsT cell activation T cell killer function

Vaccination

Cell-based vaccines using irradiated tumors with adjuvants such as BCG

Peptide- and protein-based vaccines

DNA vaccines

Vaccination: increase immunogenicity of tumor

cells

Vaccination

HPV vaccine for the prevention of cervical cancer

Oncophage (gp96): a tumor-derived heat shock protein vaccine against kidney cancer and melanoma

Vaccination: Oncophage

Summary

Manipulation of tumors for the expression of new antigens is a promising approach for the induction of anti-tumor immune responses

Vaccines may be effective against residual tumors but AIT and passive immunotherapy have potentials for the treatment of primary tumors

Suggested Reading

Janeway’s Immunobiology, 7th edition: Chapter 15; Pgs. 672-678