Tumor Immunopathy

What is the difference between tumor specific vs associated antigens

Tumor-specific antigens,

• only on tumor cells 

• Mutated host proteins

• (e.g., HIV, HTLV, EBV, KSHV, HPV)

Tumor-associated antigens

• found on both normal and tumor cells

Describe CD4/8 roles in Tumor response

Describe the problem w/ CD8

CD4/8 roles

• CD4 T Cells Role in Tumor Immune Responses

  •  produce cytokines -> effective CTL generation

    • TNFa and IFNy -> increases MHCI expression on tumor cells

• CD8+ T lymphocyte Role

  • surveillance + kill tumor cells 

---

Problem w/ CD8 roles:

• Lack of  costimulation to initiate response

  • Cross-presentation of internalized tumor antigens by APCs (DCs)

  • MHC class II presentation

  •  CD4+ cell help 

    •  B7.1(CD80), B7.2 (CD86)

    • Cytokines listed above

[REVIEW] Lymphocyte Recognition of Transformed Cells

Describe the role of NK cells in tumor suppression

 Natural Killer (NK) cells

• Can Kill b/c tumor cells can have LOWERED MHC-1 expression

Describe methods (5) of Immune Evasion by Tumor Cell

• Low immunogenicity:

  • NO peptide:MHC ligand

  • No Adhesion Molecules

  • No Costim. Molecules

• Tumor treated as self antigens:

• Antigenic modulation:

  • Ab binds to tumor cell -> cell endocytose + degrade

• Tumor induced Immune suppression:

  • Secrete Factors (TGF-B) -> inhibit T cells

  • Induction of Treg cells via tumors

• Tumor induced privileged site:

  • Secrete factors -> physical barrier

List the two types of Therapy Against Tumors

• Drugs that kill dividing cells or block cell division.

  • (hair loss, gut inflammation, immune suppression, blood clots, liver/kidney dysfunction)

• immunotherapy: tumor-specific.

  • Augment weak host immune response 

    • (active immunotherapy).

  • Admin of tumor-specific antibodies and/or T cells 

    • (passive immunotherapy)

List the Different forms of immunotherapy

• Stem cell transplants (bone marrow transplants)

• Active immunization with tumor vaccines

• Adoptive immunotherapy by adoptive transfer of tumor specific-T cells

• Passive immunotherapy w/ anti-tumor antibody infusions.

• Strong adjuvants coupled w/ tumor peptides

• Vaccination against oncogenic viruses

• Transfection of tumor cells w/ costimulatory molecule genes or cytokine genes and re-infusion.

• CAR T cells

• Bispecific antibodies

Describe immunotherapy using Abs

• What is it?

• Problem/Solution

Therapy With Antibodies

• What is it?

  • Abs against tumor antigens 

    • (initially called “magic bullets”)

  • Effector fxn similar

    • Opsonization

    • Phagocytosis

    • Activation of complement

• Problem: 

  • Increased mutations of tumor antigens.

    • Possible sln: antibody cocktails

    • Alt. strat:

      • Abs coupled to immunotoxins -> delivery of cytotoxic agents specifically to tumor cells

        • EX: ricin, diphtheria toxin

What is Check Point Blockade? Via?

Check Point Blockade

• Use of monoclonal abs -> block inhibitory signaling 

  • Via CTLA-4* or PD-1 * on T cells

NOTE:

• Immune checkpoint pathways are in addition to Signal 1 & Signal 2

• Several different receptors on T cells, and ligands on APC or tumor cells fine tune the immune response by enhancing T cell activation or increasing T cell inhibition (immune checkpoints).

What is the method that won the 2018 Nobel Prize in Physiology or Medicine

Describe how Bi-specific Antibodies work?

Bi-specific Antibodies

Method:

• Abs has two arms

  • One grabs myeloma cell

  • Other directly engage a key immune cell (NK/T)

  • The NK/T cells destroy cancer

---

NOTE:

This unique approach is really a combination of two strategies at the same time:

1. A monoclonal antibody that targets myeloma cells and induces the immune system to destroy the myeloma cell – sometimes called “humoral” immunity.

2. A monoclonal antibody that engages a local immune cell to directly kill the myeloma cell – sometimes called “cellular” immunity

Describe Cellular Therapy method

Describe Hematopoietic Stem Cell Transplant

• Two Types

• Method

Hematopoietic Stem Cell Transplant

• Two Types:

  • Autologous 

    • CD34+ hematopoietic stem from pt. Bone marrow

  • Allogenic:

    • CD34+ hematopoietic stem from donor

• Method:

  1. Stem cells collected/ cryopreserved

  2. Chemo therapy -> kills immune cells in bone marrow

     1. melphalan or other drug(s

     2. Admin 1-2 days prior to stem cell infusion

  3. Stem cell infusion 

  4.  new stem cells replace the cells that the chemotherapy destroyed

Describe Chimeric T Cell Receptor (CAR-T)

Method

1. T cells isolated from patient blood 

2. given lentiviral vector expressing CD19 directed chimeric T cell receptor (CAR)

3. T cells w/ Car infused back into pt.

4. Now T cell have kill capabilities and recognition capabilities

Describe one way we can use CRISPR/Cas9 Technology to combat cancer

Describe Augmentation of Immunity by Cytokines and Costimulators

• Problem

• Sln

• Potential cytokines?

• Problem:

  • B cell origin tumor cells lacks costimulatory and MHC class II molecules.

• Sln:

  • Vaccination w/ tumor cells transfected w/ B7 molecules -> protective immunity against unmodified tumor cells.

• Various types of potential Cytokine expression vectors:

  • IL-2 and IL-12 

    • (stimulates NK and CTL activity).

  • GM-CSF 

    • (rejection or regression of tumor growth).

  • IFN 

    • (increases cytolytic activity of NK cells and expression of MHC class I molecules on tumor cells)

Describe Therapeutic Vaccination with Tumor Cells or Tumor Antigen

• Good vaccine candidates

• Procedure

• Good vaccine candidates:

  • Peptides recognized by tumor-specific CTLs

• Procedure:

  • Administration of peptides with adjuvants.

  • Use of APCs (dendritic cells):

    • Pulsing APCs in vitro with peptide prior to administration

    • Transfection with genes that encode these peptides -> class I presentation.