Tumor Immunity

Question 1

Tumor Antigen Recognition

Answer 1

Cancer cells express MHC class I (usually) but lack co-stimulatory molecules so CD8 cells cannot directly be activated by tumor cells. They require an APC to become activated (cross-presentation). Once CD8 CTL are activated, they mediate effector functions and can directly see MHC I/peptide (tumor antigen) and no longer require the presence of co-stimulatory proteins.

Question 2

What are the two pathways by which T cells recognize tumor cells as “foreign?”

Answer 2

Exogenous pathway &

Endogenous pathway

Question 3

Recognizes Class II MHC; APCs capture tumor proteins (shed or from dying cells) from the microenvironment, process the proteins and present the peptide antigens

Answer 3

Exogenous pathway

Question 4

Tumor cells themselves can process cytoplasmic proteins into peptides (antigens) that get presented by MHC class I.

Answer 4

Endogenous pathway

Question 5

What are some barriers to cancer immunity?

Answer 5

Expansion and recruitment of regulatory cells

Secretion of immunosuppressive cytokines

Question 6

How can clinical responses to cancer cells be increased?

Answer 6

Cancer immunotherapy – learning how to turn off the suppressive components of the immune response that prevent immune cells from recognizing and killing cancer cells

Question 7

What are the three approaches to cancer immunotherapy?

Answer 7

1. Monoclonal antibodies
2. Adoptive cellular immunotherapy
3. Vaccines

Question 8

Potential targets for monoclonal antibody therapy.

Answer 8

1. tumor associated blood vessels
2. vascular growth factors or their receptors
3. diffuse malignant cells
4. tumor cells within a solid tumor
5. tumor associated stroma

Question 9

Two approved MAb.

Answer 9

Her2/Neu for breast cancer

CD20 (B cell marker) for B cell lymphoma

Question 10

MAb’s used to interfere with immune checkpoints

Answer 10

Immune checkpoints are inhibitory pathways that maintain self tolerance and modulate the duration/magnitude of an immune response

Examples: CTLA4, PD-1, LAG-3

Question 11

What are possible monoclonal antibody mechanisms of action?

Answer 11

1. Unconjugated: must rely on complement, ADCC, direct clearance by other Fc receptor-bearing cells, or the ability to block interactions between receptors and ligands involved in cancer progression
2. Antibody conjugates:
3. T cell binding epitopes

Question 12

Potential limitation of monoclonal antibodies

Answer 12

Mutation or down-regulation of tumor antigens; derived from mice or rats so they induce potent rejection response in humans

Question 13

What are tumor-infiltrating lymphocytes (TILs)?

Answer 13

Lymphocytes cultured from tumors removed by surgery then expanded in culture and given back to the patients to provide large numbers of highly activated T cells that recognize the cancer cells – one way to bypass the tumor suppressive mechanisms

Question 14

What has adoptive T cell immunotherapy been effective for?

Answer 14

Advanced metastatic melanoma

One side effect is autoimmunity – non-life threatening vitiligo, uveitis

Question 15

What are Chimeric antigen receptors (CARs)??

Answer 15

T cells are genetically engineer to express proteins (CARs) that allow them to recognize a specific protein (antigen) on tumor cells – they’re grown in laboratory and then implanted into the patient

Question 16

What are some of the risks associated with CARs?

Answer 16

1. T cells are so strongly activated that they make large amounts of pro inflammatory cytokines that result in Toxic shock-like syndrome
2. If the tumor antigen is also expressed on normal tissues there could be autoimmune toxicity
3. Tumor antigen may be lost
4. Does not work well for treating solid tumors

Question 17

Explain graft vs tumor effect.

Answer 17

Donor T cells transferred to the host become activated to host alloantigens – idea is to titrate the effect so there is enough alloreactivity that GVH is manageable but still want that to tarot residual host cancer