Flashcards in Tumor Immunity Deck (17):
Tumor Antigen Recognition
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.
What are the two pathways by which T cells recognize tumor cells as "foreign?"
Exogenous pathway &
Recognizes Class II MHC; APCs capture tumor proteins (shed or from dying cells) from the microenvironment, process the proteins and present the peptide antigens
Tumor cells themselves can process cytoplasmic proteins into peptides (antigens) that get presented by MHC class I.
What are some barriers to cancer immunity?
Expansion and recruitment of regulatory cells
Secretion of immunosuppressive cytokines
How can clinical responses to cancer cells be increased?
Cancer immunotherapy -- learning how to turn off the suppressive components of the immune response that prevent immune cells from recognizing and killing cancer cells
What are the three approaches to cancer immunotherapy?
1. Monoclonal antibodies
2. Adoptive cellular immunotherapy
Potential targets for monoclonal antibody therapy.
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
Two approved MAb.
Her2/Neu for breast cancer
CD20 (B cell marker) for B cell lymphoma
MAb's used to interfere with immune checkpoints
Immune checkpoints are inhibitory pathways that maintain self tolerance and modulate the duration/magnitude of an immune response
Examples: CTLA4, PD-1, LAG-3
What are possible monoclonal antibody mechanisms of action?
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
Potential limitation of monoclonal antibodies
Mutation or down-regulation of tumor antigens; derived from mice or rats so they induce potent rejection response in humans
What are tumor-infiltrating lymphocytes (TILs)?
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
What has adoptive T cell immunotherapy been effective for?
Advanced metastatic melanoma
One side effect is autoimmunity -- non-life threatening vitiligo, uveitis
What are Chimeric antigen receptors (CARs)??
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
What are some of the risks associated with CARs?
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