Immunotherapy Flashcards
What evidence is there to show that the immune system is important in cancer?
- Anecdotal Evidence: some tumours seem to regress or resolve on their own and two independent times, erysipelas infection lead to tumor regression
- Organ Transplantation: rare donor-derived cancers (shows dormancy and/or immunosuppression) AND generally an increase chance of developing cancer in immunosuppressed people
- immunodeficient animal experiments
- immune infiltrate and outcome correlations
What is special about RAG-deficient mice?
They lack mature B and T cells, immunosupressed
What happens when you administer a carcinogen to RAG-deficient mice?What about WT mice?
RAG-deficient: tumours grow in all
WT: tumours regressed in many of the mice (tumour was RAG-deficient derived)
What does CD3 staining show us?
Tumour infiltrating lymphocytes (TILs)
Does it matter is a tumour has high or low tumour infiltrating lymphocytes?
Yes, more TILs correlates with better prognostic outcomes (are protective)
How do Natural Killer cells work?
They can recognize antigens on the surface of a cell, where they can then bind and leads to insertion of perforin (which makes channels/holes in the membrane) and also injects Granzyme B (which leads to the triggering of apoptosis)
How are CD8 T cells similar to NK cells ? How do they differ from NK cells?
They are similar to NK cells in the sense that they recognize foreign antigens and inject granzyme b to induce apoptosis.
They are different in the sense that they recognize the foreign material via their T-cell receptor, not antibodies recognizing neoantogens, and require binding of MHC-1
What are the different types of cancer immune therapy?
- Cytokine therapy
- Cancer vaccine
- Oncolytic virus therapy
- Immune checkpoint inhibition
- Adaptive cell transfer
What are examples of cytokine therapies?
Inf-y, il-2, gm-csf
How are cytotoxic t-cell activated?
- Antigen presenting cells (e.g. dendritic cell) present peptides in MHC-II to Th cells
- This leads to cytokine/interleukin which act on cytotoxic T-cell precursors
- When Tc precursors are additionally presented with peptide in MHC-I from APCs when they mature
- Mature Tc cell become activated and attack target cells that present the same antigen in MHC-I
- to get activated, their costimulatory receptor, CD28, must also bind to B7
CD28 binding leads to what?
activation of Ras, leading tto IL-2 production, proliferation and increased survival
How do immune checkpoint inhibitors work?
what is the thought process behind it?
T-cell have a receptor called CTLA-4, which binds B7 with a higher affinity than CD28. BUT, CTLA-4 leads to inhibition of signalling via recruiting of phosphatases (coinhibitory receptor). If we block CTLA-4 via an antibody, we prevent the inhibition of T-cells, which can now kill tumor cells more efficiently.
Also, T-cells have PD-1 receptors which recognize PD-L1 on target cells. This interaction, also coinhibitory, allows us to recognize self and prevent killing, but tumor cells have adapted to contain PD-L1 to prevent immune-mediated killing. We can either block PD-1 or PD-L1 via antibodies.
What are neoantigens?
“new antigen” created through mutation of a previously normal cell (e.g. cancer cells have many neoantigens)
Immune checkpoint inhibitors are efficacious against what type of cancers?
Any that have a high mutational burder
but initially used againt melanomas and non-metastatic rectal cancers with mismacth repair defect
what is the standard treatment for rectal cancer? what other tyoe of therapy could be used?
- Neoadjuvant chemotherapy and radiation followed by surgical resection of the rectum is a standard treatment
- could use immune checkpoint inhibitors since 5-10% caused by deficiency in mismatch repair (leading to lots of neoantogens)
what is the idea behind Adoptive cell transfer (ACT) therapy, generally?
TILs represent a population of cells that are resident in tumours due to a selective recruitment and retention. So we can take some TILs, expand them ex vivo and reinfuse them.
what are issues with ACT?
Adoptive cell transfer
expensive, time, and risk (risk of cytokine storm)
what is the method of ACT?
- take tumor/blood sample from patient and grow them in culture
- isolate tumor RNA/DNA
- perform RNA-seq and select mutated sequences
- predict/make neiepitopes that could be on tumor cells
- clone them into minigenes, that cna be put on dendritic cells.
- present the DCs to TILs that are being cultured
- infuse them into pateint
or can just take TILs, isolate them, and grow them. Then infuse that mix into patient.
what is the idea behind CAR-T cells?
T cells can be modified to contain specific TCRs or Chimeric Antigen Receptors (CAR). These cells are called CAR-T cells and are made to react with the tumor.
So, we could remove T-cells from patient and genetically alter them and reinfuse them.
what are issues with CAR-T cell therapy?
expensive, time, risk, and requires knowledge of the correct target
Are there current CAR-T cell therapies available?
yes, Cd19 targeting against chemorefractory or relapsed B-cell malignancies
What is the method for generating CAR-T cells? What about newer approaches?
Generally: isolate T-cell from patient, modify them (can add one or two targets), expand them ex vivo and infuse them into patient
Newer: Make generic T-cells (CRISPR-out MHCI/II in T cells for ‘off-the-shelf’ T-cells) with specific ‘universal’ CARs (eg. targeting prevalent neoantigens)
what are TSTAs?
tumor specific transplantation antigen ( unique to tumor cells and not expressed on normal cells)
What are TATAs?
tumor associated transplantation antigen (expressed by tumor cells and normal cells)
