Lectures 9&10 - Cancer immunology Flashcards

Question

what are the steps of the Cancer immunity cycle?

Answer 1

1. Release of cancer cell antigens 2. Cancer antigen presentation 3. Priming and activatiob 4. Trafficking of T cells to tumours 5. Infiltration of T cells into tumours 6. Recognition of cancer cells by T cells 7. Killing of cancer cells back to 1

Answer 2

You can activates the immune system but don't do anything to specifically determine the antigen Can also have direct targeting antibodies Macrophage can directly engulf cells NK cells release chemicals that make pores in the tumours

Answer 3

Determine what antigens are in the tumour and cans see mutations Artificially generate mutated DNAs and inject in the form of a vaccine to create an immune response Dendritic vaccines Take dendritic cells in culture, feed them with new antigens, they start expressing antigens on surface (APC) and then inject back into tumour sites Bispecific antibodies – artificially change the antibody so it can recognise two different epitopes one recognises a T cell receptor, other recognises a tumor cell, helping to bring the T cell closer to tumour cells MORE

Answer 4

ADCs (antibody drug conjugates) label them so can have a radioactive particle, a chemotherapy targeting a tumour Can have engineered cells called CAR cells: CAR-T, CAR-NK, CAR-MA etc. - artificially loaded with antibody and then that way when we inject the cells back into the patient they can go and specifically find the tumors and point to them so you bypass unessecary steps

Answer 5

Non-specific immunotherapes monoclonal antibodies vaccines

Answer 6

Cytokines or other chemicals that stimulate the general immune response, usually used alongside other therapies example: IL-2

Answer 7

Proteins stick to specific antigens, tagging them for destruction or directly affecting them, uses include: - carrying drugs to target cells -tagging cell for destruction by immune cell - blocking signalling pathway to halt growth or proliferation

Answer 8

Vaccines are made from cancer cells, parts of cells, or antigens designed to stimulate the immune system to attack a tumour. Multiple approaches are being tested, including DC vaccines: 1. A patients DCs are removed, stimulated and re-infused with a cancer specific antigen 2. Treated DCs present the antigen to other immune cells 3. Activated immune cells, primed to recognise the cancer, mature and proliferate

Answer 9

Virus is injected inti the tumour mass, transfected cells then take over the machinery and proliferate and grow, causing the cell to rupture, killing it this not only releases antigens but also creates inflammation leading to a stronger immune response clinical trailas for this therapy for melanoma are ongoing

Answer 10

Anti-PD-1 and anti-CTLA-4 antibodies

Answer 11

Tumour cell expresses a ligand called PDL-1 PD-L1 interacts with PD-1 on the T cell and that sends a negative signal to the T cells and the T cell shuts down and stops attacking the tumour Blocker (antibody (anti-PD-1)) can come along and stop that happening

Answer 12

CTLA-4 is a ligand present on tumour-specific T cells but this when activated by B7 (receptor on tumour cell or APC) it shuts down t cell activation But this competes with the ligand CD28 (also on T cell) which identofies antibodies and trys to stop tumour cells, so anti-CTLA4 antibody used to block ligand and allow immune response to tumour cells

Answer 13

Antibody coats tumour cell Two cells can recognise this coating: NK cells – release perforin and granzymes which causes cells to lyse Macrophages: on macrophage can easily engulf up to 20 cells at a time

Answer 14

depleting Treg cells Deleting Tregs removes the immunosuppression quite a lot

Answer 15

Opdivo (nivolumab)= PD-1 Keytruda (pembrolizumab)= PD-1 Yervoy (ipilimumab)= CTLA-4 inhibitor

Answer 16

FMT = Fecal microbiota transplantation Correlations between microbiome and effectivness of immunotherapy Can now transplant good microbiota e.g. FMT into patients that are going to receive therapy Provides a much more effective immune stimulation

Answer 17

Large area of other receptors, other inhibitors we can block or other stimulating receptors we can activate (agonistic antibodies) Combination therapy and choices of combinations will also increase

Answer 18

Using neoantigens to expand T cells Taking tumor from body and taking T cells out of tumor, sequence to find out what the mutations are or can expand the TILs (tumour infiltrating lymphocytes) in culture e.g. using IL-2 then reinfuse them back into the patient This has been donme in trials for breast cancer and melanoma

Answer 19

Chimeric antigen receptor (CAR) A T cell itslef has a TCR which recognises the antigen CAR takes away this opportunity and only allows expression of the antibodies e.g. anti CD20 or anti-CD19 or any other antigen that the tumours expressed, this way we bypass all the T cell activations required

Answer 20

What they've done with new generations is the chimeric receptor, downstream of that you can put immunostimulant molecules to generate a powerful positive signal to activate the T cells 1) T Cell Collection 2) T Cell Transfection 1 . Binding 2. Fusion 3. Integration 4. Transcription and protein expression 5. CAR cell membrane insertion 3) T Cell Adoptive Transfer +1—Lymphodepleting conditioning 4) Patient Monitoring a) Disease response —CT scans —Bone marrow biopsies —Peripheral blood flow cytometry b) CAR-T Cell persistence —Immunohistochemistry of bone marrow biopsy -RT-PCR and flow cytometry of blood and bone marrow aspirate Although adoptive cell transfer has been restricted to small clinical trials so far, treatments using these engineered immune cells have generated some remarkable responses in patients with advanced cancer.

Answer 21

Recently pubished 10 year data from patients that started treatment 10 years ago, most still had some CAR T cells in their bodies This means it can sit quietly and if the tumour comes back it can be activated again Side effects of CAR T cell therapy: There are side effects but they are not as bad as the cancer itself Immune activation – can potentially lead to damage of other tissues

Answer 22

First monoclonal antibody (mAb) approved for the treatment of cancer Has since treated millions of people Being used to treat an expanding number of autoimmune disorders Despite success some diseases/patients are resistant

Answer 23

Antibody – opsonises CD20 on tumour cell surface Macrophages and tumour cells come and cause tumour cell disruption One of the things that the tumour cells do is remove this antibody from the surface – internalisation of the antibody receptor complex Tumors are actively removing the antibody from surface and evading destruction

Answer 24

Antibody CD32B has a homologue which is almost 94% identical to Antibody CD32A, so difficult to generate a specific antibody, manages to create one that can recognise the 6% difference Treated with either rituximab (purple) or hCD32B mAb (blue) and both together (green) and together the depletion of the B cells is much longer CD32B mAb is also called 6G11

Answer 25

Made PDXs – using mice which are lacking an immune system and Engraph them with the patient cells Got blood cells from patients Showed that the patient cells can populate the mice Then started treating them When you combine rituximab with new drug 6G11 (the CD32B mAb) we can significantly reduce tumour burden Even some patients who didn’t respond at all to rituximab, when used in combination started to respond more

Answer 26

Phase I/II

Answer 27

1. Release of cancer cell antigens Chemotherapy Radiation therapy Targeted therapy C2. ancer antigen presentation Vaccines GM-CSF IFN-a Anti-CD40 (agonist) TLR agonists 3. Priming and activation Anti-CTLA4 Anti-CD137 (agonist) Anti-OX40 (agonist) Anti-C027 (agonist) IL.12 IL-2 4. Trafficking of T cells to tumors 5. Infiltration of T cells into tumors Anti-VEGF 6. Recognition of cancer cells by T cells CARs 6. Killing of cancer cells Anti-PD-L1 Anti-PD1 IDO inhibitors