Lecture 14: immunotherapy Flashcards
(22 cards)
3 signals for T cell activation
- TCR interaction with MHC II-Antigen
- CD28-CD80/86 (co-stimulation)
- Cytokines
Mechanism of adaptive cytotoxic responses
Tc cells release lytic granules and kill the target cell upon contact
We inject irradiated cells of tumor A.
Effect when injecting viable cells of A and B
- A: Host rejects tumor cells, no tumor
- B: proliferation of cells, tumor growth
Are tumors immunogenic ?
Yes (see slide 9)
Three types of therapeutic cancer vaccines
- Non-targeted vaccines (peptide vaccines)
- Vaccination with ex-vivo generated DCs pulsed with tumor antigens
- In vivo DC targeting
DC vaccine mechanism
- Inject immature DCs from patient with tumor-cell lysates, apoptotic or necrotic cells, recombinant protein, RNA
- Mature them
- Re-inject them in patient with RNA and peptides
(deso les kheys c’est long)
Adoptive T cell transfer mechanism
- Activate and select tumor specific T cells from the tumor mass
- Inject them (whole cells or tumor-antigen specific T cells) in the patient at the same time as irradiation
Challenges in adoptive T cell transfer (5)
- Target specificity of transferred T cells
- T-cell exhaustion
- The immunosuppressive nature of tumor
microenvironment - Autoimmunity
- Clear benefits only in melanoma
TCR transfer mechanism
- Extract tumor T cells
- Avid testing -> create viral vector encoding tumor-specific TCR
- Create human T cell expressing tumor-specific TCR
- Expand and inject into patient
Challenges of TCR transfer
- Matching HLA restriction elements (TCR is specific to a given HLA/peptide)
- Possibility of «on target» toxicities
Engineering of chimeric antigen receptors (CARs) mechanism (+ 1 challenge)
- Attach antibody specific to tumor antigen of activation motif
- Clone antigen receptor in retroviral vector
- Inject T cells expressing this receptor in patient
Challenges: on target-off tumor toxicity
2 differences between CARs and TCR
- CARs recognize MHC/HLA-nonrestricted structures on the surface of target cancer cells
- TCRs recognize mainly intracellular antigens that have been processed and presented as peptide complexes with MHC/HLA molecules
CTLA-4 mechanism
Binds to CD80/86 on APC and blocks co-stimulation of CD28 on T cells (signal 2)
Effect of blocking CTLA-4
Unleash T cell activation
PD-L1 mechanism
Induces unresponsiveness by attenuating antigen-specific signals
Which type of patients have longer PFS (progression free survival) after anti-PD1 ?
Patients with higher non-synonymous mutations
Effects of mismatch-repair deficiency on T cells, link with anti-PD1
- More mutation associated neoantigens in tumor -> more non-functional T cell infiltration
-Anti-PD1 reactivates non-functional T cells
Challenges of targeting PD1-PDL1 pathway
- PD-L1 expression is not always a biomarker of potential response to treatment
- Immune-related adverse events
- «pseudo-progression» or even «iper-progression»
2018 nobel Prize
James P. Allison : CTLA-4, american immunologist (1948), executive director of immunotherapy platform at the MD Anderson Cancer Center, Regental Professor and Founding-Director of James P. Allison Institute, director of the Cancer Research Institute (CRI) scientific advisory council, one of the first people to isolate the T-cell antigen receptor complex protein.
Tasuku Honjo: PD-L1, Japanese physician-scientist and immunologist (1942), foreign associate of the National Academy of Sciences of the United States, member of German Academy of Natural Scientists Leopoldina, and also as a member of the Japan Academy
Characteristics of a cold tumor
- More immunosupressive cytokines
- High number of Tregs and MDSCs
- Few Th1, NK and TCD8 cells
- Few functional APCs
Characteristics of hot tumors
- MoreTh1 chemokines
- High number of effector immune cells
- High number of functional APCs
2 steps of anti-angiogenic therapy
- Anti-angiogenesis (vascular normalization, more T cells, less suppression)
- Immune checkpoint blockade (-> tumor regression)
