work in progress
Rational design of combination immune therapies
Different ideas how to strengthen the immune response to tumours:
1. Increasing the 'visibility' of the tumour to the immune system
- Intratumoral oncolytic virus injection:
- T-Vec = Imlygic (Chesney et al.)
- Coxsackievirus A21 (Curti et al.)
- Entinostat (johnson et all)
- Cobimetinib + anti-PDL1
2. More T-Cells into the tumour
CD19 Chimeric antigenic receptor T-cells + Pembro (Maude et al)
CEA T-Cell bispecific antibody plust Atezo (Tabernero et al)- colon
3. 'Force field'- make the environment more favourable for T-Cells
IDO- deletes tryptohpan, produces toxic kynurenine: inhibits T-Cells
4. Enhance T cell attack:
- block negative checkpoints
- activate positive checkpoints
How to test all possible combinations in a rational way?
- is there a reason to believe 2 agents work together?
- does the new treatment slow down tumour progression?
Resistance to Immunotherapy
T-cell inflamed versus non-flamed tumour environment
Vaccine-responders had a T-cell inflamed phenotype and favours response to checkpoint inhibitors (find old BMS study on Ipi)
source: Nature Immunology 2013
CD8, FoxP3, PDL1, IDO present in T cell-inflamed, but absent in T cell non-inflamed
Primary resistance might by caused by absence of a T cell-inflamed environment. How can one create such a favourable environment?
The injections with viruses- like T-Vec- is thought to 'wake up' the environment
3 major hypothesis for primary resistance
- somatic differences (tumours are different)
- host differences (patients are genetically different- polymorphism in immune regulatory genes, so their immune systems react differently)
- environmental differences (like microbiota, pathogen exposure)
Most likely, all 3 factors are important
What can biomarkers tell you?
- risk prediction
- monitor response to treatment
- predict response to treatment
Prognostic versus predictive?
Profiles associated with response to PD1 blockade
- high mutational load: better response to PD1
- Hugo Cell 2016- profiles of people who do not respond to PD1
PDL1 expression is associated with better response to PD1 blockade but it is not predictive. And in 30% of times, not even consistent in the SAME tumour.
CD8 T cell infiltrate predicts response to PD1
JAK 1/2 mutations associated with acquired resistance to PD1-blockade
Daniel Sanghoon Shin et al. Cancer Discovery 2017
Hugo Cell 2016
Gao Cell 2016
Yusko, 2017 (unpublished)- mutational load associated with PD1 response but overlap huge, so clinical value limited right now
Huang et al. Nature 2017