Hierarchical oncology combination therapy: which level leads to success?

The traditional preclinical combination experiment in Oncology for two drugs A and B is as follows. A cancer cell-line is exposed to increasing concentrations of drug A alone, drug B alone and also various concentrations of the combination for a fixed amount of time. That is we determine what effect drug A and B have as monotherapies which subsequently helps us to understand what the combination effect is. There are many articles which describe how mathematical/computational models can be used to analyse such data and possibly predict the combination effect using information on monotherapy agents alone. Those models can be either based on mechanism at the pathway or phenotype level (see CellCycler for an example of the latter) or they could be machine learning approaches. We shall call combinations at this scale cellular as they are mainly focussed on analysing combination effects at that scale. What other scales are their?

We know that human cancers contain more than one type of cell-population so the next scale from the cellular level is the tissue level.  At this level we may have populations of cells with distinct genetic backgrounds either within one tumour or across multiple tumours within one patient. Here we may find for example that drug A kills cell type X and drug B doesn’t, but drug B kills cell-type Y and drug A doesn’t. So the combination can be viewed as a cell population enrichment strategy as it is still effective even though the two drugs do not interact in any way.

Traditional drug combination screening, as described above, are not designed to explore these types of combinations. There is another scale which is probably even less well known, the human population scale …

A typical human clinical combination trial in Oncology can involve combining new drug B with existing treatment A and comparing that to A only. It is unlikely that a 3rd arm in this trial looking at drug B alone is likely to occur.  The reason for this is that if an existing treatment is known to have an effect then it’s unethical to not use it. Unless one knows what effect the new drug B has on its own, it is difficult to assess what the effect of the combination is. Indeed the combination may simply enrich the patient population. That is, if drug A shrinks tumours in patient population X and drug B doesn’t, but drug B shrinks tumours in patient population Y and drug A doesn’t, then if the trial contains both X and Y there is still a  combination effect which is greater than drug A alone.

Many people reading this blog are probably aware that when we see positive combination affects in the clinic that it could be due to this type of patient enrichment. At a meeting in Boston in April of this year a presentation from Adam Palmer suggests that two thirds of marketed combinations in Oncology can be explained in this way, see second half (slide 27 onwards) of this presentation here. This includes current immunotherapy combinations.

We can now see why combinations in Oncology can be viewed as hierarchical. How appreciative the research community is of this is unknown.  Indeed one of the latest challenges from CRUK (Cancer Research UK), see here, suggests that even they may not be fully aware of it. That challenge merely focusses on the well-trodden path of the first level described here. Which level is the best to target? Is it easier to target the tissue and human population level than the cellular one? Only time will tell.