Dmitry Gabrilovich (AstraZeneca)
Responses to interview questions from Tal Behar, Precision Medicine World Conference
1. Trial Design
Question:
In myeloid-targeting combination trials in solid tumors, what’s the most common trial-design mistake you see
(patient selection, timing, endpoints, assays), and what one change would you make first to avoid false
“no-signal” outcomes?
Answer:
The challenges with myeloid cell targeting go beyond trial design alone.
First, cellular and pathway redundancy must be considered. Cellular redundancy refers to the
ability of cells from different lineages, primarily granulocytic and monocytic/macrophage populations,
to compensate for each other’s function. As a result, simultaneous targeting of multiple myeloid populations
is likely necessary.
Pathway redundancy reflects compensation by distinct molecular mechanisms within the same cell. Therefore,
identifying and targeting shared pathological pathways is preferable to targeting individual molecules.
Second, approaches must focus on the pathological state of myeloid cells, not on indiscriminate
depletion of all myeloid cells. The pathological states of myeloid cells are now well defined and extensively
described in the literature.
Third, patient selection should be based on the presence of myeloid expansion and tumor infiltration
on a patient-specific basis. A substantial proportion of patients, up to one-quarter in many cancer types, do not
exhibit myeloid expansion. In these patients, myeloid-targeted therapies are unlikely to be effective.
Fourth, treatment scheduling should be reconsidered. Current approaches typically rely on continuous
and prolonged treatment, which may facilitate compensatory responses due to the high plasticity of myeloid cells.
Intermittent therapy at higher doses may prove more beneficial.
2. Translational Biomarkers
Question:
If you could standardize one translational biomarker or assay across myeloid-checkpoint trials, what would it be,
and what would you want it to prove early in patients (mechanism and likelihood of response)?
Answer:
The most effective and practical approach for patient selection is assessing the presence of
pathological myeloid cells, including macrophages and myeloid-derived suppressor cells (MDSCs),
in pre-treatment tumor biopsies.
These biopsies are routinely available for most patients and do not require additional invasive procedures.
Relevant markers are well reported, and numerous studies demonstrate a strong association between myeloid
infiltration and clinical outcomes.
What remains missing is a direct association between these biomarkers and response to myeloid-targeted therapies.
Blood-based assays are widely used, and markers of MDSCs are well established. However, assay variability can be
significant, requiring rigorous control over sample acquisition and analysis. While this is achievable in
academic settings, it presents a major challenge for harmonization in large-scale multicenter trials.
On-treatment biopsies and blood samples provide excellent material to assess target engagement
and should be incorporated early in clinical development. Demonstrating even a modest association with clinical
outcomes in a small initial cohort can provide sufficient confidence to advance a therapy into larger trials.
Without such associations, it becomes difficult to understand why a combination therapy fails or produces
inconsistent clinical signals.
3. Message to the PMWC Community
Question:
Are there any other points you would like to share with the PMWC community?
Answer:
Myeloid cells are a critical component of the tumor microenvironment and represent one of the major factors
limiting the success of current cancer therapies.
Targeting these cells is one of the most exciting opportunities to enhance clinical benefit, including in
patient populations that otherwise respond poorly to treatment. However, success will depend on applying
smart, biologically informed approaches such as those outlined above.
