Series: What Early Human Data Tells Us
Early oncology trials have traditionally begun in patients for sound safety and ethical reasons. As more therapies act on defined, measurable immune pathways, some early pharmacology questions can now be answered in healthy participants. Published CHDR work shows both the precedent and the potential of this approach, while also making clear that careful selection is essential.
This is the sixth article in the series What Early Human Data Tells Us. It builds on earlier discussions of benchmarking inflammatory models, interpreting early inflammation signals, using controlled immune challenges before patient studies, defining meaningful anti-inflammatory response, and combining challenge models in one individual. Here the question is who can help answer the earliest pharmacology questions in immuno-oncology.
Why Oncology Began with Patients
For much of modern oncology, first-in-human studies used cytotoxic medicines whose effects on rapidly dividing cells could cause serious and lasting harm. Exposing a healthy person to those risks offered no prospect of therapeutic benefit. Early studies therefore enrolled patients, often with advanced disease and limited treatment options, where the risk could be justified by the possibility of benefit and drug activity could be observed in the disease setting.
That approach remains appropriate for many compounds. Immuno-oncology adds further considerations: some agents can trigger broad, prolonged or difficult-to-reverse immune effects, and the tumour microenvironment may be central to how a drug works. For those medicines, a healthy immune system may not provide the relevant biology, and the potential risks may not be acceptable in people who cannot benefit directly.
Patient studies also bring sources of variability that can complicate early pharmacology. Disease burden, prior anticancer treatment, concomitant medicines and differences in tumour biology can all affect immune measurements. In addition, the traditional focus on finding a maximum tolerated dose may not identify the best dose for targeted or immunomodulatory drugs, whose pharmacological activity can plateau below the dose that produces dose-limiting toxicity. Early biomarker data can therefore help separate the question of tolerability from the question of whether a dose engages and modulates its intended pathway.
Where Healthy Participant Studies Can Add Value
The rise of targeted medicines and immunomodulators creates opportunities to study selected mechanisms before entering patient cohorts. A pathway that is present in healthy people and can be measured in blood or accessible tissue may allow investigators to characterise pharmacokinetics, target engagement and early pharmacodynamics under controlled conditions. A defined immune challenge can add a further step: it generates a timed biological response against which drug effects can be assessed in vivo.
Healthy participants can reduce some sources of background variation, including differences in disease state, prior therapy and concomitant medication. They can also support intensive sampling and tightly controlled study procedures. Together, these features may make a pharmacodynamic signal easier to interpret and study execution more consistent. These are advantages to be tested in each programme, not a guarantee that every healthy participant study will be faster, less variable or more informative than a patient study.
The approach is most compelling when three conditions are met: the target is active and measurable without cancer; there are credible pharmacodynamic endpoints close enough to the mechanism to inform a decision; and the anticipated risk is acceptable for people without disease, with effects expected to be limited or reversible. When the mechanism depends on tumour-specific biology, carries substantial or persistent immune risk, or lacks interpretable endpoints, patient-first development may remain the better choice.
Evidence from Published Human Studies
A systematic review by Radanović and colleagues examined immunotherapeutic compounds with mechanisms relevant to oncology that had previously been tested in healthy participants. The search identified 38 compounds. Across the included studies, 86% assessed safety, 82% assessed pharmacokinetics and 57% included at least one pharmacodynamic endpoint. Those endpoints ranged from cytokines and immune-cell phenotyping to ex vivo functional assays.
Most reported adverse events were grade 1 or 2, although severe events were also reported. The review therefore supports feasibility for selected mechanisms; it does not suggest that immunomodulatory compounds are inherently safe for healthy people. The authors also noted the value of integrating healthy participant studies into proof-of-mechanism programmes, including the opportunity to inform dose selection before patients are exposed to doses that may not engage the target.
The findings should be interpreted within the scope of the review. The review included published studies available through October 2020, and it was not designed as a head-to-head comparison of healthy participant and patient trials. It establishes a clinical precedent and shows that pharmacodynamic assessment is possible, but it does not quantify whether healthy participant studies reduce variability, shorten timelines or improve later-stage success.
Read the review: Integration of healthy volunteers in early phase clinical trials with immuno-oncological compounds.
An In Vivo Example from CHDR
A later CHDR study illustrates how a controlled immune challenge could support oncology-focused pharmacology. Thirteen healthy men took part: three in a baseline validation group and ten who received a single intravenous dose of lipopolysaccharide (LPS) at 1 or 2 ng/kg. Blood and bone marrow were sampled at baseline and four hours after the challenge. LPS produced a rapid, transient inflammatory response in blood, while the bone marrow showed a different pattern of cellular and transcriptional activity.
The investigators identified 91 LPS-induced oncology-relevant targets in blood and 24 in bone marrow. MYC expression increased in bone marrow, with a dose-dependent rise in c-Myc protein also observed. The challenge and bone-marrow sampling were reported as safe and well tolerated in this small, closely monitored study. The results identify candidate pharmacodynamic markers and show that bone marrow measurements are feasible in this setting.
This was a model-characterisation study, not a trial of an investigational cancer therapy. Its transcriptomic findings are hypothesis-generating and would need prospective validation in drug studies. Nor does acute LPS stimulation reproduce a tumour or its microenvironment. Its value is narrower and practical: for a suitable drug targeting a pathway engaged by the challenge, it may provide a controlled human context in which to ask whether the drug produces the expected pharmacological effect in vivo.
What This Means for Early Development
In an appropriately selected programme, a healthy participant study can help establish exposure, target engagement and an initial pharmacodynamic dose range before the first patient cohort. Where a controlled challenge is relevant, it can also test whether the drug changes a defined immune response rather than only moving a resting biomarker. Fewer disease-related confounders may produce cleaner endpoint interpretation, while predictable visits and intensive sampling can support more complete and consistent datasets.
The practical gain is earlier, better-grounded decision-making: investigators may be able to choose which dose and endpoints merit evaluation in patients or recognise sooner that the expected pharmacology is absent. The evidence does not show that healthy participants can replace patient studies, establish antitumour efficacy or eliminate uncertainty. It shows that, for mechanisms and risk profiles that fit, early human pharmacology need not always begin in a patient population.
The evolving role of healthy participants is therefore selective and complementary. When guided by a clear mechanistic question, credible biomarkers and a careful safety rationale, these studies can make early immuno-oncology development more interpretable and help reserve patient exposure for programmes that are ready to answer disease-specific questions.
