When a promising cell therapy moves from the laboratory to patients, how confidently can researchers say the preclinical evidence supports testing it in people?
A new study led by a uOttawa Faculty of Medicine team has examined that important question. Recently published in eBioMedicine, the study looked at how preclinical evidence is presented in clinical trial protocols for cell therapies—and identified opportunities to make the connection between lab findings and human trials more transparent.
Making a robust lab-to-clinic connection
“Early-phase clinical trials of cell therapies are incredibly time and resource intensive,” says Dr. Manoj Lalu, who is a co-corresponding author along with Dr. Dean Fergusson. “There have been some fabulous success stories like CAR-T cell therapy. However, we still need to find ways to make the translational process more efficient.”
Cell therapies hold enormous promise, but translating lab findings into successful treatments can prove quite challenging. Before an experimental therapy is tested in people, researchers typically rely on preclinical studies using cells, animals and other lab models to develop a case that the treatment could work. Yet there are no shortage of promising therapies that struggle to make the transition from the lab into successful human trials.
“What we've seen from studying this area for almost a decade is that there are opportunities to improve,” Dr. Lalu says. “For instance, our work suggests that researchers could do more to ensure that the doses, timing, and models used in the lab are relevant to downstream clinical trial.”
“Our work suggests that researchers could do more to ensure that the doses, timing, and models used in the lab are relevant to downstream clinical trial.”
Dr. Manoj Lalu
— Associate Professor, Lead – Blueprint Translational Research Group
First author Matthew Jeffers, a PhD candidate at the Faculty’s School of Epidemiology and Public Health, systematically examined protocols from 305 registered cell therapy trials. Of these, 209 incorporated preclinical evidence. While 95 percent of those protocols reported at least one element related to the therapy’s mechanism of action, fewer made clear connections between the lab evidence and specific aspects of the clinical trial.
As an example, evidence informing intervention parameters such as dose or route of administration appeared in 69 per cent of protocols, while only 24 per cent explicitly justified why the preclinical model was relevant to the patients and disease being studied.
“The team’s study found that preclinical evidence is often used to demonstrate biological plausibility, but less often to justify key aspects of trial design,” says Jeffers, who is co-supervised by Drs. Lalu and Fergusson and is a member of the Blueprint Translational Research Group at the Ottawa Hospital Research Institute.
Drilling down on details
For cell therapies, small details can be particularly important. Results may depend on the laboratory model used, how the therapy is delivered, the dose and timing, and how the cellular product is manufactured.
“The challenge is that these details and the reasoning for why they are or are not important are not always made clear when a trial is described,” Jeffers says. “A protocol might cite promising laboratory results without clearly explaining how the model, dose, or other experimental conditions relate to what will actually be done in patients.”
“The team’s study found that preclinical evidence is often used to demonstrate biological plausibility, but less often to justify key aspects of trial design”
Matthew Jeffers
— Study's first author, PhD candidate at the School of Epidemiology and Public Health
Making those connections explicit could help regulators, clinicians, research ethics boards, patients and other researchers assess the rationale for a trial and identify gaps before one begins, according to Dr. Lalu.
The study—funded by Canada’s Stem Cell Network—builds on earlier work by the collaborative team which examined regulatory guidance from around the world to determine what regulators expect from preclinical evidence before a cell therapy enters human testing.
From evidence to better trials
The findings point to practical opportunities for improving how preclinical evidence is communicated — without necessarily requiring more experiments.
Researchers could more explicitly explain why a particular preclinical model is relevant to the patients being studied, how laboratory findings informed the proposed dose and route of administration, and whether laboratory outcomes are meaningful for what researchers hope to achieve in patients. They could also describe how robust the findings are and whether they were reproduced across different experimental conditions or models.
“The goal is not necessarily to require more preclinical experiments,” Jeffers explains. “It may be about doing a better job of explaining and integrating the evidence that already exists.”
Next steps
The research team’s next move is to translate these findings into practical tools and guidance that researchers can use when designing and reporting trial-enabling preclinical studies.
At the uOttawa Faculty of Medicine and its world-class affiliated partners, the work reflects part of our approach to translational research: not only generating promising discoveries, but strengthening the pathway that carries those discoveries successfully from the lab to patients.
Ultimately, clearer connections between preclinical evidence and clinical trial decisions could help make cell therapy research more transparent, rigorous and efficient—while giving everyone involved a stronger understanding of why a promising therapy is ready to take its next leap.