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Presage Biosciences
A device that tests multiple cancer drugs in living tumor tissue could guide treatment selection in patients with lymphoma and other cancers, according to researchers.
They also believe the device, called CIVO, could help speed up drug development by testing the efficacy of candidate drugs in very small doses while sparing patients side effects.
CIVO is a handheld microinjection platform that can deliver small doses of up to 8 drugs or combinations of drugs into a tumor.
The device proved effective for testing multiple cancer drugs in xenograft mouse models, dogs, and humans with lymphoma.
Richard Klinghoffer, PhD, of Presage Biosciences in Seattle, Washington, and his colleagues described their research with CIVO in Science Translational Medicine. The research was funded by Presage Biosciences, the National Institutes of Health, and Seattle Children’s Hospital Neuro-Oncology Fund.
About CIVO
CIVO is designed for tumors near the skin surface, such as lymphoma or skin and breast cancer.
The technology enables the placement of multiple columns of drugs directly into the tumor along the needle axis, spanning the full depth of the tumor. This makes it possible to assess drug effects with multiple biomarkers and in multiple regions along the injection axis to capture the heterogeneity of response within the tumor.
Later (typically 24 to 72 hours after injection), the tumor is resected for subsequent analysis, and responses are measured with multiple immunohistochemistry-based assays and high-resolution scanning.
Results in mice
In xenograft lymphoma models, CIVO microinjection of well-characterized anticancer agents (vincristine, doxorubicin, mafosfamide, and prednisolone) induced spatially defined cellular changes around sites of drug exposure, specific to the known mechanisms of each drug. And the observed localized responses predicted responses to the same drugs systemically delivered in animals.
In pair-matched drug-resistant and drug-sensitive lymphoma models, CIVO correctly demonstrated tumor resistance to doxorubicin and vincristine.
The researchers also identified an unexpected enhanced sensitivity to the active form of cyclophosphamide in multidrug-resistant lymphomas compared with chemotherapy-naïve lymphomas.
And a CIVO-enabled in vivo screen of oncology agents revealed that a novel mTOR pathway inhibitor exhibits significantly increased tumor-killing activity in the drug-resistant setting compared with chemotherapy-naïve tumors.
Results in dogs and humans
Dogs with lymphoma showed no toxicity when injected with drugs via CIVO. And the researchers said they observed robust, easily tracked, drug-specific responses in the animals.
For lymphoma patients, the researchers used CIVO to inject microdoses of vincristine into the tumors in patients’ lymph nodes. Cells surrounding the injections died, and there were no serious adverse events, although patients did report mild discomfort.
“This analysis creates a comprehensive portrait of drug response that has never been seen before this early in the drug development process,” Dr Klinghoffer said. “Using this technology, we can assess how drugs, both as single agents and in combinations, impact the biology of tumor cells in the context of the native tumor microenvironment.”
“[T]ranslation of CIVO to the clinical setting has enabled assessment on all aspects of tumor biology, including drug effects on tumor-infiltrating immune cells. This sets the stage for a new type of pre-phase 1 clinical study in which multiple drugs or drug combinations can be tested simultaneously, directly in a patient’s own tumor, without toxicity associated with systemic drug delivery.”
