New devices test drugs where they will need to work: inside tumors

Two independent teams of scientists have described microtechnologies that could allow the testing of multiple drugs and drug combinations directly within tumors – both xenografted tumors in animals and tumors that are still within the patients themselves.

The teams, one from Presage Biosciences Inc., Celgene Corp. and academic collaborators and one from MIT, Third Rock Ventures and Kibur Medical Inc., published their approaches back to back in the April 22, 2015, issue of Science Translational Medicine.

The approach offers not only "the potential of a major clinical advance," MIT's Michael Cima told BioWorld Insight, but could also "completely change the way you do experimental design" for preclinical studies.

For all the efforts to get "the right drug to the right patient at the right time," as personalized medicine is often described, in practice drug dosing for cancer remains a guessing game to a disturbing degree.

Approaches from tumor genome sequencing, which looks to be on its way to becoming standard of care, to the use of mouse "avatars" aim to understand tumors better outside of patients before treating the patients.

LIMITATIONS

In practice, though, current methods have significant limitations.

The presence of a mutation is far from a guarantee that a patient will respond to a drug targeting the mutated gene – in fact, recent research suggests that in the absence of the correct control sequences, the chances that a patient will respond to targeted drugs identified through genome sequencing is no more than 50 percent. (See BioWorld Today, April 16, 2015.)

Mouse avatars seem to be more predictive, but in practice, testing with that approach is limited to a few drugs per patient.

The devices now described in Science Translational Medicine could enable the comparison of different options within tumors themselves, essentially allowing for test runs of different drugs or biologics before committing to a particular systemic therapy.

Such an approach could not only be useful for seeing how well a drug does at killing tumor cells. Surviving cells "can be the most interesting," Presage's chief scientific officer, Richard Klinghoffer, told BioWorld Insight, because they are the single-cell embodiment of minimal residual disease and can give important clues to drug resistance and relapse.

Also, "we do see immune responses to the drugs we are injecting," he added, which means the technique can be used to test immunotherapies which work by activating the immune response rather than by directly inducing apoptosis.

The details of the two methods differ. But the basic principle is the same for both approaches.

Both inject very small amounts of multiple drugs directly into different regions of a tumor, which is otherwise left undisturbed for a period of time. Either the injected region or the whole tumor can then be excised, and the different regions that were exposed to different drugs can be compared to see which drug or combination was most effective at killing tumor cells.

The MIT team has delivered up to 10 drugs at a time with the approach, though Cima said that, in principle, several dozen drugs could be delivered simultaneously.

The Presage microinjection device, which the company has named CIVO, can be used to deliver up to eight different drugs.

CIVO has been tested on four patients in a clinical trial, though the results are not being used to make treatment decisions in that particular trial. It is being used to guide treatment decisions in dogs.

DRUG COMBINATIONS

Presage has partnerships with Celgene and Takeda Pharmaceutical Co. Ltd. subsidiary Millennium Pharmaceuticals Inc. that aim to use the technology to rapidly identify promising drug combinations in preclinical experiments.

For MIT's technology, clinical use is still in the future.

"I could be surprised," Cima said, "but I don't really see a GMP supply of these [microdevices] for a few years," and so clinical use is still a ways off.

Kibur Medical is still a virtual start-up, albeit one that is co-founded among others by serial entrepreneur Robert Langer and Cima, who has half a dozen start-ups under his belt himself, and has attracted funding from Third Rock Ventures.

But in the meantime, Cima added, "there is a path forward commercially that is very near-term" for the use of the technology in preclinical studies.

In fact, he said, when he gave a talk describing the technology at the NIH last year, there was a lot of interest by basic researchers in getting their hands on the system.

His team currently is selecting laboratories that could beta-test the technology in their own laboratories, and expects such testing to start "within six months."

Directly microinjecting multiple drugs into a single tumor will allow researchers to compare the effects of potentially several dozen drugs in one animal, cutting down on animal use as well as experimental variability.

Presage's Klinghoffer also noted that the technology allows researchers to change the way preclinical development is done, by initially bypassing ADME-Tox concerns – the question of how a drug is taken up and metabolized by a living organism – and first establishing whether a candidate drug has any biological activity.

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