AACR: By microdosing tumors, Takeda and Presage examine how to trigger the immune system to help fight cancer

By using a device that allows researchers to see how tiny amounts of cancer drugs perform while inside the body, Takeda has shown that two of its investigational therapies could potentially help break down the barriers that protect solid tumors from being targeted by the human immune system.

Through an ongoing collaboration with Presage Biosciences and its CIVO technology, the researchers were able to inject a series of cancer drug microdoses directly into a living tumor and observe the results.

On a basic level, the CIVO platform is not far removed from bacteria testing methods that have been used for decades. In that process, a culture in a petri dish is studded in circles with different antibiotics to see which has the greatest effect. The difference, of course, is that CIVO—short for comparative in vivo oncology—is performed in live tissue.

Presage’s injection device embeds parallel channels of different medicines straight down into a tumor. After 24 hours, the intact tumor is surgically removed, and slices of the tissue are analyzed to see which channel started to produce the best results.

“So we get to see what’s tightly linked to the drug’s mechanism of action, what is more disparate, and start to connect the dots around scientific hypotheses and the tangible questions that we ask ourselves throughout the next steps of preclinical and clinical development,” Chris Arendt, Ph.D., head of Takeda's oncology cell therapy and therapeutic area unit, said in an interview.

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In early studies of two therapies presented at the annual meeting of the American Association for Cancer Research, researchers at Presage and Takeda showed that each drug was able to turn “cold” tumors to “hot” in some cases, meaning that cancer cells that had previously been able to repel the body’s immune system had begun to show signs of improvement.

One experiment analyzed Takeda’s first-in-class SUMOylation inhibitor—known as TAK-981, or subasumstat—in patients with head and neck squamous cell carcinoma. Another evaluated TAK-676, a STING agonist, in mouse models of melanoma. Both therapies aim to ultimately trigger the body’s type I interferon pathway, which helps orchestrate a broader immune response to an invader.

Takeda hopes these therapies could help make tumors more receptive to other chemotherapies or immune-based cancer treatments such as checkpoint inhibitors, which have produced varying ranges of benefit depending on patient subgroups.

With CIVO and TAK-981, researchers saw the same variations among patients, with some responding strongly to the therapy and others being less sensitive.

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“Cancer patients all come with their own unique tumors, so I’d be shocked if we saw absolutely homogenous responses,” Presage CEO Rich Klinghoffer said in an interview. “That’s what we’ve been working with when you’re running xenograft models, because they’re relatively homogenous from mouse to mouse. But humans are unique, and everybody comes with their own unique, angry tumor microenvironment.”

“The really encouraging thing about Takeda’s compounds is that at least across the patients, the fundamental hypothesis holds up," Klinghoffer added. "They’re both eliciting the anticipated biological effect."

Those positive data are also being delivered much earlier than they would be in a typical research program, Arendt noted. 

“Having that insight early is just so valuable,” Arendt said. “Without this sort of approach, we’d be waiting until a fair way into development, to a point where we’d be able to collect biopsies.”

“Usually we're doing that once we've established an appropriate dose,” he added. “So this really accelerates that learning curve.”

Presage has also launched preclinical and phase 0 cancer research collaborations with Celgene, Bristol Myers Squibb, Merck and Maverick Therapeutics—the latter two announced alongside a $13 million fundraising round in March 2021, which included $6 million from Takeda Ventures. Maverick would go on to be acquired by Takeda in a $525 million deal.

Going forward, Presage is working to develop a newer generation of its CIVO system with a physically smaller injection device that will allow it to target tumors at earlier stages of growth.