NEW YORK – The National Institutes of Health's Advanced Research Projects Agency for Health (ARPA-H) has awarded Rice University up to $45 million to develop prototypes of an implantable device that manufactures immunotherapies inside cancer patients' bodies and adjusts dosing in response to biomarkers it measures.
The award is part of the White House Cancer Moonshot's initiative to accelerate technology breakthroughs in cancer. Omid Veiseh, an associate professor of bioengineering at Rice and the principal investigator for the project, described the Targeted Hybrid Oncotherapeutic Regulation (THOR) device as a "living drug factory" inside the body. The three-inch-long rod-like device, currently in the prototyping stage, comprises a miniaturized bioreactor containing human epithelial cells engineered to produce immune modulating therapies, a system for detecting biomarkers, onboard electronics, and a wireless rechargeable battery.
Veiseh's group has been developing cellular therapeutics that function as bioreactors in the body for about four years. In the biotech industry, many drugs currently on the market are biologics and are made by cells in bioreactors in manufacturing plants. His vision is to build implantable bioreactors, "so we can bring that biomanufacturing into the patient" and develop a technology that can sense biomarkers and respond by releasing the appropriate dose of drugs.
As an example of a similar technology, Veiseh pointed to artificial pancreas systems, which are already in advanced development, with multiple devices approved by the FDA. Such a device includes a continuous glucose monitoring system, an insulin pump, and a computer processor that controls the insulin dose in response to patients' glucose levels. "The hope with this project is to focus on immuno-oncology and bring that perspective to [cancer]" with a device that provides feedback-regulated drug production inside the patient's body, he said.
Similarly, Veiseh envisions the THOR device, which is in early stages of development, will be able to monitor biomarkers including PD-L1, interferon gamma, and other cytokines, and produce an anti-PD-1 antibody and interleukin-2 on demand that can generate a localized immune response against cancer. The device will also be able to monitor biomarkers of toxicity such as the liver function markers alanine transaminase (ALT) and aspartate transaminase (AST) for the purpose of modulating dosing. The sensor in THOR will use protein fragments to detect the analyte of interest and trigger an electrical signal detected by the device.
Clinical trial of cellular drug factories
Veiseh's lab at Rice invented the cellular drug manufacturing technology that will be used in THOR and spun out a biotechnology company, Avenge Bio, to develop it further. Avenge's LOCOcyte allogeneic cell-based immunotherapy platform is an off-the-shelf encapsulated cell product that generates immune effector molecules inside the body. It is delivered in capsule form close to the tumor so it can stimulate the innate and adaptive immune system without the toxic effects of systemic immunotherapy. Avenge Bio's lead product, AVB-001, is a hydrogel packet that is 1.5 millimeters in diameter and contains 40,000 cells engineered to produce IL-2.
In a preclinical study, IL-12-producing cells implanted in mice eradicated local and distant colorectal tumors and, when paired with a checkpoint inhibitor, shrank metastatic melanoma, demonstrating the potential of the cellular drug manufacturing technology. Avenge Bio is now conducting a Phase I/II clinical trial of AVB-001 in patients with high-grade serous adenocarcinoma of the ovary, primary peritoneum, or fallopian tube. The researchers will be monitoring patients for safety and adverse events, establishing a maximum-tolerated dose and recommended Phase II dose, and looking for signs of efficacy by tracking objective response rate, duration of response, progression-free survival, and overall survival.
Avenge Bio's cellular drug manufacturing technology that's being employed for AVB-001 will also be a key component of THOR. In THOR, which is being developed by Veiseh's group and not Avenge, the engineered epithelial cells will be surrounded by a porous hydrogel, allowing nutrients from the patient's body to diffuse in as fuel for the bioreactor. The gene expression in the cells is then controlled remotely using electrogenetics, a new approach within the field of synthetic biology in which electrical stimulation is used to induce gene expression in engineered cells.
The drugs manufactured by the cells diffuse out as they are produced and drain into the lymph nodes, where they activate the immune system. The device lasts 60 days and can be removed after that. In that time, Veiseh said THOR is designed to "educate the immune system" to recognize the cancer and prevent it from recurring. If after the first administration of this approach, a patient's cancer is not fully eradicated, the device could be implanted again.
Accelerated development timeline
Veiseh's group has built THOR prototypes, but they are not yet fully integrated and ready for testing. The recent award from ARPA-H will jump-start the project by allowing Veiseh to immediately build a large multi-disciplinary team with the expertise to build the device and produce a fully functional prototype.
An important advantage Veiseh hopes to show is that THOR can provide treatment immediately in response to signals from the tumor. "Today, cancer is treated a bit like a static disease, which it's not," Veiseh said. "Clinicians administer a therapy and then wait four to six weeks to do radiological measurements to see if the therapy is working. You lose quite a lot of time if it's not the right therapy. The tumor may have evolved into a more aggressive form."
In contrast, with THOR implanted in a patient, the dose or type of therapy could theoretically be adjusted in real time and remotely. "That's going to be a game changer for patients," Veiseh said.
Initially, all control and decision-making will be done by the provider based on signals transmitted by THOR, using a computer or a smartphone-like device. But in the long term, Veiseh envisions a smart device powered by artificial intelligence that could independently make dosing decisions, similar to an artificial pancreas system.
"As we treat more and more patients [with THOR], the devices are going to learn what type of biomarker readout better predicts efficacy and toxicity and make adjustments based on that," he speculated. "Between the information you have from the first patient versus the millionth patient you treat, the algorithm is just going to get better and better."
In the first clinical trial planned for THOR, Veiseh's group will test the device in patients with refractory and recurrent ovarian cancer. However, since the device occupies the peritoneal cavity, it could potentially be useful in treating cancers that affect other organs in that part of the body, including the pancreas, colon, rectum, kidney, and liver.
Veiseh said his group is starting with ovarian cancer because of the large unmet need in this setting and because it provides an opportunity to test whether the device can activate the immune system against ovarian cancer, which thus far has been recalcitrant to immunotherapy approaches. If successful in ovarian cancer, he and his team would like to test THOR in other cancers that metastasize within the abdomen, such as pancreatic, colorectal, bladder, and liver cancer.
In terms of intellectual property, Veiseh said the anti-PD-1 antibody produced by the bioengineered cells in THOR would differ in genetic sequence from marketed immunotherapies like Merck's Keytruda (pembrolizumab), and therefore, wouldn't conflict with other drugmakers' patents. His group has filed patents on THOR and their approach to manufacturing drugs using engineered cells within the body. "We're not administering a drug at all, we're administering [cells within a device] that genetically encode a drug," Veiseh said.
Veiseh said the $45 million award is consistent with the ARPA-H's mission to support transformative biomedical and healthcare breakthroughs. He quipped that THOR may "sound science fictional, but actually, if you break down each of the [device] components," they are based on mature technologies.
"What hasn't happened yet is, there hasn't been a hyper-focused effort to really bring all these pieces together," he explained. "That is exactly the purpose of [the agency], to fund ideas that maybe would mature on their own over a 20-year horizon, but with their large investment and ability to provide the logistics needed to bring a group like this together, perhaps we can get there on a five-year horizon."
The grant also aligns with societal goals outlined by the White House Office of Science and Technology Policy in March to advance US biotechnology and biomanufacturing. One of these, for example, is developing sensors that detect indicators of health and investing in novel technologies such as synthetic biology to collect multiomic data.
If all goes well, Veiseh said, his group could begin studying THOR in the first human clinical trial within four years. He expects to spend the first two and a half years building prototypes, testing them in rodents, and refining the list of biomarkers to be used in the device. It will take another year to set up protocols according to FDA's good manufacturing practices requirements and to test a final prototype on large animals, he estimated, leading to a first-in-human trial in year four.
His group is already working with clinicians to collect samples from ovarian cancer patients so they can identify markers that are predictive of treatment response. "We have the advantage of the ongoing trial that Avenge has, where we can see how effective those [biomarkers] have been, and we'll leverage that toward further design and refinement of this new system," Veiseh said, adding that Avenge Bio expects the Phase I/II trial of AVB-001 to read out in one to two years.
Should THOR successfully complete clinical trials and reach the commercialization stage, Veiseh plans to form a new company or license the technology to an existing company. "We know that the further we advance it in terms of getting that human data, the more likely it is that this could then be transferred to another entity," he said.