NEW YORK – Umoja Biopharma and Seattle Children's Hospital this month officially began enrolling teens and young adults with advanced osteosarcoma to a first-in-human trial, called ENLIGHTen-01, which will investigate Seattle Children's autologous CAR T-cell therapy plus Umoja's small molecule fluorescein tag, UB-TT170.
The autologous CAR T-cell therapy — an asset that belongs to Seattle Children's Therapeutics, a nonprofit venture associated with the hospital — is designed to target fluorescein. Umoja's UB-TT170, or "TumorTag" molecules, meanwhile, are designed to "tag" the tumor cells with the fluorescein that the CAR T cells target. To accomplish this, the bispecific molecules selectively bind to folate receptors on the surface of osteosarcoma cells, effectively labeling them with fluorescein.
According to Navin Pinto, an associate professor of pediatrics at Seattle Children's and the principal investigator on the new trial, the two-part treatment — of both the autologous CAR T-cell infusions and the TumorTag infusions — could ideally improve the cell therapy's safety by ensuring that the CAR T cells are only active in the presence of UB-TT170. By administering UB-TT170 intermittently, he said, the regimen could also help prevent CAR T-cell therapy exhaustion, which is a common barrier to developing cell therapy for many solid cancers.
Pinto shared that the trial, which will likely involve 21 osteosarcoma patients between ages 15 and 30, is officially open for enrollment, and that since the majority of osteosarcoma cells express one if not both isoforms of the folate receptor, investigators will not need to screen patients for folate receptor status first.
According to Pinto, the first infusion of the therapy will likely occur about a month after the first patient is enrolled, to account for the manufacturing turnaround time for the patient-specific fluorescein-specific CAR T cells. Manufacturing will take place in Seattle Children's Cure Factory, its good manufacturing practice (GMP)-compliant cell therapy facility.
The primary goals of the trial are to establish the treatment's safety, the feasibility of manufacturing the fluorescein-specific CAR T cells, and the pharmacokinetics of the UB-TT170 combined with the fluorescein-specific CAR T cells.
Umoja's in vivo cell therapy ambitions
Umoja CEO Andrew Scharenberg was eager to clarify that the trial underway at Seattle Children's using the ex vivo manufactured autologous CAR T-cell therapy will serve as a proof of concept for the company to establish the efficacy of its TumorTag system. The firm has its sights on a different type of CAR T-cell therapy delivery — one that involves no GMP manufacturing facilities, no monthlong production processes, and no lymphodepleting chemotherapy regimens before infusions of pricey, n-of-1 products.
If the Seattle Children's trial demonstrates the efficacy of the TumorTag technology, Umoja wants to use it with its "VivoVec" in vivo CAR T-cell therapies, which involve injecting viral vector-derived nanoparticles directly into patients' lymph nodes so that the T-cell engineering that would otherwise take place in a facility ex vivo occurs inside the patient's body. The marriage of Umoja's two technologies will ensure that these engineered cells inside the body will recognize and go after the "tags" that the TumorTag technology has made the tumors express.
Theoretically, Scharenberg believes, this could get around some of the key issues hindering CAR T-cell therapy development in solid tumors, including the all-too-common issue of antigen loss or heterogeneity. If the tumor cells are made to reliably express a target with an Umoja TumorTag, then the CAR T cells — which will be designed to target those TumorTags — can, in theory, continue to selectively target cancer cells.
There's a third element of the treatment, too, which Umoja is calling the "RACR," short for rapamycin-activated cytokine receptor. This is meant to allow the in vivo engineered CAR T-cells to expand and activate in the body without lymphodepleting chemotherapy.
"When you go in vivo, you don't have the option of giving systemic chemotherapy because the T cells that we are going to be delivering our CAR payload to … we need them to be alive and vigorous," explained Scharenberg. "In order to get them to expand into a therapeutic population, we need to be able to duplicate some of the conditions that are present in the ex vivo manufacturing process, and the most important part of that is expansion in growth-promoting cytokines."
This, he said, is accomplished by delivering a receptor — the RACR — that provides the interleukin signature to allow the cells to expand in the patient.
The whole regimen has a long way to go before the Seattle-based startup, which launched in late 2020 and closed its Series B financing round last summer, can confidently say it's safe and effective in human patients. Before Umoja pairs the different elements of the platform and begins testing it as one — the VivoVec in vivo CAR T-cell therapy with RACR, and the TumorTag bispecific molecules — the firm is independently evaluating the elements in their own proof-of-concept trials: one with the TumorTag and one with the VivoVec and RACR.
"The vision of the company is to bring together in vivo delivery with a way to sustain that T-cell population in the patient and then to controllably direct that T-cell population to attack a tumor," Scharenberg said. "That's three new technologies all being brought together. … It just looked like it would be too much to be done all at once."
According to Scharenberg, the company decided to evaluate the elements of the therapy before studying them together based on feedback from the US Food and Drug Administration's Center for Biologics Evaluation and Research (CBER). The firm held a meeting with regulators to discuss its strategy before designing studies or filing investigational new drug applications.
Having officially filed its IND for UB-TT170 and launched the Seattle Children's osteosarcoma trial, the TumorTag piece of the therapy is the first element of the treatment to enter the clinical development phase. But Umoja has plans to bring the VivoVec therapy to the clinic soon, too, according to Scharenberg.
As of now, Umoja's plan is to have a pre-IND meeting with the FDA this summer to discuss the design of the VivoVec Phase I trial, and then file an IND for the in vivo approach next year. Scharenberg couldn't specify exactly which patient population Umoja would be targeting with the VivoVec first-in-human trial, but it will likely be in hematologic malignancies with CD19-directed CAR T cells, because CD19 is an established target with proven efficacy.
Even though the ultimate goal will be to pair the VivoVec and TumorTag platforms together to force effective targets upon the tumors, the company, in wanting to show proof of concept with VivoVec, decided to go after an established target.
Eyeing new delivery methods
There are, to be sure, concerns about the VivoVec in vivo approach. One is that many heavily pretreated patients have low lymphocyte counts, and the in vivo VivoVec CAR T-cell therapy relies on, as Scharenberg described, "rapidly and effectively accessing enough lymphocytes to get a good CAR T-cell delivery in the patient's body."
This is one of the reasons that Umoja just this week announced a new collaboration with a Dallas-based firm called Lupagen that makes a device called the Side CAR-T system. In this bedside device, a patients' lymphocytes can go through apheresis and come into first contact with the VivoVec drug outside the body, in a closed loop before reinfusion back into the patient.
"With the Lupagen system, you can collect the lymphocyte in the exact amount you want," Scharenberg said. "You then expose our product to those lymphocytes and the initial contact with our drug product starts."
After VivoVec is incorporated into the lymphocytes in this controlled closed loop in the device, which the firm calls "extracorporeal in vivo," the cells go back into the body, and the actual gene delivery and transformation of the cells into CAR T cells continues in vivo over the next day or so.
"It's still in vivo gene delivery, just in a very controlled fashion, and offers us some advantages in order to be able to control the interaction of our drug product with the lymphocytes," he explained.
The collaboration is brand new, and Scharenberg isn't yet sure whether the device will fit into the firm's clinical development plans for its early-phase VivoVec trials. Still, one option could be to use it specifically in patients with lower lymphocyte counts and inject VivoVec directly into the body for patients with higher lymphocyte counts. This would involve prescreening patients and assigning them to one trial arm or another. Umoja has yet to decide.
Under the terms of their collaboration agreement, Lupagen has agreed not to develop or commercialize its Side CAR-T device for delivering any viral vectors for oncology indications. Umoja, meanwhile, has the option to opt into an exclusive, worldwide agreement to develop the device for oncology.
Though the firm has work to do in terms of determining the best clinical trial approach for the in vivo aspect of its treatment platform, Scharenberg was confident that the preclinical work the firm has published so far is sufficient to take its therapy to the clinic.
Just last week during the American Society for Gene and Cell Therapy, Alissa Brandes, a principal scientist at Umoja, presented on the preclinical activity and safety of the VivoVec product, which Umoja has dubbed UB-VV100, including in humanized mice and in dogs.
"These preliminary safety studies have demonstrated a favorable safety and biodistribution profile using two models," Brandes said in her presentation. "These findings support the potential of Umoja's VivoVec platform for generating safe and effective CAR T cells in vivo, potentially expanding patient access to CAR T technology in both hematologic and solute tumors without the need for ex vivo cell manufacturing or lymphodepletion."
Confident in the preclinical data, Scharenberg said the rest of the pre-IND to-do list hinges on regulatory conversations.
"The only missing piece is identifying exactly the GLP [good laboratory practice] toxicology studies that [FDA] wants to see," he said. "You don't have to do this, but if you do your studies without having a discussion with the FDA and then you submit your IND and they disagree, that creates a delay. … We want to have a collaborative interaction."
Scharenberg's focus on collaborating closely with CBER officials, especially given the complex nature of the therapy Umoja is trying to develop, echoes closely what many drugmakers in the early stages of cell and gene therapy development have expressed.
Meanwhile, staffing and resource challenges have overburdened the agency in its ability to accommodate all of the early-stage startups like Umoja seeking personalized feedback. For this reason, many are hoping that in the coming years, resources and provisions in the seventh Prescription Drug User Fee Act reauthorization may begin to help ease this burden.