Overcoming Cell Therapy Design Challenges To Treat AML And Other Life-Threatening Diseases
By Chris Ehrlich, CEO, CERo Therapeutics
From its conceptualization in the 1980s, the clinical trial landscape for cell-based therapies has had challenges. Personalized, living therapies require a nontraditional clinical trial design, and at the outset of 2025, CERo Therapeutics began a Phase 1 trial of CER-1236, a genetically-engineered, multifunctional T cell that functions at the interface of the innate and adaptive immune systems.
Personalized cell-based therapy clinical programs present unique challenges and require thoughtful strategies to overcome them. Herein, discover the unique safety and limited efficacy endpoints of a Phase 1/1b setup and the key go/no-go signals to look for in such a program, including cell expansion as a critical early immunoresponse indicator, and comments from one of this particular trial’s principal investigators Stephen Strickland, Jr., MD, MSCI, director of leukemia research at Sarah Cannon Research Institute (SCRI).
The Logistical And Time-Sensitive Challenges Of CAR-T Therapy Trials
In contrast to clinical trials that test a mass-produced drug where all patients receive a standardized dose, each dose of a cell therapy is a unique product manufactured from a single patient's cells. This leads to high product variability, as the health and quality of a patient's T cells prior to manufacture can differ significantly.
This makes the manufacturing process incredibly complex, necessitating a procedure that consistently yields a sufficient dose with enough modified functional cells even from very different patients. That process requires apheresis (collecting the patient's cells), shipping to a specialized manufacturing facility, a multi-week manufacturing process, a battery of quality control tests, and finally, shipping the finished product back to the clinical site for infusion. This intricate chain can be both time-consuming and costly, often making it difficult to enroll and treat a number of patients within a reasonable time frame.
Patient accrual in engineered T cell therapy trials also differs from traditional trial design. Given the difficulty of testing off-target effects in animal models and the magnitude of toxicities that can occur, cell therapy trials adopt a “one patient at a time” paradigm in which a single patient is closely monitored for dose-limiting toxicities before the subsequent patient can receive therapy. This pace, long manufacturing timelines, and small patient populations, particularly in rare cancers like acute myeloid leukemia (AML), make it difficult to achieve the statistical power sought in traditional randomized controlled trials.
Overcoming Challenges And Designing Trials With AML Patients In Mind
Recognizing these challenges from the outset, planning the Phase 1 trial in AML required a patient-centric and adaptive design. The two-part study has begun with dose escalation — as most contemporary Phase 1 clinical trials do — to test safety and determine the highest tolerated dose to find a recommended dose for Phase 2, followed by an expansion phase to evaluate efficacy. Primary outcome measures include incidence of adverse events (AEs) and serious adverse events (SAEs), incidence of dose-limited toxicities, and estimation of overall response rate (ORR), complete response (CR), composite complete response (cCR), and measurable residual disease (MRD). Secondary outcome measures include pharmacokinetics (PK).
“Trials are varied, and some of the challenges stem from the diseases that they target,” said Dr. Strickland. “In most patients suffering from AML, their disease is so proliferative that keeping them stable for the time required for CAR-T manufacturing can be difficult. This trial design aims to address that by allowing bridging therapy once the necessary samples have been collected to help maintain control. There is a clear direction on how to handle that intermediate care.”
Bridging Therapy is treatment to keep the AML cell numbers low while the cell product is being manufactured. A key part of the design was to establish a centralized manufacturing and logistics model to also bring down the length of time needed to manufacture the cells. The CERo team worked closely with the manufacturing team at UC Davis to develop a manufacturing protocol, build expertise in CER-1236 processes, and use state-of-the-art release assays. This close relationship helped to produce a robust manufacturing process capable of producing CER-1236 for treatment at multiple dose levels with a rapid turnaround, which is critical in a rapidly progressing disease such as AML. This model streamlines the sample logistics and mitigates the risk of a manufacturing failure. CER-1236's unique genetic modifications also confer a potential advantage in manufacturing, making the engineered cells more capable of withstanding the rigors of the process, ensuring a more consistent final product that is both reliable and efficient to administer.
Many CAR-T clinical trials start at extremely low doses to prioritize patient safety, which can extend the dose escalation stage, as these low doses are less likely to have clinical efficacy. The trial design for CER-1236 harnessed a comprehensive set of preclinical safety data generated in close concert with the FDA to start at a dose comparable to approved CAR T cells. This approach allowed CERo to start at a likely safe dose while increasing the probability of detecting efficacy signals and reducing the overall time needed to identify the recommended dose, potentially offering more effective treatment opportunities to the patients enrolled in the trial.
Unique Benefits Of A Phase 1/1b Design
The Phase 1/1b trial structure for CER-1236 is intentionally designed to be flexible and informative. Unlike later-stage trials focused on hard efficacy endpoints such as overall survival or progression-free survival, the primary goals of this early-stage trial are to establish safety and tolerability. This approach offers hope to patients with very few options, like those suffering from late-stage AML.
This design allows the research team to gather crucial data on how the therapy behaves in humans without emphasizing significant clinical responses in a small number of patients. The early-stage trial is about learning, and early results are intriguingly positive.
As mentioned, the trial began at a dose level comparable to commercial CAR-T cell therapies and provides a flexible protocol to adjust the dose, including the administration of multiple doses. This approach was utilized with the trial’s second patient, based on patient responses and safety signals. The multi-dose escalation was authorized by the IRB following review of initial pharmacokinetic data from the first two enrolled patients, which showed cell expansion and effectively doubled the amount of cell product infused in each subject relative to the previous protocol approach.
This iterative process is crucial for a new class of therapy where the optimal dose and treatment regimen are still unknown.
Cell Expansion As A Critical Early Immunoresponse Indicator
One of the most critical early indicators of a successful CAR-T or cell therapy program is T cell expansion. After infusion, the engineered cells must survive, proliferate rapidly, and persist within the patient's body to effectively combat the cancer. In vivo cell expansion, measured through quantitative polymerase chain reaction (qPCR) or flow cytometry, provides a real-time window into the biological activity of the therapy.
A robust and sustained cell expansion indicates that the therapy is engaging with the patient's cancer as designed and has the potential to lead to a clinical response. A lack of expansion, on the other hand, is a clear "no-go" signal, suggesting a fundamental failure of the product or patient-specific factors that inhibited the therapy’s function.
Other key indicators include the modulation of cytokine levels, a marker of immune activation, and the absence of significant cytokine release syndrome (CRS), a common and dangerous side effect of CAR-T therapy. The unique design of CER-1236 aims to mitigate severe CRS while still promoting an effective anti-tumor response.
To date, through three patients, rapid cell expansion has been observed in the first two weeks following infusion, and a moderate contraction by 28 days. In addition, no evidence of traditional toxicity and side effects was observed in all three patients treated in the initial cohort. With the third re-dose of the second patient underway and the initial patient in the higher dose cohort administered the drug, the signs are showing “go” so far.
What This Means For Future Trial Design
The clinical development of cell-based therapies is a complex journey. The path is paved with challenges that require innovative and flexible trial designs. A creative and adaptive approach is necessary to overcome traditional obstacles. By focusing on safety, developing a robust manufacturing process, and tracking key early indicators like cell expansion, personalized trial designs like these are not only advancing a promising new therapy but also helping to rewrite the playbook for future personalized medicine trials. The ultimate goal should and always will be offering a new cancer treatment paradigm and renewed hope to patients.
About The Authors:
Chris Ehrlich is CERo’s current CEO. He brings significant biotechnology industry, business development, venture capital, investment banking, and SPAC experience. He also currently serves as the CEO of Launch One Acquisition Corp. He previously served as the CEO of Phoenix Biotech Acquisition Corp. and Locust Walk Acquisition Corp. He was also a senior managing director at Locust Walk Partners, where he was involved with sourcing and leading multiple transactions for emerging biopharmaceutical companies, including the sale of Xyphos Biosciences, Inc. to Astellas in 2019 and the sale of Thar Pharmaceuticals to Grunenthal in 2018. Prior to Locust Walk Partners, he was a managing director at InterWest Partners (“InterWest”), a venture capital firm.