The Friends of Cancer Research (Friends) held a webinar to update progress on its project aimed at accelerating the development of engineered cell therapies for cancer patients. Jeff Allen, PhD, President and CEO of Friends, said the organization formed a working group to streamline the process of bringing safe and effective therapies such as chimeric antigen receptor (CAR) T-cell therapies to cancer patients through FDA approval. These therapies have emerged as "an important new treatment pillar," he said, especially for hematologic malignancies.
Allen noted the working group will release a white paper containing its recommendations prior to a May 2023 meeting of the organization. The paper will address a number of issues related to accelerating the development of next-generation cell therapies. Speakers at this webinar discussed the path needed to formulate a regulatory framework and policies that support flexible data generation and trial designs for cell therapies. These issues will be presented at the upcoming May meeting.
A brief Friends project summary noted that "data extrapolation to advance new versions of investigational products has occurred for several decades across therapeutic classes as our understanding of these drug classes improves."
For example, the information cites how research on trastuzumab was used to accelerate the development of trastuzumab and hyaluronidase-oysk. Clinical data extrapolation was possible and, due to the same manufacturing processes and drug substances, cross referencing to the biologics license application was also possible. In terms of cell therapies, the Friends project summary stated that "the FDA has on a case-by-case basis allowed sponsors to extrapolate data from an earlier T-cell product to a second-generation product."
In a webinar overview, Peter Marks, MD, PhD, Director of the FDA's Center for Biologics Evaluation and Research (CBER), said the FDA has approved six engineered T-cell products. "It really is an exciting time," he said, noting that last year the FDA received close to 100 CAR T-cell submissions from sponsors.
Marks said that, while most of these product submissions were for hematologic malignancies, there has been an uptick in submissions for solid tumors. He added that the real excitement in the field comes from the ability to make multiple genome edits, which will enable novel CAR T-cell constructs.
Marks also noted that future research in the field will include branching out from the one hematologic target, CD19, and developing allogeneic CAR-T cells, which could be transformative. He cited FDA's draft guidance document, "Studying Multiple Versions of a Cellular or Gene Therapy Product in an Early-Phase Clinical Trial," which outlines an umbrella trial approach. This strategy, which involves investigating several versions of a cell therapy product in an umbrella trial rather than initiating several trials, can streamline regulatory requirements and data collection. He said the bottleneck for cell therapies is often in the manufacturing process, which can delay products coming to market and reaching patients.
FDA staff are very open to having dialogues with sponsors during a product's development, Marks stressed. Agreeing was Ingrid Markovic, PhD, Senior Science Advisor and CMC Policy Lead in the CBER/FDA Immediate Office of the Center Director. "We certainly take industry feedback very seriously," Markovic said. She agreed with Marks that manufacturing can pose unplanned problems and sponsors should try to anticipate challenges such as a raw material supply problem. Markovic also stressed that "work really is not done when the product is on the market," and noted that it is important to follow a product when it is in clinical use.
There may be opportunities to leverage data from the development of an earlier product to a next-generation product, according to industry leaders. One presentation highlighted a case study of axicabtagene ciloleucel for relapsed or refractory adult large B-cell lymphoma and brexucabtagene autoleucel for relapsed or refractory adult mantle cell lymphoma, which are two distinct products, but with the same antigen and same vector (both target the biomarker CD19). Brexucabtagene autoleucel has also been approved for the most common form of adult acute lymphoblastic lymphoma (ALL); it is the first CAR T-cell therapy approved for adults with ALL. It was noted as an example of where a next-generation product (brexucabtagene autoleucel) was able to leapfrog over some steps in development by using data from research with the earlier product, axicabtagene ciloleucel, thus allowing brexucabtagene autoleucel to reach cancer patients faster.
Researchers were able to successfully extrapolate data from axicabtagene ciloleucel to brexucabtagene autoleucel, and industry experts believe the FDA should encourage sponsors to discuss their data extrapolation strategies with the agency. They advised looking at a primary product and a secondary product in terms of a comparable clinical profile.
It is possible to leverage programmatic stability data to streamline the development process for cell therapies, said Julie Jadlowsky, PhD, Director of Translational Science Operations in the Center for Cellular Immunotherapies at the University of Pennsylvania. She stressed that cell therapy researchers have been making a lot of advances in a relatively short amount of time. She described the two phases of patient safety follow-up at her center (short-term and long-term), a facility that focuses on first-in-human pilot and Phase I cell-based therapies. Jadlowsky said center staff members have tried to make the long-term follow-up for study subjects shorter and less burdensome. "The goal is finding a balance; how long is long enough?" she asked.
In a statement related to the Friends cell therapy initiative, Philip D. Greenberg, MD, FAACR, President-Elect of the American Association for Cancer Research (AACR) and Editor-in-Chief of the AACR journal Cancer Immunology Research, predicted in a blog that in 2023 the field of engineered cell therapies will progress very rapidly.
"We can now modify the cells to improve their function and survival after infusion into patients and their ability to target the cancer. The field is going to look very different in 2023 and 2024," said Greenberg, Professor and Head of the Program in Immunology, Clinical Research Division, and the Rona Jaffe Foundation Endowed Chair at the Fred Hutchinson Cancer Center. He said adoptive cell therapies "can be effective even in a body that has already encountered the target antigens and whose immune system is not responding to them." Greenberg emphasized that rapid advances in the field will have an enormous impact on the development of effective cell therapies for solid tumors, which so far have been a challenge.
Peggy Eastman is a contributing writer.
Questions for Next-Generation Cell Therapies
The Friends project summary paper distributed to webinar attendees cited the following key discussion questions, which the working group will consider as it writes its white paper to be presented in May.
* What learned knowledge can be applied to support the design and execution of clinical development programs for the next generation of cell therapies?
* What are key considerations for developers when proposing to introduce modifications to cell therapy products?
* Can a risk-based approach be developed to assess the potential impact a modification might have on the safety and efficacy of the product?
* What are important regulatory considerations when leveraging knowledge and data from first-generation products to support second-generation products?