Manufacturing issues have recently affected both cell therapies and genetically modified cell therapies in oncology, disadvantage patients with multiple myeloma (MM) and melanoma. Specifically, Instil Bio’s tumour-infiltrating lymphocyte (TIL) therapy, ITIL-168, has had its enrollment paused in the pivotal DELTA-1 trial due to a decrease in the rate of successful ITIL manufacture. -168. Additionally, an abstract (3588) accepted at the 2022 American Society for Hematology (ASH) meeting scheduled for December 10-13 shows that only 29% of MM patients were listed to receive T cells. chimeric antigen receptor (CAR-T) therapies received them within 12 months.
DELTA-1 is a single-arm phase II trial in metastatic melanoma evaluating the effectiveness of ITIL-168 in patients who have progressed on prior therapy. ITIL-168 is an autologous TIL therapy, which means that patients must undergo apheresis and wait for the product to be manufactured and re-injected. The clinical hold placed by Instil Bio on DELTA-1 means that Instil Bio will have to re-evaluate its manufacturing process and lose valuable clinical development time on the way to a Biologics License Application (BLA).
Meanwhile, the drug’s closest TIL competitor, Iovance Biotherapeutics’ Lifileucel, has started an ongoing BLA for patients with advanced melanoma and could hit the market as early as Q3 2023. Last year, Lifileucel was previously plagued by a different delay, which was an inability to convince the Food and US Drug Administration (FDA) that its potency tests for TILs were robust enough to lead to a uniform product. In April of this year, the FDA provided new comments on potency testing, which Iovance says will be covered in the latest BLA.
The ASH 2022 CAR-T cell summary (3588) will highlight data on MM patients (n=81) who were on a waiting list to receive treatment with Bristol Myers Squibb’s Abecma (idecabtagene vicleucel) at the University of Arkansas for Medical Sciences and the Medical College of Wisconsin. Of 81 patients listed, having received a median of six lines of treatment, 56 relapsed while awaiting apheresis. Only 29% of patients successfully received the CAR-T product within 12 months, and 31.9% of patients died while waiting for CAR-T cells, which is a striking number and highlights the pathway of problematic access to CAR-T cells that many US-based doctors have warned of.
Since the advent of CAR-T cells, failure to manufacture a product has been a common occurrence in the process of developing cell therapies in oncology, and many parts of the process are still manual and unlikely to be automated. Established CAR-T products such as of Gilead Yescarta (axicabtagen ciloleucel) and Novartis Kymriah (tisagenlecleucel) frequently reports a manufacturing success rate of over 80%, and these companies have had both the time and the resources to invest in improving their manufacturing process. However, a successful fabrication rate does not specifically correlate with the length of time between apheresis and fabrication, resulting in many patients relapsing with aggressive disease and requiring further treatment. This is an inherent challenge with autologous technology, even if the manufacturing process is still improved.
These challenges should lead to much faster adoption of allogeneic cell therapies if they prove equally effective in long-term studies, but also move a percentage of patients away from manufactured cell therapies and towards other ready-to-use products. use, such as bispecific antibodies or antibody-drug conjugates.
Companies with competing products should learn from these lessons in order to preemptively address manufacturing issues with their own therapies. However, the immature nature of the technology naturally leads to an approach where process development is incremental and problems are identified and improved as they arise. Careful selection of outsourcing partners is paramount, as is the development of in-house capabilities for much of the manufacturing process, an approach favored by Gilead and Novartis. Industry leaders surveyed by GlobalData mentioned that investing more in automation will be key to scalable manufacturing.