Developing Interleukin-2 For Cell Therapies: Key Considerations
By Carlos Bañado, CEO, ARScience Bio
Interleukin-2 (IL-2) has a long and evolving history in therapeutic use, beginning with its approval by the U.S. FDA in 1992 as Proleukin (aldesleukin), a high-dose recombinant IL-2 therapy for metastatic renal cell carcinoma and later for metastatic melanoma. While effective in stimulating immune responses, high-dose IL-2 was associated with severe toxicities, limiting its broader adoption. Over the years, IL-2 biosimilars have been developed to improve accessibility and reduce costs, though their use has remained primarily in oncology. With the rise of cell and gene therapies (CGT), IL-2 has taken on new roles: ex vivo, it is routinely used to activate and expand T cells — including CAR-T and tumor-infiltrating lymphocyte (TIL) therapies — prior to reinfusion; in vivo, IL-2 is increasingly employed as an adjuvant to support the engraftment, proliferation, and persistence of therapeutic cells post-infusion. Modern strategies now explore low-dose and engineered IL-2 variants to selectively target regulatory T cells (Tregs) or effector T cells, offering safer and more precise immune modulation in both cancer and autoimmune indications.
Recombinant human IL-2 (rH IL-2) in particular is widely used to enhance the efficacy of adoptive cell therapies, including TILs and natural killer (NK) cell therapies. By promoting cell expansion, survival, and functionality, interleukins help optimize therapeutic outcomes in cancer immunotherapy and regenerative medicine. Let’s look closer at the expanding role of IL-2 in the cell and gene therapy sector and compare ex vivo and in vivo approaches.
The Expanding Role Of Interleukin-2 In CGT
In recent years, the clinical use of interleukins — particularly low-dose rH IL-2 — has grown significantly, driven by promising results in modulating immune responses. As of early 2024, over 200 active clinical trials were investigating rH IL-2, many of which focus on oncology and autoimmune disorders.1 A substantial portion of these trials involve the use of rH IL-2 in combination with Tregs, underscoring its potential in enhancing the efficacy of cell-based therapies.
This growing interest reflects not only rH IL-2’s therapeutic promise but also the evolving complexity of CGT manufacturing and regulatory pathways. Optimizing dosing strategies, delivery mechanisms, and in vivo activity of cytokines like rH IL-2 remains a critical area for innovation, particularly when used as adjuvants to support the persistence and expansion of infused cells.
A key milestone was reached in February 2024 when the FDA granted accelerated approval to Lifileucel, an autologous TIL therapy developed by Iovance Biotherapeutics, the first approved T cell therapy for a solid tumor indication. Lifileucel’s post-infusion protocol includes rH IL-2 administration to promote the expansion and survival of the transferred lymphocytes — a strategy that reinforces rH IL-2’s critical role in next-generation immunotherapies.2
This approval not only validates rH IL-2's utility as an immunomodulatory agent but also paves the way for broader applications across CGT platforms. Future advancements in rH IL-2 engineering, delivery, and combination approaches may further unlock its potential in supporting the development of durable, scalable, and effective cell-based treatments.
Applications And Impact On Development
Interleukins can be utilized both ex vivo and in vivo, with each approach presenting distinct challenges in development, regulatory approval, and manufacturing. Ex vivo applications involve using interleukins to stimulate and expand immune cells outside the body before they are reintroduced into the patient, as seen in adoptive cell therapies such as TIL or CAR T cell therapies. In these cases, interleukins function as part of the cell culture process, requiring compliance with GMP standards for ex vivo cell processing.
There are several in vivo applications for rH IL-2 and other interleukins, including cancer immunotherapy (normally requiring high doses of rH IL-2), cell therapy support (post-infusion to expand and sustain T cells in CAR-T, TCR-T, and TIL therapies or to enhance NK cell survival in NK cell therapy), autoimmune and inflammatory diseases (normally using low-dose rH IL-2 to expand Tregs to suppress autoimmunity and inflammation, and also in infectious diseases and organ transplantation.
However, when interleukins are administered in vivo as therapeutic agents, additional regulatory and manufacturing challenges arise. In vivo administration necessitates stringent assessments of pharmacokinetics, biodistribution, immunogenicity, and potential systemic toxicities. Extensive dose optimization studies are required to balance efficacy and safety, as excessive immune activation can lead to severe adverse effects, such as cytokine release syndrome (CRS).
From a manufacturing perspective, in vivo interleukin products must adhere to drug product GMP standards, including rigorous formulation and stability studies, sterile fill/finish processes, and strict cold chain logistics to ensure bioactivity and safety. These added complexities make the development and commercialization of in vivo interleukin therapies significantly more demanding. While ancillary materials are normally regulated by ISO 20399 (for cell/gene therapy materials) and USP <1043>, the in vivo approval process will require a complex and lengthy biologic license application (BLA).
To add complexity, many of these ex vivo uses involve combinations of IL-2 with another drug or therapy — and on top of this, all these uses may require a different dose, formulation, or administration route. An oncology patient in a hospital setting will have different requirements than an inflammatory disease patient who is treated at home. A lyophilized product might be preferred for infusion, while an ambulatory patient who requires dose adjustment might benefit from a liquid formulation with a pen device.
These are all key decisions that you don’t want to change further down the road and have a huge impact in all the development phases. So, a good target product profile (TPP) becomes fundamental as the very first step of the development phase. One example of this is scale: in process development, you need to define the scale you will produce at the GMP site, considering how much clinical material you will need and how large the commercial batches will be.
In my next article, I’ll continue the discussion on IL-2 by discussing important manufacturing considerations.
References
- clinicaltrials.gov
- https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-lifileucel-unresectable-or-metastatic-melanoma
About The Author:
Carlos Bañado is CEO and board member of ARScience Biotherapeutics. Previously, he served as founder CEO of mAbxience, a biotech company focused on development, manufacturing, and commercialization of biosimilar monoclonal antibodies. Bañado is a pharmaceutical entrepreneur, being partner at Laboratorios Copahue SA, a pharmaceutical company focused on dermatology; board member and investor in Nanox Release Technologies, a nanotechnology company; and also worked with Celnova Pharma Inc., a pharmaceutical company specialized in complex therapeutic classes. He has served on the board of several companies and has broad international experience.