Periodic Reporting for period 1 - Tune_IT (Tuning Immune T cells for cancer therapy)
Berichtszeitraum: 2024-01-01 bis 2025-06-30
The problem: Loss of function of adoptively transferred T cells for cancer immunotherapy.
Adoptive cell therapy (ACT) recently became an important treatment modality for cancer. Over 400 clinical ACT trials are ongoing mainly exploiting T cells, now also expanding to other immune cells such as tumor infiltrating lymphocytes (TIL) and NK cells. ACT products require extensive ex vivo manipulation and expansion of (genetically engineered) patient T cells prior to reinfusion back into patients to attack cancer cells. Unfortunately, T cell exhaustion and loss of function after reinfusion form a major obstacle in currently used ex vivo expansion protocols, There is an urgent medical need to significantly enhance the quality of ACT products to improve both responsiveness and relapse time in patients.
The solution: Dedicated tuning of T cells during ex vivo expansion to preserve their anti- cancer function and prevent exhaustion.
In the body, T cells are activated by antigen presenting cells (APC) to initiate an immune response. As patient-derived APC are often immunosuppressed, much effort is spent on developing 'artificial antigen presenting cells' (aAPC) to expand immune cells for ACT. We developed a unique polymeric aAPC platform, termed immunofilaments, that provide a highly flexible-, scalable-, GMP compliant- and affordable- solution for robust production of (CAR)T cells for ACT.
Development of this novel technology for clinical use aims at:
1. Improved ACT products, as tuning of T cells by immunofilaments during ex vivo expansion will outperform current aAPC products, by preventing T cell exhaustion improving longevity after ACT.
2. Improved patient responses, because of better T cell function, but also for a prolonged period of time.
3. Broadly applicable treatment approach, as this highly flexible technology platform can be extended to also tune TIL- or NK- cell based ACT products.
Adoptive cell therapy (ACT) recently became an important treatment modality for cancer. Over 400 clinical ACT trials are ongoing mainly exploiting T cells, now also expanding to other immune cells such as tumor infiltrating lymphocytes (TIL) and NK cells. ACT products require extensive ex vivo manipulation and expansion of (genetically engineered) patient T cells prior to reinfusion back into patients to attack cancer cells. Unfortunately, T cell exhaustion and loss of function after reinfusion form a major obstacle in currently used ex vivo expansion protocols, There is an urgent medical need to significantly enhance the quality of ACT products to improve both responsiveness and relapse time in patients.
The solution: Dedicated tuning of T cells during ex vivo expansion to preserve their anti- cancer function and prevent exhaustion.
In the body, T cells are activated by antigen presenting cells (APC) to initiate an immune response. As patient-derived APC are often immunosuppressed, much effort is spent on developing 'artificial antigen presenting cells' (aAPC) to expand immune cells for ACT. We developed a unique polymeric aAPC platform, termed immunofilaments, that provide a highly flexible-, scalable-, GMP compliant- and affordable- solution for robust production of (CAR)T cells for ACT.
Development of this novel technology for clinical use aims at:
1. Improved ACT products, as tuning of T cells by immunofilaments during ex vivo expansion will outperform current aAPC products, by preventing T cell exhaustion improving longevity after ACT.
2. Improved patient responses, because of better T cell function, but also for a prolonged period of time.
3. Broadly applicable treatment approach, as this highly flexible technology platform can be extended to also tune TIL- or NK- cell based ACT products.
The aim of Tune-IT is to 1) validate if a new polymer platform (immunofilaments, figure 1) we developed, can effectively expand T cells for adoptive cell therapy (ACT) in cancer patients, and 2) explore the potential market and feasibility to develop a commercial product through a start-up.
ACT became an important treatment modality for cancer. Immune T cells from patients. ACT products require extensive ex vivo manipulation and expansion of (genetically engineered) patient T cells prior to reinfusion back into patients to attack cancer cells. Unfortunately, T cell exhaustion and loss of function after reinfusion form a major obstacle in currently used ex vivo expansion protocols. In Tune-IT we tested the potential of producing T cells that maintain their function.
Objective 1. Validate that immunofilaments effectively expand T cells and are suitable to produce high quality ACT products.
We carried out detailed analyses (T-cell activation, expansion and phenotype analyses), fine-tuned immunofilaments decorated with various combinations/densities/ratios of immunomodulators to optimize ex vivo T cell expansion without loss of function or exhaustion. We could demonstrate that in particular with immunofilaments decorated with immunostimulators anti-CD3 and anti-CD28 effectively supported T cell expansion. Interestingly, we observed that immunofilaments can expand T cells even in the absence of the cytokine IL-2, that is used in all expansion protocols thus far. In addition, we demonstrated that the majority of the expanded cells remained multifunctional without becoming exhausted. In conclusion, our results demonstrate that immunofilaments are potent in expanding T cells without loss of function and compete out current products (no cytokines required).
Objective 2. Investigate if the platform can be developed into a commercial product through Simmunext biotherapeutics, a recent start-up.
To ultimately translate our exciting findings to the clinic, we needed a commercial entity to generate sufficient funds to develop the immunofilament platform towards clinical application. We initiated Simmunext Biotherapeutics as a Radboudumc start-up.
1) As a first task, we have spended significant effort in translating lab-scale to industrial-scale (GMP) production of immunofilaments. For this we have developed new production technologies to scale-up from mg to gram quantities of product. In addition, we developed several techniques analyse produced immunofilaments with standardized validated methods. This will facilitate the development of synthetic off-the-shelf solutions to fight cancer.
2) We have further developed our IP position (4 patents).
3) We have performed a market analysis and explored the market for kits used for immune cell expansion (estimated between $81.5–1,113 million annually) and approached various biotech industries active in the ACT market and gauged their interest in our technology. With one of them, we have an initial collaboration and they are currently testing our product for potential clinical application.
4) we successfully applied for several grants (NWO-take-off2, Dutch cancer society, Oncode, Oostnl) to expand our activities.
5) We have presented our work at a variety of scientific and biotech conferences (e.g. CIMT, BioEquity, BioEurope, NVVI).
6) We had discussions with investors, most of them told us it was still too early stage for them.
7) We have approached > 20 oncologists to gauge interest for clinical applications in vivo and have even started to work on a preliminary clinical protocol.
IMain achievements:
1. we demonstrated that immunofilament are an can efficiently expand T cells remaining their multifunctional profile
2. We demonstrated that we can scale up towards industrial quantities and that we can produce under GMP conditions
3. We noticed that there is interest by biotech to further develop this platform.
ACT became an important treatment modality for cancer. Immune T cells from patients. ACT products require extensive ex vivo manipulation and expansion of (genetically engineered) patient T cells prior to reinfusion back into patients to attack cancer cells. Unfortunately, T cell exhaustion and loss of function after reinfusion form a major obstacle in currently used ex vivo expansion protocols. In Tune-IT we tested the potential of producing T cells that maintain their function.
Objective 1. Validate that immunofilaments effectively expand T cells and are suitable to produce high quality ACT products.
We carried out detailed analyses (T-cell activation, expansion and phenotype analyses), fine-tuned immunofilaments decorated with various combinations/densities/ratios of immunomodulators to optimize ex vivo T cell expansion without loss of function or exhaustion. We could demonstrate that in particular with immunofilaments decorated with immunostimulators anti-CD3 and anti-CD28 effectively supported T cell expansion. Interestingly, we observed that immunofilaments can expand T cells even in the absence of the cytokine IL-2, that is used in all expansion protocols thus far. In addition, we demonstrated that the majority of the expanded cells remained multifunctional without becoming exhausted. In conclusion, our results demonstrate that immunofilaments are potent in expanding T cells without loss of function and compete out current products (no cytokines required).
Objective 2. Investigate if the platform can be developed into a commercial product through Simmunext biotherapeutics, a recent start-up.
To ultimately translate our exciting findings to the clinic, we needed a commercial entity to generate sufficient funds to develop the immunofilament platform towards clinical application. We initiated Simmunext Biotherapeutics as a Radboudumc start-up.
1) As a first task, we have spended significant effort in translating lab-scale to industrial-scale (GMP) production of immunofilaments. For this we have developed new production technologies to scale-up from mg to gram quantities of product. In addition, we developed several techniques analyse produced immunofilaments with standardized validated methods. This will facilitate the development of synthetic off-the-shelf solutions to fight cancer.
2) We have further developed our IP position (4 patents).
3) We have performed a market analysis and explored the market for kits used for immune cell expansion (estimated between $81.5–1,113 million annually) and approached various biotech industries active in the ACT market and gauged their interest in our technology. With one of them, we have an initial collaboration and they are currently testing our product for potential clinical application.
4) we successfully applied for several grants (NWO-take-off2, Dutch cancer society, Oncode, Oostnl) to expand our activities.
5) We have presented our work at a variety of scientific and biotech conferences (e.g. CIMT, BioEquity, BioEurope, NVVI).
6) We had discussions with investors, most of them told us it was still too early stage for them.
7) We have approached > 20 oncologists to gauge interest for clinical applications in vivo and have even started to work on a preliminary clinical protocol.
IMain achievements:
1. we demonstrated that immunofilament are an can efficiently expand T cells remaining their multifunctional profile
2. We demonstrated that we can scale up towards industrial quantities and that we can produce under GMP conditions
3. We noticed that there is interest by biotech to further develop this platform.
We further developed start-up company, Simmunext, to further develop the immunofilament platform towards a commercial product
We observed that immunofilaments are able to expand T-cells ex vivo, even in the absence of IL-2
We have now a much better idea about what our platform can offer to Biotech, and that finding a partner is now of utmost importance to make the next step.
We observed that immunofilaments are able to expand T-cells ex vivo, even in the absence of IL-2
We have now a much better idea about what our platform can offer to Biotech, and that finding a partner is now of utmost importance to make the next step.