Periodic Reporting for period 4 - ARTimmune (Programmable ARTificial immune systems to fight cancer)
Período documentado: 2024-05-01 hasta 2025-07-31
Immunotherapy has entered centre stage as a novel treatment modality for cancer. Immune checkpoint inhibitors and engineered T cells have delivered unprecedented clinical benefit, yet toxicity and immunosuppression remain major obstacles. These limitations illustrate the pressing need for new strategies that unleash the immune system against tumours, but in a more controlled, safe, and durable manner.
In ARTimmune we pursued a radically different approach: the development of fully synthetic immune niches. These are engineered microenvironments designed to locally instruct immune cell function, generate bursts of cytotoxic T cells for tumour destruction, and at the same time avoid the systemic side effects seen with conventional immunotherapies.
We exploited advanced chemical tools to construct polymer-based scaffolds decorated with immune-modulating molecules. These immunofilaments are semiflexible polyisocyanopeptide (PIC) polymers coupled to antibodies, cytokines, or peptide–MHC complexes. We demonstrated that immunofilaments were highly effective in activating and expanding human and mouse T cells ex vivo, including tumour-specific and CAR-T cells. Importantly, immunofilaments retained full bioactivity of their cargo and provided a dynamic interface that better mimicked natural antigen-presenting cells (APCs).
As a next step, immunofilaments were immobilised on beads to form immunobrushes, creating a synthetic cell-like surface. These immunobrushes outperformed rigid benchmark systems, driving efficient expansion of T cells even at very low antibody density. They were capable of selectively expanding rare tumour-specific T cells present at <0.001% of total lymphocytes, demonstrating remarkable sensitivity and clinical potential.
To extend this concept to tissue niches, we developed 3D cryogel scaffolds based on hyaluronic acid (HAGM). These porous, semi-rigid matrices can be injected through a needle, after which they regain their shape and provide a local niche for immune cells. We showed that cryogels could harbour large numbers of T cells, maintain their viability, and promote multifunctional activation with reduced exhaustion. When preloaded with T cells, scaffolds retained them after injection in vivo, while also allowing infiltration of endogenous immune cells.
In vivo validation was an essential component of ARTimmune. Radiolabelled immunofilaments distributed to lymphoid organs and were well tolerated with no observable toxicity. In mouse tumour models, even a single injection of antigen-specific immunofilaments significantly inhibited tumour growth and metastasis formation. Cure rates reached 50%, and survival increased to 75% when combined with immune checkpoint blockade. These results underline the therapeutic promise of synthetic immune niches as stand-alone or combination therapies.
In summary, ARTimmune has demonstrated that it is feasible to mimic essential immune cell functions using synthetic, immune-reactive polymers. Immunofilaments, immunobrushes, and cryogel scaffolds all proved capable of potently activating and expanding tumour-reactive T cells. These findings open the door to a new class of biomaterial-based immunotherapies that move beyond systemic maximum-tolerated-dose regimens with high toxicity, towards local, modular, and low-dose interventions that might nonetheless induce systemic tumour immunity.
In ARTimmune we pursued a radically different approach: the development of fully synthetic immune niches. These are engineered microenvironments designed to locally instruct immune cell function, generate bursts of cytotoxic T cells for tumour destruction, and at the same time avoid the systemic side effects seen with conventional immunotherapies.
We exploited advanced chemical tools to construct polymer-based scaffolds decorated with immune-modulating molecules. These immunofilaments are semiflexible polyisocyanopeptide (PIC) polymers coupled to antibodies, cytokines, or peptide–MHC complexes. We demonstrated that immunofilaments were highly effective in activating and expanding human and mouse T cells ex vivo, including tumour-specific and CAR-T cells. Importantly, immunofilaments retained full bioactivity of their cargo and provided a dynamic interface that better mimicked natural antigen-presenting cells (APCs).
As a next step, immunofilaments were immobilised on beads to form immunobrushes, creating a synthetic cell-like surface. These immunobrushes outperformed rigid benchmark systems, driving efficient expansion of T cells even at very low antibody density. They were capable of selectively expanding rare tumour-specific T cells present at <0.001% of total lymphocytes, demonstrating remarkable sensitivity and clinical potential.
To extend this concept to tissue niches, we developed 3D cryogel scaffolds based on hyaluronic acid (HAGM). These porous, semi-rigid matrices can be injected through a needle, after which they regain their shape and provide a local niche for immune cells. We showed that cryogels could harbour large numbers of T cells, maintain their viability, and promote multifunctional activation with reduced exhaustion. When preloaded with T cells, scaffolds retained them after injection in vivo, while also allowing infiltration of endogenous immune cells.
In vivo validation was an essential component of ARTimmune. Radiolabelled immunofilaments distributed to lymphoid organs and were well tolerated with no observable toxicity. In mouse tumour models, even a single injection of antigen-specific immunofilaments significantly inhibited tumour growth and metastasis formation. Cure rates reached 50%, and survival increased to 75% when combined with immune checkpoint blockade. These results underline the therapeutic promise of synthetic immune niches as stand-alone or combination therapies.
In summary, ARTimmune has demonstrated that it is feasible to mimic essential immune cell functions using synthetic, immune-reactive polymers. Immunofilaments, immunobrushes, and cryogel scaffolds all proved capable of potently activating and expanding tumour-reactive T cells. These findings open the door to a new class of biomaterial-based immunotherapies that move beyond systemic maximum-tolerated-dose regimens with high toxicity, towards local, modular, and low-dose interventions that might nonetheless induce systemic tumour immunity.
ARTimmune: Summary of Work Performed and Main Results (Nov 2019–Aug 2025)
The overall aim of ARTimmune is to design synthetic immune niches that mimic lymph nodes to trigger effective anti-tumour responses. Four work packages were pursued.
WP1. Natural immune clusters as blueprint.
We developed a hanging-drop system to study human and mouse CD8 T cell interactions with dendritic cells (DCs) without interference from artificial surfaces. Antigen-specific T cells displayed distinct transcriptional profiles compared to controls, but the system proved too labour-intensive for large-scale use.
WP2. Immunofilaments and immunobrushes.
We created semiflexible polyisocyanopeptide (PIC) polymers functionalised with antibodies, peptide–MHC complexes, or cytokines. These immunofilaments efficiently activated and expanded T cells ex vivo, including CAR-T and NK cells. To better mimic antigen-presenting cells, we immobilised immunofilaments on beads to form immunobrushes. These outperformed rigid beads, even at low antibody density, and selectively expanded rare antigen-specific T cells (<0.001%).
WP3. Injectable 3D immune matrices.
We engineered porous hyaluronic acid–based cryogels (HAGM) that can be injected and regain shape in vivo. These scaffolds supported immune cell infiltration and activation, yielding multifunctional T cells with reduced exhaustion. Their modular design allows coupling of different immunostimulatory molecules, making them a versatile platform for local cancer immunotherapy.
WP4. In vivo validation.
Radiolabelled immunofilaments distributed to lymphoid organs and showed excellent biocompatibility. In tumour-bearing mice, antigen-specific immunofilaments strongly inhibited tumour growth: one injection cured 50% of animals, and combined with checkpoint blockade, survival rose to 75%. Immunofilaments also reduced lung metastases. HAGM cryogels remained stable after injection, retained loaded T cells, and recruited myeloid cells, warranting further study.
Conclusion.
We demonstrated that immune-reactive polymers can mimic natural immune cell functions, potently activating and expanding tumour-reactive T cells. Immunofilaments, immunobrushes, and cryogel niches offer a path toward local, low-dose cancer immunotherapy with systemic impact and reduced toxicity compared to conventional treatments.
The overall aim of ARTimmune is to design synthetic immune niches that mimic lymph nodes to trigger effective anti-tumour responses. Four work packages were pursued.
WP1. Natural immune clusters as blueprint.
We developed a hanging-drop system to study human and mouse CD8 T cell interactions with dendritic cells (DCs) without interference from artificial surfaces. Antigen-specific T cells displayed distinct transcriptional profiles compared to controls, but the system proved too labour-intensive for large-scale use.
WP2. Immunofilaments and immunobrushes.
We created semiflexible polyisocyanopeptide (PIC) polymers functionalised with antibodies, peptide–MHC complexes, or cytokines. These immunofilaments efficiently activated and expanded T cells ex vivo, including CAR-T and NK cells. To better mimic antigen-presenting cells, we immobilised immunofilaments on beads to form immunobrushes. These outperformed rigid beads, even at low antibody density, and selectively expanded rare antigen-specific T cells (<0.001%).
WP3. Injectable 3D immune matrices.
We engineered porous hyaluronic acid–based cryogels (HAGM) that can be injected and regain shape in vivo. These scaffolds supported immune cell infiltration and activation, yielding multifunctional T cells with reduced exhaustion. Their modular design allows coupling of different immunostimulatory molecules, making them a versatile platform for local cancer immunotherapy.
WP4. In vivo validation.
Radiolabelled immunofilaments distributed to lymphoid organs and showed excellent biocompatibility. In tumour-bearing mice, antigen-specific immunofilaments strongly inhibited tumour growth: one injection cured 50% of animals, and combined with checkpoint blockade, survival rose to 75%. Immunofilaments also reduced lung metastases. HAGM cryogels remained stable after injection, retained loaded T cells, and recruited myeloid cells, warranting further study.
Conclusion.
We demonstrated that immune-reactive polymers can mimic natural immune cell functions, potently activating and expanding tumour-reactive T cells. Immunofilaments, immunobrushes, and cryogel niches offer a path toward local, low-dose cancer immunotherapy with systemic impact and reduced toxicity compared to conventional treatments.
Immunofilaments
Next to the very efficient activation and expansion of T cells ex vivo, we obtained evidence that immunofilaments are biocompatible and safe to use in vivo. They also reach the lymphoid organs. We could demonstrate that immunofilaments can inhibit tumor growth and metastasis formation and thus might be further developed towards novel types of immunotherapy.
Immunobrushes
So far, most artificial antigen presenting cells consist of solid surfaces. With the design of immunobrushes, we showed already that a much better T cell activation is obtained by outcompeting current benchmarks. Apparently, immunobrushes better mimic natural antigen presenting cells to form an immunological synapse.By direct comparison of immunobrushes with natural dendritic cells, we could demonstrate that immunobrushes perform equally well as antigen presenting cell.
Injectable synthetic immune niches.
We engineered 3D macroporous hydrogels to mimic a natural lymph node architecture. Our initial promising results clearly show that these synthetic immune niches can be modified such to activate antigen presenting cells or directly activate T cells in vitro. Moreover, we believe that in particular the injectability of these cryogels is certainly beyond the state of the art. Yet, further research is needed to optimize their use in vivo.
Next to the very efficient activation and expansion of T cells ex vivo, we obtained evidence that immunofilaments are biocompatible and safe to use in vivo. They also reach the lymphoid organs. We could demonstrate that immunofilaments can inhibit tumor growth and metastasis formation and thus might be further developed towards novel types of immunotherapy.
Immunobrushes
So far, most artificial antigen presenting cells consist of solid surfaces. With the design of immunobrushes, we showed already that a much better T cell activation is obtained by outcompeting current benchmarks. Apparently, immunobrushes better mimic natural antigen presenting cells to form an immunological synapse.By direct comparison of immunobrushes with natural dendritic cells, we could demonstrate that immunobrushes perform equally well as antigen presenting cell.
Injectable synthetic immune niches.
We engineered 3D macroporous hydrogels to mimic a natural lymph node architecture. Our initial promising results clearly show that these synthetic immune niches can be modified such to activate antigen presenting cells or directly activate T cells in vitro. Moreover, we believe that in particular the injectability of these cryogels is certainly beyond the state of the art. Yet, further research is needed to optimize their use in vivo.