BLOG

Most tumors are composed of up to 50% of macrophages: what if we used them to destroy cancer from inside? The first time I read about the Chimeric Antigen Receptor strategy was in 2012 when Emily Whitehead was treated for an acute lymphoblastic leukemia resisting all treatments. Long story short: she survived and celebrated her 10-year remission in 2022! By engineering T cells, amazing results in hematological diseases treatment have been achieved! But solid tumors are sneaky. To avoid infiltration, they build a dense wall composed of fibroblasts, endothelial cells and extracellular matrix. Then, they assure to go low under the radar with few tumor-specific and tumor-associated antigens (HER2, CEA, MSLN…), mutation process and antigen heterogeneity. And they undermine the battlefield: the tumor microenvironment attracts MDSC, TAM, Tregs to promote anti-inflammatory space, secretes cytokines (IL-2, TGF-β, …), chemokines (CCL2, CXCL8, CXCL12), growth factors (EGF, IGF-1, PDGF) and express immune checkpoint. Not really the best environment for T-cells… To go through this issue, many options are on the table: Tandem and Bispecific CAR-T cells to target multiple antigens, BiTEs to recruit bystander T cells, CARs expressing chemokine receptors to enhance tumor infiltration, checkpoint inhibitors to prevent exhaustion, FAP - CAR-T to break down physical barriers…. But, the TME negative effect remains highly efficient and CAR-T treatments struggle to disrupt it. And now, CAR-M enters! Macrophages are not just cancer cells predators, they are also incredibly effective in tumors infiltration, microenvironment and extracellular matrix reshapes through TNF-a, IL-1, IL-6, IL-12 and MMP secretion and therefore immune cells infiltration and activation (T-cells, dendritic cells, NK cells). Furthermore, most tumors are already infiltrated by macrophages. But, like a two-faced Janus, macrophages have two opposing profiles: M2, promoting growth and metastasis, and M1, pro-inflammatory and fighting cancer. Tumor-Associated Macrophages are mostly M2. But the real twist? M2 can be reprogrammed into M1, turning the enemy into an ally by: - In situ reprogramming (AAV, Vpx-modified lentivirus) - Ex vivo priming (iPSC, PBMC, THP-1) CAR-M is a recent strategy: many details remain to be adjusted to enhance their activities, such as intracellular signaling pathways (CD3ζ, CD147, MerTK, Megf10, TLR) A lot of studies are also investigating combination therapies with checkpoint inhibitors, anti-CD47 to disrupt the CD47-SIRPα inhibitory pathway, furin-inhibition and even CAR-T! (Greiner et al., 2024; Pierini et al., 2025).

Par Julien

Could a single molecular modification unlock the full potential of IL-2 as a therapeutic in cancer and autoimmune diseases?   For this first post, I wanted to talk about one of the most used and studied cytokine! Due to the severe side-effects of IL-2 treatment, many research programs aim to enhance efficacy while minimizing toxicity. Indeed, high-dose IL-2 treatments are known to provoke vascular leak syndrome (VLS) and eosinophilic infiltration of cardiac and pulmonary tissues by: • 𝐍𝐨𝐧-𝐬𝐩𝐞𝐜𝐢𝐟𝐢𝐜 𝐚𝐜𝐭𝐢𝐯𝐚𝐭𝐢𝐨𝐧: CD8+ cytotoxic T cells, CD4+ effector T cells, NK cells, eosinophils and Tregs • 𝐓𝐫𝐢𝐠𝐠𝐞𝐫𝐢𝐧𝐠 𝐜𝐲𝐭𝐨𝐤𝐢𝐧𝐞 𝐬𝐭𝐨𝐫𝐦 Furthermore, due to its low half-life (12.9 min for the first phase, then 85 min for the second; Konrad et al. Cancer Research, 1990), IL-2 treatments require frequent administration, increasing adverse effects risks.   𝑂𝑘, 𝑏𝑢𝑡 𝑤ℎ𝑦 𝑑𝑜𝑒𝑠 𝑃𝐸𝐺 𝑤𝑜𝑟𝑘? PEGylation is a covalent attachment of a polyethylene glycol chains, which modify the structural properties of IL-2, enhances drug properties by: • 𝐈𝐧𝐜𝐫𝐞𝐚𝐬𝐢𝐧𝐠 𝐦𝐨𝐥𝐞𝐜𝐮𝐥𝐚𝐫 𝐬𝐢𝐳𝐞 to reduce renal clearance, prolonging half-life. • 𝐑𝐞𝐝𝐮𝐜𝐢𝐧𝐠 𝐩𝐫𝐨𝐭𝐞𝐨𝐥𝐲𝐭𝐢𝐜 𝐝𝐞𝐠𝐫𝐚𝐝𝐚𝐭𝐢𝐨𝐧 by increasing steric hindrance, hydrophilicity, structural stabilization, aggregation reduction and proteolytic hotspots interaction reduction. • 𝐀𝐥𝐭𝐞𝐫𝐢𝐧𝐠 𝐫𝐞𝐜𝐞𝐩𝐭𝐨𝐫 𝐛𝐢𝐧𝐝𝐢𝐧𝐠 𝐚𝐟𝐟𝐢𝐧𝐢𝐭𝐲: it masks IL-2 regions, including epitopes recognized by immune receptors, complement proteins or neutralizing antibodies.   Well that’s not so simple (as always in biology!)…   Preclinical studies in 2024 demonstrate the efficacy of PEGylated IL-2 in the 𝐬𝐩𝐞𝐜𝐢𝐟𝐢𝐜 𝐚𝐜𝐭𝐢𝐯𝐚𝐭𝐢𝐨𝐧 of CD8+ T cells and NK cells or Tregs. 👉 For cancer therapies, SAR-444245, a PEGylated IL-2 variant, effectively activated CD8+ T and NK cells, over Tregs, without inducing VLS or eosinophilia. (Ma et al., Cancer Res Commun, 2024). 👉 For autoimmune diseases, SAR-336 achieved significant Treg expansion (x5 - x15) and inflammation reduction in lupus and graft-versus-host disease in mouse models (Ptacin et al., Commun Med, 2024).   𝐻𝑜𝑤𝑒𝑣𝑒𝑟, 𝑡ℎ𝑒 𝑐𝑙𝑖𝑛𝑖𝑐𝑎𝑙 𝑠𝑡𝑢𝑑𝑖𝑒𝑠 𝑠ℎ𝑜𝑤 𝑚𝑜𝑟𝑒 𝑚𝑖𝑡𝑖𝑔𝑎𝑡𝑒 𝑟𝑒𝑠𝑢𝑙𝑡𝑠…   In metastatic melanoma, the combination of bempegaldesleukin (BEMPEG) and nivolumab yielded an objective response rate of 27.7%, failing to surpass nivolumab monotherapy (36.0%) (Diab et al., J Clin Oncol, 2023). Similar results were observed in advanced urothelial carcinoma (Siefker-Radtke et al., Urol Oncol, 2024) Could these differences be attributed to an excessively reduced receptor-binding affinity, patient heterogeneity or/and tumor immunogenicity?