Cytokines are a class of small proteins that play key regulatory roles in immune signaling cascades. Due to their multifunctional roles in lymphocytes, cytokines have long been considered promising cancer immunotherapeutics. Systemically administered cytokines are potent immunotherapeutics but can cause severe dose-limiting toxicities.
IL-2 is the first immunotherapeutic approach to be effective against advanced cancers. As a monotherapy, it elicited an overall response rate of 17% in metastatic melanoma. Despite clinical validation, dose-limiting toxicities have greatly hampered the clinical application of cytokines in oncology. This can be attributed to the high doses that must be administered to achieve effective tumor concentrations, which trigger activation of systemic lymphocytes. To address this issue, researchers have designed cytokines that are able to remain in the tumor after local administration. However, although these tumor-localized cytokines are able to induce regression of treated lesions, responses in distant untreated tumors are generally more modest.
Recently, the team of Darrell J. Irvine and K. Dane Wittrup from MIT published an article titled "Local delivery of cell surface-targeted immunocytokines programs systemic antitumor immunity" in Nature Immunology. This article introduces an innovative immunotherapy strategy that effectively enhances local and systemic tumor immune responses and significantly improves tumor regression rates by locally delivering immune cytokines (αCD45-IL-15 and αCD45-IL-12) targeting CD45 (PTPRC). At the same time, it reduces systemic toxicity and provides a new, safe and effective approach for cancer immunotherapy.
| Cat.No. | Product Name | Price |
|---|---|---|
| CLKO-2159 | PTPRC KO Cell Lysate-Hela | Inquiry |
| CSC-SC012714 | Panoply™ Human PTPRC Over-expressing Stable Cell Line | Inquiry |
| CSC-DC012714 | Panoply™ Human PTPRC Knockdown Stable Cell Line | Inquiry |
| CLOE-2506 | Mouse Ptprc Insect Cell Lysate | Inquiry |
| CLOE-2505 | Mouse Ptprc(His/GST) Insect Cell Lysate | Inquiry |
| CLOE-2507 | Mouse Ptprc HEK293 Cell Lysate | Inquiry |
| CSC-RT2499 | Human PTPRC Knockout Cell Line-Hela | Inquiry |
| CLOE-1743 | Human PTPRC HEK293 Cell Lysate | Inquiry |
| LV23134L | human PTPRC (NM_080923) lentivirus particles | Inquiry |
| LV23135L | human PTPRC (NM_080921) lentivirus particles | Inquiry |
| LV23136L | human PTPRC (NM_002838) lentivirus particles | Inquiry |
| AD13189Z | Human PTPRC adenoviral particles | Inquiry |
The researchers designed and synthesized immunocytokines targeting CD45 (αCD45-IL-15 and αCD45-IL-12), which were fused to CD45 through antibodies to enhance their local retention and signal transduction effects in tumors. These immunocytokines targeting CD45 can effectively retain in tumors and draining lymph nodes, and prolong the signal transduction time, thereby enhancing the effector function of T cells.
Next, the researchers conducted in vivo experiments in mouse models. In MC38 colorectal cancer and B16F10 melanoma mouse models, they injected these immunocytokines locally into tumors and analyzed their distribution and effects in tumors and draining lymph nodes by fluorescent labeling and flow cytometry. CD45-targeted immunocytokines showed longer retention and stronger signal transduction effects in tumors and draining lymph nodes, and this treatment significantly improved the tumor regression rate compared to non-targeted cytokines.
Figure 1. αCD45-cytokine therapy eradicates injected tumors and primes robust systemic anti-tumor responses. (Santollani L, et al., 2024)
The researchers analyzed the effects of immune cytokines by examining T cell proliferation, differentiation, and related signaling pathways (such as STAT5 phosphorylation), and used RNA sequencing and gene expression analysis to study changes in T cell gene expression after treatment. αCD45-Cyt (αCD45-IL-15 and αCD45-IL-12) treatment induced a potent T cell response, especially in the draining lymph nodes, where T cells showed gene expression characteristics similar to acute antiviral responses. This enhanced effector T cell response contributed to tumor regression.
They also tested the effects of αCD45-Cyt treatment on locally treated tumors and untreated distant tumors, and evaluated the systemic antitumor immune response it triggered. The analysis showed that this local treatment not only regressed the treated tumors, but also regressed untreated distant tumors by inducing a strong systemic immune response. Finally, the toxicity and safety of the combined use of IL-12 and IL-15 were evaluated by monitoring the weight and health of the mice. Compared with traditional systemic cytokine therapy, αCD45-Cyt treatment showed better safety and lower toxicity while achieving significant anti-tumor effects.
This study demonstrated that local targeted delivery of cytokines can effectively enhance tumor regression rates. It can also induce a strong systemic anti-tumor immune response while maintaining low toxicity, showing good clinical application prospects.
Reference
Santollani L, et al. Local delivery of cell surface-targeted immunocytokines programs systemic anti-tumor immunity. Nature Immunology, 2024.