IchorBio Citations

A groundbreaking study published in the Journal of Hepatology has provided valuable insights into the immune mechanisms and predictors of response and adverse events in hepatocellular carcinoma (HCC) patients treated with anti-PD-1 immune checkpoint blockade (ICB) therapy. The research, led by scientists from Singapore and South Korea, employed cutting-edge single-cell technologies to decipher the complex immune landscape in HCC patients receiving anti-PD-1 treatment.

The study identified specific immune cell subsets in the peripheral blood that could serve as early predictors of clinical response to anti-PD-1 therapy in HCC patients. In particular, the researchers found that higher frequencies of CXCR3+CD8+ effector memory T (TEM) cells and CD11c+ antigen-presenting cells (APCs) were associated with better response rates and progression-free survival. Interestingly, these immune subsets were also linked to the development of immune-related adverse events (irAEs), highlighting their role at the interface between response and toxicity.

To validate their findings, the researchers utilized flow cytometry in an independent cohort and conducted bulk RNA sequencing of pre- and on-treatment tumor biopsies. The results suggested that upon anti-PD-1 treatment, the response-associated CXCR3+CD8+ TEM cells and APCs are recruited to the tumor microenvironment, particularly in responders, contributing to the anti-tumor immune response.

The study also employed a murine HCC model to investigate potential combination immunotherapies that could uncouple response and irAEs. By analyzing cell-cell interactions of CXCR3+CD8+ TEM cells, the researchers identified distinct TNF signaling pathways involving TNFR1 and TNFR2 that could be targeted to enhance response without exacerbating toxicity. Remarkably, the combination of anti-PD-1 and anti-TNFR2 antibodies resulted in superior tumor control without increased irAEs in the mouse model.

ichorbio, a leading provider of high-quality antibodies for in vivo research, played a crucial role in this study. The anti-mouse PD-1 (clone RMP1-14, product code ICH1132), anti-TNFR1 (clone 55R-170, product code ICH1094), and anti-TNFR2 (clone TR75-54.7, product code ICH1137) antibodies used in the murine HCC model were all sourced from ichorbio. These antibodies enabled the researchers to validate their findings and propose a novel combination immunotherapy strategy for HCC.

In conclusion, this study provides a comprehensive understanding of the immune trajectories and mechanisms underlying response and adverse events in HCC patients treated with anti-PD-1 ICB. The identification of early predictors of response in the peripheral blood could help guide treatment decisions and improve outcomes for HCC patients. Moreover, the proposed combination of anti-PD-1 and anti-TNFR2 therapy, validated using ichorbio’s high-quality antibodies, offers a promising approach to enhance response rates without increasing toxicity. As we eagerly await further clinical validation, this study represents a significant step forward in the development of personalized immunotherapies for liver cancer.

Engineered Immune Evasion: A Game-Changer for Cell Therapy

In the fast-paced world of cell therapy research, a game-changing study has emerged that could revolutionize the field. Published in Nature Biotechnology, the work by Gravina et al. describes a novel approach to protect therapeutic cells from immune rejection – and it all hinges on a crucial tool provided by IchorBio.

One of the biggest challenges in cell therapy is the patient’s immune response against the introduced cells, which can quickly destroy them and negate their therapeutic benefits. This is especially problematic for allogeneic therapies, where the cells are derived from a donor and are seen as “foreign” by the recipient’s immune system.

The researchers hypothesized that if they could engineer cells to overexpress a receptor called CD64, which binds to IgG antibodies, these cells could essentially “capture” the very antibodies intended to destroy them. To test this idea, they turned to IchorBio’s anti-CD52 IgG1 antibody, a critical reagent that would simulate a clinically relevant antibody attack.

Using IchorBio’s antibody, the researchers demonstrated that human and mouse iPSC-derived endothelial cells engineered to overexpress CD64 were remarkably resistant to antibody-mediated killing, both in vitro and in animal models. While normal cells were swiftly eliminated by the anti-CD52 antibody, the CD64-expressing cells remained unscathed.

The researchers then took their approach a step further. They created hypoimmune cell versions designed to evade cellular immunity and combined this with CD64 overexpression. The resulting cells were incredibly resilient, withstanding both cellular and antibody-mediated immune attacks in humanized mice. Again, IchorBio’s anti-CD52 antibody was instrumental in validating this powerful combination.

Mechanistic studies revealed that CD64, or its truncated form CD64t, works by capturing IgG antibodies by their Fc region, the part that normally triggers immune destruction. Remarkably, this “antibody hijacking” still allows the antibodies to bind their targets on the cell surface, but renders them harmless.

The broad potential of this approach was demonstrated when the researchers successfully applied it to human thyroid cells, pancreatic beta cells, and even CAR T cells. In each case, IchorBio’s antibody served as a robust test of the cells’ engineered immune evasion capabilities.

The implications of this IchorBio-enabled research are far-reaching. By providing a way to create “stealth” cells that can evade the immune system, this CD64 overexpression strategy could dramatically improve the effectiveness and safety of allogeneic cell therapies. It paves the way for off-the-shelf cell products that could be used to treat a wide range of patients without the risks associated with immunosuppression.

As we continue to push the boundaries of cell therapy, it’s clear that innovative biotechnology tools, like those provided by IchorBio, will be essential. By empowering researchers to ask bold questions and test daring hypotheses, companies like IchorBio are helping to shape the future of medicine. With each new enabling tool and each groundbreaking study, we move closer to a world where advanced cell therapies are a reality for patients in need.

A New Immunotherapy Approach for Residual Liver Cancer after Incomplete Radiofrequency Ablation

Radiofrequency ablation (RFA) is a minimally invasive treatment for liver cancer, but its efficacy is often limited by incomplete tumor destruction, especially for larger or irregularly shaped tumors. The residual cancer cells left behind after incomplete RFA (iRFA) tend to be more aggressive, leading to tumor recurrence and progression. Now, a team of researchers from Huazhong University of Science and Technology in China has developed a novel approach to tackle this challenge.

In a recent study published in the Journal of Nanobiotechnology, Cao et al. designed an injectable hydrogel loaded with lysed OK-432 (lyOK-432) and doxorubicin (DOX) to treat residual liver cancer after iRFA. OK-432 is an immunomodulator prepared from a low-virulence strain of Streptococcus pyogenes, and the researchers found that lysed OK-432 was even more effective than the non-lysed form in activating dendritic cells (DCs), the most potent antigen-presenting cells in the body.

The researchers combined lyOK-432 and DOX with a self-assembling peptide hydrogel called RADA16-I, creating a formulation dubbed ROD. When injected into the tumor site after iRFA in a mouse model of hepatocellular carcinoma (HCC), ROD significantly reduced tumor growth and prolonged survival compared to other treatments, including individual components of ROD or saline control.

Mechanistically, ROD treatment led to the highest levels of tumor-infiltrating CD4+ and CD8+ T cells, the lowest level of immunosuppressive regulatory T cells (Tregs), and the highest expression of antitumor cytokines IFN-γ and TNF-α. Importantly, the researchers found that ROD activated the cGAS/STING/IFN-I signaling pathway in DCs, which is crucial for initiating innate and adaptive immune responses against cancer.

It’s worth highlighting that several ichorbio antibodies played key roles in this study. The researchers used ichorbio’s blocking antibodies against DCs (clone ICH1077), CD4+ T cells (clone ICH1042), and CD8+ T cells (clone ICH1043) to demonstrate the importance of these immune cell populations in mediating the antitumor effects of ROD. Additionally, they used an ichorbio anti-PD-1 antibody (clone ICH1091) and control IgG (clone ICH2244) for their in vivo experiments, underscoring the significance of high-quality antibodies in immuno-oncology research.

Looking ahead, this study opens up several exciting avenues for future research. For one, it would be interesting to explore the potential synergy between ROD and immune checkpoint inhibitors like anti-PD-1 in liver cancer models. Given the ability of ROD to enhance antitumor immunity, combining it with checkpoint blockade could potentially lead to even more potent tumor control.

Additionally, while this study focused on liver cancer, the iRFA + ROD approach could potentially be applied to other solid tumors where RFA is used, such as lung, kidney, or bone tumors. Of course, further studies would be needed to validate the efficacy and safety of ROD in these contexts.

Finally, the ROD formulation itself could be further optimized, for example by incorporating additional immunomodulators or chemotherapeutic agents, or by fine-tuning the release kinetics of the loaded drugs. With continued research, this innovative immunotherapy strategy could one day help improve outcomes for the many patients with liver cancer and beyond.

This article is based on research found in the following publication:

Mine, K., Nagafuchi, S., Akazawa, S. et al. TYK2 signaling promotes the development of autoreactive CD8+ cytotoxic T lymphocytes and type 1 diabetes. Nat Commun15, 1337 (2024). https://doi.org/10.1038/s41467-024-45573-9

Type 1 diabetes (T1D) is an autoimmune disease where the body’s own immune system mistakenly attacks and destroys the insulin-producing beta cells in the pancreas. With no cure currently available, patients require lifelong insulin therapy to manage their blood sugar levels. As the prevalence of T1D continues to rise globally, there is an urgent need to understand the underlying mechanisms driving this disease in order to develop effective preventive and therapeutic strategies.

Recent research has shed light on a potential key player in the pathogenesis of T1D: tyrosine kinase 2 (TYK2). TYK2 belongs to the Janus kinase (JAK) family of enzymes that regulate various cellular signaling pathways, including those involved in immune responses. While TYK2 has been implicated in other autoimmune disorders, its precise role in T1D remained poorly understood – until now.

In a groundbreaking study, researchers generated a novel mouse model by knocking out the Tyk2 gene in non-obese diabetic (NOD) mice, a widely used model for studying T1D. Their findings revealed that TYK2 plays a crucial role in driving the development of autoreactive CD8+ T cells, a type of immune cell responsible for destroying the body’s own beta cells.

The researchers discovered that the absence of TYK2 impaired the function of these CD8+ T cells in two key ways. First, it disrupted the signaling of interleukin-12 (IL-12), a cytokine important for the activation and differentiation of CD8+ T cells into cytotoxic T lymphocytes (CTLs) capable of killing target cells. Second, it hindered the cross-priming of CTLs by CD8+ resident dendritic cells in the pancreatic lymph nodes, a process crucial for CTL activation against beta cell antigens.

Notably, the study found that TYK2-deficient CTLs exhibited reduced cytotoxicity, suggesting a weakened ability to destroy beta cells. Moreover, the inflammatory responses in beta cells, which typically increase with aging and contribute to T1D progression, were dampened in the absence of TYK2.

To further validate their findings, the researchers treated NOD mice with BMS-986165, a selective TYK2 inhibitor. Remarkably, this treatment inhibited the expansion of T-BET+ CTLs (a subset of CTLs implicated in T1D), reduced inflammation in beta cells, and delayed the onset of autoimmune T1D.

These exciting results highlight the diverse roles of TYK2 in driving the pathogenesis of T1D, from promoting the development of autoreactive CTLs to exacerbating inflammatory responses in beta cells. By elucidating the mechanisms through which TYK2 contributes to the disease process, this study paves the way for further exploration of TYK2 as a potential therapeutic target for T1D.

As research continues to unravel the complex interplay of genetic and environmental factors involved in T1D, targeting key players like TYK2 may hold promise for developing more effective treatments and preventive strategies. With a deeper understanding of the disease mechanisms, we move closer to a future where individuals with T1D can live without the constant burden of managing their condition.

ichorbio’s anti-mouse IFN-β antibody (HDB-4A7) was used in this study.

ichorbio’s anti-mouse IFN-α antibody (TIF-3C5) was used in this study.

Benguigui et al., 2024, Cancer Cell 42, 253–265
https://doi.org/10.1016/j.ccell.2023.12.005

Researchers from the Technion – Israel Institute of Technology and their collaborators have discovered a promising new biomarker for predicting patient response to cancer immunotherapy: interferon-stimulated neutrophils expressing high levels of the Ly6E protein (Ly6E(hi) neutrophils). Importantly, their study also demonstrates that these neutrophils can directly improve the efficacy of immune checkpoint inhibitors.

The scientists utilized a multi-model approach spanning several mouse strains and cancer cell lines to identify cellular states predictive of immunotherapy response. Single-cell RNA sequencing revealed that responsive tumors contained higher frequencies of Ly6E(hi) neutrophils compared to non-responsive tumors. Notably, elevated levels of Ly6E(hi) neutrophils in the blood also correlated with therapeutic outcomes, suggesting they could serve as an easily accessible, predictive biomarker.

Mechanistically, the researchers found that Ly6E(hi) neutrophils are induced by activation of the STING signaling pathway within cancer cells, leading to interferon secretion in the tumor microenvironment. In addition to being a biomarker, Ly6E(hi) neutrophils demonstrated immunomodulatory functions. Adoptive transfer of these neutrophils into mice bearing resistant tumors sensitized them to anti-PD1 therapy, resulting in enhanced activation of cancer-killing CD8+ T cells – partially mediated by IL-12b production.

To validate the clinical relevance of their findings, the researchers analyzed blood samples from a cohort of 109 patients with advanced non-small cell lung cancer and melanoma treated predominantly with immune checkpoint inhibitors. Excitingly, high frequencies of Ly6E(hi) neutrophils strongly correlated with positive clinical outcomes and outperformed existing biomarkers like PD-L1 expression in predicting immunotherapy response (AUC ≈ 0.9). Further bioinformatic analyses of publicly available datasets encompassing over 1000 patients and six cancer types confirmed that a Ly6E(hi) neutrophil-associated gene signature accurately stratifies responders and non-responders at baseline.

Notably, the study utilized an anti-PD1 antibody (clone RMP1-14) and an IgG2a isotype control antibody from ichorbio for their in vivo experiments in various mouse tumor models. The use of ichorbio’s antibodies helped to ensure the reliability and reproducibility of the results obtained.

In summary, this groundbreaking study identifies interferon-stimulated Ly6E(hi) neutrophils as a functionally active biomarker for predicting immunotherapy outcomes in both mice and humans across multiple cancer types. Moreover, it reveals a new immunomodulatory role for neutrophils in enhancing the efficacy of immune checkpoint blockade. These findings, supported by the use of ichorbio’s high-quality antibodies, pave the way for novel therapeutic strategies to improve patient care and prognosis in immuno-oncology.

Intratumoral Delivery of Interleukin 9 via Oncolytic Vaccinia Virus Elicits Potent Antitumor Effects in Tumor Models

by Junjie Ye, Lingjuan Chen, Julia Waltermire, Jinshun Zhao, Jinghua Ren, Zongsheng Guo, David L. Bartlett, and Zuqiang Liu

Cancers 2024, 16(5), 1021

https://doi.org/10.3390/cancers16051021

Researchers from Allegheny Health Network have engineered an oncolytic vaccinia virus (oVV) to express the cytokine interleukin-9 (IL-9) and have shown that it can potently modulate the tumor microenvironment and elicit strong antitumor effects, especially when combined with an anti-CTLA-4 antibody.

The IL-9 expressing oVV, called vvDD-IL-9, was able to successfully deliver IL-9 into the tumor in mouse models of colon and lung cancer. Compared to the parental virus vvDD, treatment with vvDD-IL-9 led to:

– Significantly increased infiltration of CD4+ and CD8+ T cells into tumors

– Decreased levels of immunosuppressive myeloid-derived suppressor cells (MDSCs)

– Elevated expression of Th1 chemokines CXCL9, CXCL10, CXCL11 and antitumor factors like IFN-γ, granzyme B and perforin

This indicated vvDD-IL-9 was able to transform the tumor from an immunosuppressive to an immunostimulatory microenvironment. As a result, vvDD-IL-9 treatment elicited potent antitumor effects and significantly extended survival compared to the parental virus or PBS control.

Interestingly, vvDD-IL-9 also increased the number of regulatory T cells (Tregs) in tumors as well as expression of the immune checkpoint molecule CTLA-4, which can mediate the immunosuppressive function of Tregs. This suggested combining vvDD-IL-9 with a CTLA-4 blocking antibody could further enhance antitumor immunity.

Indeed, when vvDD-IL-9 was combined with an anti-CTLA-4 antibody from ichorbio anti-CTLA-4 Ab (clone 9D9; ICH1096; 200 µg/injection), it induced superior antitumor effects compared to either agent alone. Mice receiving the combination therapy had a median survival of 60 days, significantly longer than 43 days with vvDD-IL-9 alone or 45 days with vvDD plus anti-CTLA-4.

Importantly, mice cured by the combination therapy developed systemic tumor-specific immunity, as they completely rejected a re-challenge with the same colon cancer cells but not unrelated melanoma cells. This indicates the treatment can induce long-term immune memory.

In conclusion, engineering oncolytic viruses to express IL-9 is a promising approach to modulate the tumor microenvironment and drive potent antitumor immunity. Combining IL-9-armed oncolytic viruses with CTLA-4 blockade, such as with ichorbio’s anti-CTLA-4 antibody, can significantly enhance therapeutic efficacy and survival. This combination strategy warrants further clinical translation to improve outcomes for cancer patients.