“Combined JAK inhibition and PD-1 immunotherapy for non-small cell lung cancer patients” by Divij Mathew et al
Science (2024)
Abstract:
Persistent inflammation driven by cytokines such as type-one interferon (IFN-I) can cause immunosuppression. We show that administration of the Janus kinase 1 (JAK1) inhibitor itacitinib after anti–PD-1 (programmed cell death protein 1) immunotherapy improves immune function and antitumor responses in mice and results in high response rates (67%) in a phase 2 clinical trial for metastatic non–small cell lung cancer. Patients who failed to respond to initial anti–PD-1 immunotherapy but responded after addition of itacitinib had multiple features of poor immune function to anti–PD-1 alone that improved after JAK inhibition. Itacitinib promoted CD8 T cell plasticity and therapeutic responses of exhausted and effector memory–like T cell clonotypes. Patients with persistent inflammation refractory to itacitinib showed progressive CD8 T cell terminal differentiation and progressive disease. Thus, JAK inhibition may improve the efficacy of anti–PD-1 immunotherapy by pivoting T cell differentiation dynamics.
Why this matters:
Type-1 interferon, which promotes anti-tumor activity, may also induces chronic inflammation and T cell suppression, likely representing a major mechanism of immunotherapy resistance. In this paper, the investigators showed that inhibition of interferon signaling could restore effector T cell function and promote effective anti-tumor immunity in murine models. In addition, they showed that pharmacologic JAK inhibition could enhanced anti-PD-1 therapy in a phase II study of first-line treatment of patients with metastatic non-small cell lung cancer with PD-L1 expression 50%. Thus, JAK inhibition may be a more general strategy for reversing interferon-related immune suppression and improve therapeutic responses of T cell targeted immunotherapy.
“Expression of tumor antigens within an oncolytic virus enhances the anti-tumor T cell response” by Mason J. Webb et al
Nat Commun (2024)
Abstract:
Although patients benefit from immune checkpoint inhibition (ICI) therapy in a broad variety of tumors, resistance may arise from immune suppressive tumor microenvironments (TME), which is particularly true of hepatocellular carcinoma (HCC). Since oncolytic viruses (OV) can generate a highly immune infiltrated, inflammatory TME, OVs could potentially restore ICI responsiveness via recruitment, priming, and activation of anti-tumor T cells. Here we find that on the contrary, an oncolytic vesicular stomatitis virus, expressing interferon-ß (VSV-IFNß), antagonizes the effect of anti-PD-L1 therapy in a partially anti-PD-L1-responsive model of HCC. Cytometry by Time of Flight shows that VSV-IFNß expands dominant anti-viral effector CD8 T cells with concomitant relative disappearance of anti-tumor T cell populations, which are the target of anti-PD-L1. However, by expressing a range of HCC tumor antigens within VSV, combination OV and anti-PD-L1 therapeutic benefit could be restored. Our data provide a cautionary message for the use of highly immunogenic viruses as tumor-specific immune-therapeutics by showing that dominant anti-viral T cell responses can inhibit sub-dominant anti-tumor T cell responses. However, through encoding tumor antigens within the virus, oncolytic virotherapy can generate anti-tumor T cell populations upon which immune checkpoint blockade can effectively work.
Why this matters:
The role of anti-viral versus anti-tumor T cell responses following oncolytic virus therapy is controversial. In this study, an oncolytic VSV encoding IFNß preferentially expanded VSV-specific T cells over subdominant tumor antigen-specific T cells resulting in a lack of therapeutic benefit when combined with anti-PD-L1 treatment in a model of hepatocellular carcinoma (HCC). However, when HCC-specific antigens were encoded in the VSV, anti-PD-L1 therapeutic responses were seen. This data may also provide insight into recent failures of oncolytic viruses and checkpoint blockade and identified a strategy for future combination studies.
“Inhalable extracellular vesicle delivery of IL-12 mRNA to treat lung cancer and promote systemic immunity” by Mengrui Liu et al
Nat Nanotechnol (2024)
Abstract:
Lung carcinoma is one of the most common cancers and has one of the lowest survival rates in the world. Cytokines such as interleukin-12 (IL-12) have demonstrated considerable potential as robust tumour suppressors. However, their applications are limited due to off-target toxicity. Here we report on a strategy involving the inhalation of IL-12 messenger RNA, encapsulated within extracellular vesicles. Inhalation and preferential uptake by cancer cells results in targeted delivery and fewer systemic side effects. The IL-12 messenger RNA generates interferon-γ production in both innate and adaptive immune-cell populations. This activation consequently incites an intense activation state in the tumour microenvironment and augments its immunogenicity. The increased immune response results in the expansion of tumour cytotoxic immune effector cells, the formation of immune memory, improved antigen presentation and tumour-specific T cell priming. The strategy is demonstrated against primary neoplastic lesions and provides profound protection against subsequent tumour rechallenge. This shows the potential for locally delivered cytokine-based immunotherapies to address orthotopic and metastatic lung tumours.
Why this matters:
IL-12 is a potent cytokine with anti-tumor activity but treatment has been complicated by systemic toxicity. In this study, the investigators built upon data from the Cancer Genome Atlas showing that IL-12 expression correlates with improved prognosis in patients with lung cancer. To utilize IL-12 therapy they developed a local delivery strategy using an inhalable IL-12 mRNA extracellular vesicle. This study demonstrates that local cytokine delivery may be a general strategy for improving therapeutic potential while limiting systemic toxicity.
“Neoadjuvant immunotherapy in locally advanced mismatch repair-deficient colon cancer” by Myriam Chalabi et al
New Engl J Med (2024)
Abstract:
Mismatch repair–deficient (dMMR) tumors can be found in 10 to 15% of patients with nonmetastatic colon cancer. In these patients, the efficacy of chemotherapy is limited. The use of neoadjuvant immunotherapy has shown promising results, but data from studies of this approach are limited.
METHODS
We conducted a phase 2 study in which patients with nonmetastatic, locally advanced, previously untreated dMMR colon cancer were treated with neoadjuvant nivolumab plus ipilimumab. The two primary end points were safety, defined by timely surgery (i.e., ≤2-week delay of planned surgery owing to treatment-related toxic events), and 3-year disease-free survival. Secondary end points included pathological response and results of genomic analyses.
RESULTS
Of 115 enrolled patients, 113 (98%; 97.5% confidence interval [CI], 93 to 100) underwent timely surgery; 2 patients had surgery delayed by more than 2 weeks. Grade 3 or 4 immune-related adverse events occurred in 5 patients (4%), and none of the patients discontinued treatment because of adverse events. Among the 111 patients included in the efficacy analysis, a pathological response was observed in 109 (98%; 95% CI, 94 to 100), including 105 (95%) with a major pathological response (defined as ≤10% residual viable tumor) and 75 (68%) with a pathological complete response (0% residual viable tumor). With a median follow-up of 26 months (range, 9 to 65), no patients have had recurrence of disease.
CONCLUSIONS
In patients with locally advanced dMMR colon cancer, neoadjuvant nivolumab plus ipilimumab had an acceptable safety profile and led to a pathological response in a high proportion of patients. (Funded by Bristol Myers Squibb; NICHE-2 ClinicalTrial.gov number, NCT03026140.)
Why this matters:
This study reports a high rate of pathologic response (overall 98%) for neoadjuvant immunotherapy in patients with non-metastatic, locally advanced dMMR colon cancer. The study is important because it suggests that immunotherapy may be especially effective when used prior to surgical treatment. Further research is needed to understand the immunologic mechanisms underpinning these therapeutic responses and highlights the potential to rethink the clinical development pathway for immuno-oncology agents.