Phase II study to determine the anti-tumor activity and safety of simlukafusp alfa (FAP-IL2v) combined with atezolizumab in esophageal cancer.

PURPOSE: Reported here are results from the esophageal squamous cell carcinoma (SCC) cohort of a Phase II, non-comparative, basket study, evaluating the anti-tumor activity and safety of FAP-IL2v plus atezolizumab in patients with advanced/metastatic solid tumors (NCT03386721). EXPERIMENTAL DESIGN: Eligible patients had an Eastern Cooperative Oncology Group performance status of 0-1; measurable metastatic, persistent, or recurrent esophageal SCC; progression on ≥1 prior therapy; and were checkpoint inhibitor naive. Patients received FAP-IL2v 10 mg plus atezolizumab 1200 mg intravenously every 3 weeks, or FAP-IL2v weekly for 4 weeks, then every 2 weeks, plus atezolizumab 840 mg intravenously every 2 weeks. Primary endpoint was investigator-assessed objective response rate (ORR). RESULTS: In the response-evaluable population (N=34), best confirmed ORR was 20.6% (95% confidence interval [CI]: 10.4-36.8) with a complete response (CR) seen in one patient and partial responses (PR) in six patients. Disease control rate was 44.1% (CR=2.9%; PR=17.6%; stable disease [SD]=23.5%) and median duration of response was 10.1 months (95% CI: 5.6-26.7). Median progression-free survival was 1.9 months (95% CI: 1.8-3.7). Analysis of response by PD-L1 expression (Ventana SP263) resulted in an ORR of 26.7 % for patients with PD-L1-positive tumors (tumor area positivity [TAP] cut-off ≥1%; n=15) and 7.1% for patients with PD-L1-negative tumors (TAP cut-off <1%; n=14). Overall, the treatment combination was tolerable and adverse events were consistent with the known safety profiles of each drug. CONCLUSIONS: FAP-IL2v plus atezolizumab demonstrated clinical activity and was tolerable in patients with previously treated esophageal SCC.

Comprehensive analysis of fibroblast activation protein expression across 23 tumor indications: insights for biomarker development in cancer immunotherapies.

Introduction: Fibroblast activation protein (FAP) is predominantly upregulated in various tumor microenvironments and scarcely expressed in normal tissues. Methods: We analyzed FAP across 1216 tissue samples covering 23 tumor types and 70 subtypes. Results: Elevated FAP levels were notable in breast, pancreatic, esophageal, and lung cancers. Using immunohistochemistry and RNAseq, a correlation between FAP gene and protein expression was found. Evaluating FAP's clinical significance, we assessed 29 cohorts from 12 clinical trials, including both mono and combination therapies with the PD-L1 inhibitor atezolizumab and chemotherapy. A trend links higher FAP expression to poorer prognosis, particularly in RCC, across both treatment arms. However, four cohorts showed improved survival with high FAP, while in four others, FAP had no apparent survival impact. Conclusions: Our results emphasize FAP's multifaceted role in therapy response, suggesting its potential as a cancer immunotherapy biomarker.

A Composite Decision Rule of CD8+ T-cell Density in Tumor Biopsies Predicts Efficacy in Early-stage, Immunotherapy Trials.

PURPOSE: To examine whether CD8+ T-cell numbers in paired tumor biopsies in early-stage clinical trials can be used as an early indicator of clinical benefit for cancer immunotherapies. EXPERIMENTAL DESIGN: Paraffin sections of tumor biopsies were stained immunohistochemically for CD8+ T cells, which were digitally enumerated. The tumor biopsies were from cancer patients in early-phase trials testing novel immunotherapeutic agents. Paired biopsies taken before the start of treatment and on-treatment were compared. A total of 155 patients were used as the training set and an additional 221 patients were used as the validation set. RESULTS: Using the Cox proportional hazard model, a ≥0.9- increase in fold change (FC) on a ln scale in CD8+ T cells (corresponding to a 2.5-fold increase on the linear scale), from baseline, demonstrated a greater association with prolonged progression-free survival and allowed improved differentiation between groups above and below the threshold. Similarly, a ≥6.2 threshold in geometric mean of the on-treatment density (OTD) of T cells, which approximately corresponds to 500 cells/mm2, correlated with longer PFS. The combination of both criteria (FC and OTD) provided the best discrimination between clinically nonactive and active compounds. CONCLUSIONS: We propose that a composite score of CD8+ T-cell density in paired biopsies taken before and on-treatment may be a new biomarker to inform on clinical outcomes in early immunotherapy clinical trials.

Type I IFN controls chikungunya virus via its action on nonhematopoietic cells.

Chikungunya virus (CHIKV) is the causative agent of an outbreak that began in La Réunion in 2005 and remains a major public health concern in India, Southeast Asia, and southern Europe. CHIKV is transmitted to humans by mosquitoes and the associated disease is characterized by fever, myalgia, arthralgia, and rash. As viral load in infected patients declines before the appearance of neutralizing antibodies, we studied the role of type I interferon (IFN) in CHIKV pathogenesis. Based on human studies and mouse experimentation, we show that CHIKV does not directly stimulate type I IFN production in immune cells. Instead, infected nonhematopoietic cells sense viral RNA in a Cardif-dependent manner and participate in the control of infection through their production of type I IFNs. Although the Cardif signaling pathway contributes to the immune response, we also find evidence for a MyD88-dependent sensor that is critical for preventing viral dissemination. Moreover, we demonstrate that IFN-alpha/beta receptor (IFNAR) expression is required in the periphery but not on immune cells, as IFNAR(-/-)-->WT bone marrow chimeras are capable of clearing the infection, whereas WT-->IFNAR(-/-) chimeras succumb. This study defines an essential role for type I IFN, produced via cooperation between multiple host sensors and acting directly on nonhematopoietic cells, in the control of CHIKV.