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Background: Hepatocellular carcinoma has high recurrence rates after surgery; however, there are no approved standard-of-care neoadjuvant or adjuvant therapies. Immunotherapy has been shown to improve survival in advanced hepatocellular carcinoma; we therefore aimed to evaluate the safety and tolerability of perioperative immunotherapy in resectable hepatocellular carcinoma. Methods: In this single-centre, randomised, open-label, phase 2 trial, patients with resectable hepatocellular carcinoma were randomly assigned (1:1) to receive 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery at 6 weeks) followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for 2 years, or 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery) plus one dose of 1 mg/kg of ipilimumab intravenously concurrently with the first preoperative dose of nivolumab, followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for up to 2 years plus 1 mg/kg of ipilimumab intravenously every 6 weeks for up to four cycles. Patients were randomly assigned to the treatment groups by use of block randomisation with a random block size. The primary endpoint was the safety and tolerability of nivolumab with or without ipilimumab. Secondary endpoints were the proportion of patients with an overall response, time to progression, and progression-free survival. This trial is registered with ClinicalTrials.gov (NCT03222076) and is completed. Findings: Between Oct 30, 2017, and Dec 3, 2019, 30 patients were enrolled and 27 were randomly assigned: 13 to nivolumab and 14 to nivolumab plus ipilimumab. Grade 3–4 adverse events were higher with nivolumab plus ipilimumab (six [43%] of 14 patients) than with nivolumab alone (three [23%] of 13). The most common treatment-related adverse events of any grade were increased alanine aminotransferase (three [23%] of 13 patients on nivolumab vs seven [50%] of 14 patients on nivolumab plus ipilimumab) and increased aspartate aminotransferase (three [23%] vs seven [50%]). No patients in either group had their surgery delayed due to grade 3 or worse adverse events. Seven of 27 patients had surgical cancellations, but none was due to treatment-related adverse events. Estimated median progression-free survival was 9·4 months (95% CI 1·47–not estimable [NE]) with nivolumab and 19·53 months (2·33–NE) with nivolumab plus ipilimumab (hazard ratio [HR] 0·99, 95% CI 0·31–2·54); median time to progression was 9·4 months (95% CI 1·47–NE) in the nivolumab group and 19·53 months (2·33–NE) in the nivolumab plus ipilimumab group (HR 0·89, 95% CI 0·31–2·54). In an exploratory analysis, three (23%) of 13 patients had an overall response with nivolumab monotherapy, versus none with nivolumab plus ipilimumab. Three (33%) of nine patients had a major pathological response (ie, ≥70% necrosis in the resected tumour area) with nivolumab monotherapy compared with three (27%) of 11 with nivolumab plus ipilimumab. Interpretation: Perioperative nivolumab alone and nivolumab plus ipilimumab appears to be safe and feasible in patients with resectable hepatocellular carcinoma. Our findings support further studies of immunotherapy in the perioperative setting in hepatocellular carcinoma. Funding: Bristol Myers Squibb and the US National Institutes of Health.

Mouse syngeneic tumor models are widely used tools to demonstrate activity of novel anti-cancer immunotherapies. However, advanced prostate cancer is difficult to treat due to a lack of effective approaches for disrupting immune tolerance. RM-1 is a murine prostate cancer cell line derived from a Ras/Myc-induced prostate cancer. RM-1 is of particular interest because it is an aggressive, nonimmunogenic, potentially metastatic prostate line that is androgen independent. Subcutaneous growth kinetics were evaluated for RM-1 cells implanted at two cell inocula (1.0E+06 and 5.0E+05 cells/implant). RM-1 grew aggressively across both implant conditions, producing 100% take rate, a median tumor volume doubling time of ~2 days, and a median time to euthanasia criteria (2000 mm3) of ~11 days. Bioanalysis of tumor-infiltrating lymphocyte (TIL) composition via flow cytometry confirms that the RM-1 tumor model has characteristics of a nonimmunogenic or a “cool” tumor. CD4+ T cell and CD8+ T cell populations ranged from 0.7 to 1.9% of the CD45+ cells. Comparatively, G-MDSC and M-MDSC populations were much higher at 8.3 and 63.8% of CD45+ cells. This type of TIL profile is ideal for combination therapies, providing a clear opportunity to turn a “cool” tumor “warm” and therefore potentially more responsive to treatment. To further characterize the RM-1 model, we evaluated anti-mPD-1, anti-mPD-L1, and anti-mCTLA-4. As expected, based on the TIL profile, single agent treatment with checkpoint inhibitors produced minimal anticancer activity, with no tumor regressions, and Citation Format: Justin Snider, Derrik Germain, Patrick Allison, Alden Wong, Sylvie Kossodo. Model characterization and tumor immune profile assessment for syngeneic RM-1 murine prostate cancer in male C57BL/6 mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1664.

TPS9600 Background: Immune checkpoint inhibitors (ICIs) are approved for multiple malignancies, however, durable remission rates with ICI monotherapy remains low. Combined treatment with anti-CTLA-4 and anti-PD1 has shown higher response rates in several cancers but is associated with up to 60% grade 3/4 immune-related adverse events (irAEs) leading to frequent treatment discontinuation. The need for corticosteroids to control irAEs may further diminish anti-tumor activity. A multi-disciplinary approach using clinical, preclinical, and translational analyses implicated the IL-6/Th17 axis in both ICI-related autoimmunity and resistance. Further, preliminary data showed that targeting interleukin 6 (IL-6) could be an effective approach to reduce irAEs while maintaining and possibly boosting the antitumor immune response. Methods: We are conducting a phase II, open-label, single center study to evaluate the use of combination treatment with tocilizumab (toci; anti-IL6), ipilimumab (ipi; anti-CTLA4) and nivolumab (nivo; anti-PD1) as a front-line therapy for patients (pts) with treatment-naïve advanced cutaneous melanoma (cohort 1), urothelial carcinoma (cohort 2), and EGFR mutant non-small cell lung cancer after tyrosine kinase inhibitors failure (cohort 3) (NCT04940299). Ten pts per disease site will be enrolled, plus an additional 25 melanoma pts in an expansion cohort. Key inclusion criteria are age ≥18 years (yrs) and histologically confirmed locally advanced or metastatic disease, with specific eligibility criteria defined for each cohort. Patients with interstitial lung diseases, autoimmune diseases, infection, or conditions requiring immunosuppressive therapies are not eligible, but stable asymptomatic brain mets are allowed. Ipi/Nivo dosing is as per approved disease indications: in cohort 1 &2, ipi 3 mg/kg + nivo 1 mg/kg is administered intravenously (IV) every 3 weeks (wks) for 4 doses then nivo 480 mg/4 wks up to 2 yrs. In cohort 3, IV ipi 1 mg/kg/6 wks + nivo 3 mg/kg/2 wks is administered up to 2 yrs. In all 3 cohorts, subcutaneous (SQ) toci 162 mg/2wks is administered up to 12 wks. Imaging is every 12 wks up to 2 yrs or until dose-limiting toxicities or progression. The primary outcome is safety/tolerability of the triple therapy. The secondary outcomes are antitumor efficacy and overall survival. Additionally, tumor and blood samples are being collected for longitudinal immune analysis, including gene expression and multiplex histochemistry to identify predictive biomarkers of response, resistance, and toxicity. The trial opened in October 2021 and has enrolled 14 patients to date. Clinical trial information: NCT04940299.

2511 Background: While ICB has significantly improved clinical outcomes across several cancer types, only 15-20% of patients develop a durable response. Thus, novel and targetable biomarkers are needed. There is increased appreciation of the role of the gut microbiome, and TLS and B-cells in the TME in response to ICB. Here, we investigate the association between these two determinants of response in patient specimens from three randomized phase 2 neoadjuvant ICB trials of nivolumab +/- ipilimumab (melanoma (MEL; NCT02519322; n=23), non-small-cell lung cancer (NSCLC; NCT03158129; n=31), sarcoma (SARC; NCT02301039; n=17). Methods: Patients were categorized as responders (R) or non-responders (NR) based on major pathologic response, as defined in each histotype (MEL and NSCLC viable tumor ≤10%; SARC hyalinization>30%). Baseline fecal samples were profiled via 16S rRNA gene sequencing from all three cohorts to assess the composition of patient gut microbiomes. Transcriptional profiles of biopsies collected pre-ICB for MEL and SARC, and post-ICB for MEL, SARC, and NSCLC were used to assess TLS (CXCL13, CCL18, CCL19, CCL21) and B-cell (PAX5, CD79B, CR2, MS4A1) signatures in the TME, by calculated mean values of normalized gene expressions. Comparison between samples were carried out using the Wilcoxon signed-rank test. Results: There were 21 R overall (NSCLC n=9; MEL n=9; SARC n=3). Despite significant differences in alpha and beta diversity across cohorts, relative abundance of Ruminococcus was significantly higher in R (p=0.003; NSCLC p

BackgroundIntegrin αvβ8 activates TGFβ in immune cells. αvβ8 inhibitors have been shown to potentiate immune checkpoint blockade (ICB) in preclinical models [1]. Radioimmunotherapy (RIT) induces immunogenic cell death and antigen presentation, however it concurrently activates immunosuppressive pathways. Interestingly, αvβ8 immunosuppressive activity was implicated in radiotherapy resistance [2]. We have explored whether antagonizing αvβ8 overcomes the suppressive effect of TGFβ and restores anti-tumor immunity in advanced ICB and RIT resistant tumors.MethodsEfficacy was evaluated after combination treatment with low dose radiation, αvβ8 (clone C6D4) and PD-1 (clone J43) mAb in an advanced CT26 colon cancer syngeneic mouse model. Mice were treated at tumor volume of >120 mm3 and euthanized at 2,000 mm3. Flow cytometry and transcriptomic analysis were used to assess the mechanism of action. Tumor volumes are presented as mean±SEM. Statistics were performed by one-way ANOVA, or log-rank test. Bone marrow derived dendritic cell (BMdDC) cultures were isolated from C57BL/6 mice.ResultsCell death, including radiation-induced apoptosis, induced immunoregulatory and maturation program in a population of ex vivo cultured BMdDC, recently described as mregDC/DC3 [3,4]. mregDC/DC3 signature was associated with increased αvβ8 expression, suggesting a role of this integrin in inducing an immunosuppressive phenotype.A CT26 model was established to mimic the progression of late-stage tumors and was unresponsive to radiation, ICB and RIT. In CT26 implanted mice, αvβ8 is expressed on tumor stoma, and is not detectable on cancer cells. Addition of αvβ8 mAb to RIT markedly increased tumor regression (P=0.0067) and survival (PAbstract 595 Figure 1Complete response (CR) with improved survival when αvβ8 inhibition is added to RIT in CT26 syngeneic model of colorectal cancer in an advanced, ICB and RIT unresponsive stage. (A) Effect of combination therapy with low dose radiation (small animal radiation research platform (SARRP) at 5 Gray (Gy) on the day of staging (day 10)), PD-1 mAb (10 mg/kg twice weekly for 2 weeks) and αvβ8 mAb (7 mg/kg three times weekly for 3 weeks) measured by tumor burden. 5Gy+PD-1 and 5Gy+αvβ8 has a minimal effect on tumor growth inhibition showing slight improvement relative to radiation alone (5Gy+IgG). Addition of αvβ8 antagonism (5Gy+αvβ8+PD-1) improves anti-tumor responses leading to CR in 8 of 10 mice. (B) Kaplan-Meier Curve presenting time to progression. 5Gy+IgG improved survival over monotherapy with either αvβ8 or PD1 mAb. 5Gy+αvβ8+PD-1 resulted in a profound improvement of the survival over all other treatment conditionsConclusionsInhibition of αvβ8 in combination with RIT eradicated an advanced tumor, unresponsive to the respective monotherapies or conventional RIT. The anti-tumor effect was driven by enhancement of adaptive immunity, improvement of DC function and reduced tumor tolerance. These data provide evidence that αvβ8 inhibition enhances RIT and may be effective against ICB refractory tumors.ReferencesReszka-Blanco NJ,Yadav V, Krumpoch M, Cappellucci L, Cui D, Dowling JE, et al., Inhibition of integrin αvβ8 enhances immune checkpoint induced anti-tumor immunity by acting across immunologic synapse in syngeneic models of breast cancer. AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1559.Jin S, Lee WC, Aust D, Pilarsky C, Cordes N, β8 integrin mediates pancreatic cancer cell radiochemoresistance. Mol Cancer Res. 2019; 17(10): 2126–2138.Maier B, Leader AM, Chen ST, Tung N, Chang C, LeBerichel J, et al., A conserved dendritic-cell regulatory program limits antitumour immunity. Nature. 2020; 580 (7802): 257–262.Garris CS, Arlauckas SP, Kohler RH, Trefny MP, Garren S, Piot C, Engblom C, et al., Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12. Immunity. 2018; 49(6): 1148–1161.Dodagatta-Marri E, Ma H-Y, Liang B, Li J, Meyer DS, Chen S-Y, et al., Integrin αvβ8 on T cells suppresses anti-tumor immunity in multiple models and is a promising target for tumor immunotherapy. Cell Report. 2021; 36(1): 109309Ethics ApprovalAll animal work was approved by the site Institutional Animal Care and Use Committee and was performed in conformance with the Guide for the Care and Use of Laboratory Animals within an AAALAC-accredited program. Humane euthanasia criteria were predetermined on the basis of body weight and defined clinical observations.