The Sentinel


Saturday, November 10, 2018

SITC 2018 Scientific Highlights - Nov. 9

The Society for Immunotherapy of Cancer (SITC) is pleased to present highlights from the first day of the 33rd Annual Meeting in Washington, D.C.

Oxygen Concentration Influences T cell Motility within Solid and Hematologic Malignancies

Tomasz Zal, PhD (MD Anderson Cancer Center, Houston, TX, USA) presented research investigating the effect of oxygen concentrations upon T cell motility within tumors. Previous research suggests that hyper-oxygenation can improve response to immunotherapy, but its effects upon T cell motility are unknown. To investigate this question, Dr. Zal described the development of a novel microscopy method that allows for measurement of oxygen concentrations using a novel FaST-PLIM method - based upon PtP-C343 phosphorescence lifetimes - while simultaneously assessing T cell motility. Initial evaluation of bone marrow samples from patients with acute lymphoblastic leukemia (ALL) using this approach revealed that T cell motility is reduced in hypoxic regions, specifically with oxygen pressure less than 5 mmHg. Regions with oxygen pressure greater than 5 mmHg contained T cells with normal T cell motility. In support, T cell motility in solid lung tumor samples was also decreased in regions with oxygen pressure less than 5mmHg. Interestingly, treatment of an ALL mouse model with an inhibitor of oxidative phosphorylation (IACS-10759) increased oxygen concentrations within the bone marrow, but did not restore T cell motility. In contrast, supplementation of oxygen to the lung tissues increased oxygen pressure and recovered T cell motility. Together, these data suggest that T cell motility is reduced in hypoxic regions of tumors, and that hyper-oxygenation can restore T cell surveillance that could potentially enhance immunotherapeutic efficacy.

Meta-Analysis Reveals Correlations Between Response to Anti-PD-1/PD-L1 Therapy and Biomarker Assessment Methods

Steve Lu, BS (Johns Hopkins University, Baltimore, MD, USA) presented data from a meta-analysis comparing associations between response to anti-PD-1/PD-L1 immune checkpoint inhibitors (ICI) and specific biomarker assessment methods including PD-L1 immunohistochemistry (IHC), tumor mutational burden (TMB) evaluation, gene expression profiling (GEP), and multiplex immunofluorescence (IF). In all, data from 8021 patient samples from greater than 10 tumor types (44 published studies total) were included in the analysis, with investigators noting the type of biomarker analysis used in the study as well as the number of patients with complete response, partial response, and progressive disease. Results indicate that multiplex IF was more significantly correlated with ICI response (weighted AUC = 0.802) than PD-L1 IHC, TMB, and GEP (weighted AUC = 0.656, 0.690, 0.652, respectively). A combined approach using a combination of PD-L1 IHC, TMB, and/or GEP enhanced association with ICI response compared to the respective individual approaches (AUC = 0.733), but multiplex IF remained the strongest correlative (AUC = 0.802). This meta-analysis suggests a current hierarchy of biomarker assessment and association with ICI response. Further studies are necessary to validate these findings for each individual and combinatorial approach, and identified ICI response associations will remain in flux as new technologies become available.

Visualization of Tumors and CD8+ T cell Distribution in Patients with Advanced Solid Tumors via a Novel Anti-CD8 Minibody

Michael Gordon, MD (HonorHealth Research Institute, Scottsdale, AZ, USA) presented initial data from a phase 1 first-in-human study investigating a novel method to detect CD8+ T cell distribution in patients with solid tumors using positron emission tomography and the anti-CD8 radiolabeled minibody 89Zr-IAB22M2C. In all, 15 patients with advanced solid tumors (melanoma = 8, non-small cell lung cancer [NSCLC] = 6, hepatocellular = 1) were provided 89Zr-IAB22M2C (0.5-1.5mg, 3mCi IV) and subsequently underwent multiple PET scans over a 5-7 day period (scans = 1-2hr, 6-8hr, 24hr, 48hr, 5-7 days). No drug-related adverse reactions during administration of 89Zr-IAB22M2C were noted, with the exception of transient ADA in one patient. PET results indicate that 89Zr-IAB22M2C readily accumulates in CD8-rich tissues including bone marrow and the spleen, and that excess 89Zr-IAB22M2C was excreted through the hepatobiliary system. Tumor 89Zr-IAB22M2C uptake was noted in 10/15 patients, and very little signal was observed in background tissues including muscle, brain, and heart. 89Zr-IAB22M2C signal was observed over several days (at least day 7), and more clearly identified a secondary lesion in a patient with hepatocellular carcinoma compared to hepatic phase CECT. Together, these data indicate that 89zr-IAB22M2C is safe in patients with advanced solid tumors, and may be able to provide assistance in measuring tumor size and location, as well as CD8+ T cell distribution.

Early Phase 1 Data Suggest Combination Anti-TIM-3 and Anti-PD-1 Offers Promising Safety and Efficacy in Patients with NSCLC Treated with Prior Anti-PD-1/PD-L1 Therapy

Diwakar Davar, MD (University of Pittsburgh, Pittsburgh, PA, USA) presented data from the phase 1 AMBER trial (NCT02817633) assessing dosage, safety, and efficacy of TSR-022 – an anti-TIM3 monoclonal antibody – in combination with anti-PD-1 TSR-042 in patients with advanced NSCLC who have relapsed or are refractory to prior anti-PD-1/PD-L1 therapy. In all, 39 patients (prior pembrolizumab = 14, prior nivolumab = 23, prior atezolizumab = 5, others = 2; PD-L1 TPS greater than or equal to one percent = 16, TPS less than one percent = 8, unknown TPS = 15) received TSR-022 (100mg: n=14; 300mg: n=25, Q3W) in combination with TSR-042 (500mg Q3W). Treatment-related adverse events were observed in less than five percent of patients, with only three grade three events (100mg cohort: one fatigue, one lipase increase; 300mg cohort: one lipase increase). In all, four PR and 11 SD were observed in 31 evaluable patients across both cohorts (100mg: one PR, three SD; 300mg: three PR, eight SD). Interestingly, all four PR were observed in patients with PD-L1 TPS greater than or equal to one percent. Together, these data indicate that combination TSR-022 + TSR-042 is safe in patients with advanced NSCLC who have received prior anti-PD-1/PD-L1 therapy, and early signs of clinical efficacy support continued investigation of this treatment regimen. In addition, these data suggest that PD-L1 TPS may serve as a predictive biomarker of response for this combination strategy.

Phase 1 4280-001 Trial Offers Early Glimpse into Safety and Efficacy of Treatment of Patients with Advanced Solid Tumors with Anti–LAG-3 MK-4280 as a Single-Agent or in Combination with Pembrolizumab

Nehal Lakhani, MD, PhD (START-Midwest, Grand Rapids, MI, USA) presented data from the first-in-human phase 1 4280-001 trial (NCT02720068) investigating dosage and safety of the anti-LAG-3 antibody MK-4280 as a single-agent or in combination with anti-PD-1 pembrolizumab for the treatment of patients with advanced solid tumors. Adult patients with metastatic solid tumors (sarcoma, appendiceal, billary, colorectal, adrenocortical, breast, small intestinal, renal cell, among others) received MK-4280 (dose-escalation from 7 - 700mg Q3W) as a single agent (n = 18) or in combination with pembrolizumab (200mg Q3W, n = 15). No dose-limiting toxicities were observed in either cohort across all MK-4280 doses. Grade 3 TRAEs were observed in 50 percent (n=9) and 60 percent (n=9) of the monotherapy and combination cohorts, respectively. At data cut-off, ORR was six percent (95 percent CI: less than one – 27; one PR, two SD) in the monotherapy cohort, and 27 percent (95 percent CI: 8 – 55; four PR, 2 SD) in the combination cohort. Disease control rate was 17 percent (95 percent CI: 4 – 41) and 40 percent (95 percent CI: 16 – 68) in patients who received MK-4280 and MK-4280/pembrolizumab, respectively. These early data suggest that MK-4280 can be safely provided to patients with advanced solid tumors up to 700mg, and that administration as a single-agent or in combination with pembrolizumab may potentially provide clinical benefit.

Updated PIVOT-02 Results Demonstrate Durable Responses in Advanced Melanoma Patients Treated with NKTR-214 + Nivolumab

Adi Diab, MD (MD Anderson Cancer Center, Houston, TX, USA) presented updated data from the PIVOT-02 (NCT02983045) trial assessing efficacy and safety of the IL-2 agonist NKTR-214 in combination with anti-PD-1 nivolumab for the treatment of patients with advanced melanoma. In all, 38 patients (PD-L1 greater than or equal to 1 percent = 19, PD-L1 less than one percent = 14) treated with NKTR-214 (0.006 mg/kg Q3W) and nivolumab (360 Q3W) displayed an ORR of 53 percent (n = 20, CR = 9, PR = 11). ORR of PD-L1+ and PD-L1- patients was 68% and 43%, respectively. At median follow-up of 7.2 months, median duration of response has not yet been reached (95 percent CI: 2.6 – NR), and 85 percent (17/20) of patients have ongoing responses. Grade 3/4 TRAEs were observed in 8 patients (19.5 percent), most commonly lipase increase (n = 3) and atrial fibrillation (n = 2). Importantly, incidence of cytokine-related AEs – a concern with traditional IL-2 treatment – decreased over continued dosing. Analyses of patient peripheral blood revealed increases in CD4+ (15x, p less than 0.001), CD8+ (26x, p less than 0.001), and NK cells (4.5x, p less than 0.001) seven days post-cycle 1. Increased tumor infiltration of CD8+ T cells was also observed in patients treated with the combination regimen (baseline = 108 cells/mm2; week 3 = 712 cells/mm2). Gene expression analyses of treated patient samples also indicate a profile consistent with CD8+ anti-tumor activity. In all, these data suggest that NKTR-214 + nivolumab may provide clinical benefit as first-line treatment of patients with advanced melanoma, and that the combination promotes increased immunity within the tumor microenvironment.

Inhibition of MARCO may help Promote Anti-Tumor Activity within the Tumor Microenvironment

Dhifaf Sarhan, PhD (Karolinska Institutet, Solna, Sweden) described the role of the scavenger receptor MARCO (macrophage receptor with collagenous structure) towards modulation of immunity within tumor microenvironment. MARCO is expressed on suppressive immune cells including myeloid-derived suppressor cells and tumor-associated macrophages, commonly found in pancreatic cancer samples that also have low CD8+ T cell infiltration. Pre-clinical studies reveal that treatment of mice bearing 4T1 mammary carcinoma with an anti-MARCO antibody reduced tumor growth and metastasis. The mechanism of action, however, remains unknown. Evaluation of pancreatic cancer samples revealed that low abundance of MARCO correlated with increased T cell infiltration and survival compared to MARCO-high samples (p = 0.033 and 0.027, respectively). In addition, treatment of cytokine-polarized macrophages that display a suppressive phenotype with anti-MARCO restored IFNgamma production as well as tumor killing function, and normalized metabolism towards the levels of M1 anti-tumor macrophages. Together, these data showed that increased MARCO abundance on TAMs and MDSC may inhibit cytotoxic anti-tumor activity in the tumor microenvironment, and that treatment of patients with anti-MARCO may be a potential approach towards restoring immunity in difficult to treat diseases such as pancreatic and breast cancer.

Personalized NEO-PV-01 Vaccine Promotes Immunogenic Responses in Patients with Advanced Melanoma and NSCLC

Siwen Hu-Lieskovan (Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA) presented clinical data from the phase 1b NT-001 trial (NCT02897765) investigating efficacy of NEO-PV-01  – a personalized neoantigen vaccine that targets up to 20 unique, high quality neoantigens – in combination with nivolumab for the treatment of patients with metastatic melanoma and NSCLC. Patients received initial nivolumab for 12 weeks while NEO-PV-01 was synthesized, and then received the vaccine for an additional 12 weeks. All patients developed an immune response due to the vaccination, and 56 percent of epitopes were able to induce a CD4+ and CD8+ immune response that was detectable two weeks into treatment. 50 percent of melanoma patients achieved PR prior to NEO-PV-01 vaccination, and an additional 37 percent and 6.3 percent achieved PR and CR post-vaccination, respectively. In all, 75 percent of melanoma patients remain on treatment. In addition, 27 percent of patients with NSCLC achieved PR pre-vaccination, and an additional 25 percent achieved PR post-vaccination. 64 percent of NSCLC patients remain on treatment. Two melanoma patients treated with the combination regimen demonstrated durable responses that were detectable 52- and 70-weeks post treatment initiation, and one NSCLC patient experienced an immune response detectable 52 weeks post-initiation of therapy. In summary, data suggest that the NEO-PV-01 vaccination in combination with nivolumab may be effective in treating patients with melanoma and NSCLC, and that immunity generated by the vaccine is durable over time.

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