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Although short-term feeding studies demonstrated effects of grains, fiber, and gluten on gut microbiome composition, the impact of habitual intake of these dietary factors is poorly understood. We examined whether habitual intakes of whole and refined grains, fiber, and gluten are associated with gut microbiota in a cross-sectional study. This study included 779 participants from the multi-ethnic Food and Microbiome Longitudinal Investigation study. Bacterial 16SV4 rRNA gene from baseline stool was amplified and sequenced using Illumina MiSeq. Read clustering and taxonomic assignment was performed using QIIME2. Usual dietary intake was assessed by a 137-item food frequency questionnaire. Association of diet with gut microbiota was assessed with respect to overall composition and specific taxon abundances. Whole grain intake was associated with overall composition, as measured by the Jensen–Shannon divergence (multivariable-adjusted Ptrend for quartiles = 0.03). The highest intake quartile was associated with higher abundance of Bacteroides plebeius, Faecalibacterium prausnitzii, Blautia producta, and Erysipelotrichaceae and lower abundance of Bacteroides uniformis. These bacteria also varied by dietary fiber intake. Higher refined grain and gluten intake was associated with lower Shannon diversity (Ptrend < 0.05). These findings suggest that whole grain and dietary fiber are associated with overall gut microbiome structure, largely fiber-fermenting microbiota. Higher refined grain and gluten intakes may be associated with lower microbial diversity. Significance: Regular consumption of whole grains and dietary fiber was associated with greater abundance of gut bacteria that may lower risk of colorectal cancer. Further research on the association of refined grains and gluten with gut microbial composition is needed to understand their roles in health and disease.

PURPOSE This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430 ). METHODS We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m2) + gemcitabine (1,000 mg/m2) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 ( nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 ( nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent ( nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events. CONCLUSION The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.

S1. Gut microbiome alpha- and beta-diversity according to energy-adjusted quartiles of dietary fiber intake in the Food and Microbiome Longitudinal Investigation (FAMiLI).S2. Gut microbiome alpha- and beta-diversity according to energy-adjusted quartiles of whole grain intake in the Food and Microbiome Longitudinal Investigation (FAMiLI), stratified by race/ethnicity.S3. Gut microbiome alpha- and beta-diversity according to energy-adjusted quartiles of whole grain intake in the Food and Microbiome Longitudinal Investigation (FAMiLI).S4. Gut microbiome alpha- and beta-diversity according to energy-adjusted quartiles of whole grain intake in the Food and Microbiome Longitudinal Investigation (FAMiLI), excluding participants with self-reported inflammatory bowel disease (N=21) at enrollment.S5. Gut microbiome alpha- and beta-diversity according to energy-adjusted quartiles of refined grain (with sweets/desserts) intake in the Food and Microbiome Longitudinal Investigation (FAMiLI).S6. Gut microbiome alpha- and beta-diversity according to energy-adjusted quartiles of gluten (with sweets/desserts) intake in the Food and Microbiome Longitudinal Investigation (FAMiLI).

Although short-term feeding studies demonstrated effects of grains, fiber, and gluten on gut microbiome composition, the impact of habitual intake of these dietary factors is poorly understood. We examined whether habitual intakes of whole and refined grains, fiber, and gluten are associated with gut microbiota in a cross-sectional study. This study included 779 participants from the multi-ethnic Food and Microbiome Longitudinal Investigation study. Bacterial 16SV4 rRNA gene from baseline stool was amplified and sequenced using Illumina MiSeq. Read clustering and taxonomic assignment was performed using QIIME2. Usual dietary intake was assessed by a 137-item food frequency questionnaire. Association of diet with gut microbiota was assessed with respect to overall composition and specific taxon abundances. Whole grain intake was associated with overall composition, as measured by the Jensen–Shannon divergence (multivariable-adjusted Ptrend for quartiles = 0.03). The highest intake quartile was associated with higher abundance of Bacteroides plebeius, Faecalibacterium prausnitzii, Blautia producta, and Erysipelotrichaceae and lower abundance of Bacteroides uniformis. These bacteria also varied by dietary fiber intake. Higher refined grain and gluten intake was associated with lower Shannon diversity (Ptrend < 0.05). These findings suggest that whole grain and dietary fiber are associated with overall gut microbiome structure, largely fiber-fermenting microbiota. Higher refined grain and gluten intakes may be associated with lower microbial diversity.Significance:Regular consumption of whole grains and dietary fiber was associated with greater abundance of gut bacteria that may lower risk of colorectal cancer. Further research on the association of refined grains and gluten with gut microbial composition is needed to understand their roles in health and disease.

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Baseline disease characteristics by treatment arm

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Progression-free survival by treatment arm: Primary Cohort

Purpose:Pancreatic ductal adenocarcinoma (PDAC) is largely unresponsive to checkpoint inhibitors. Blockade of the CXCR4/CXCL12 axis increases intratumoral trafficking of activated T cells while restraining immunosuppressive elements. This study evaluates dual blockade of CXCR4 and PD1 with chemotherapy in PDAC.Patients and Methods:Multicenter, single-arm, phase II study to evaluate the safety and efficacy of motixafortide and pembrolizumab combined with chemotherapy in patients with de novo metastatic PDAC and disease progression on front-line gemcitabine-based therapy (NCT02826486). Subjects received a priming phase of motixafortide daily on days 1–5, followed by repeated cycles of motixafortide twice a week; pembrolizumab every 3 weeks; and nanoliposomal irinotecan, fluorouracil, and leucovorin every 2 weeks (NAPOLI-1 regimen). The primary objective was objective response rate (ORR). Secondary objectives included overall survival (OS), progression-free survival (PFS), disease control rate (DCR), safety, and tolerability.Results:A total of 43 patients were enrolled. The ORR according to RECISTv1.1 was 21.1% with confirmed ORR of 13.2%. The DCR was 63.2% with median duration of clinical benefit of 5.7 months. In the intention-to-treat population, median PFS was 3.8 months and median OS was 6.6 months. The triple combination was safe and well tolerated, with toxicity comparable with the NAPOLI-1 regimen. Notably, the incidence of grade 3 or higher neutropenia and infection was 7%, lower than expected for this chemotherapy regimen.Conclusions:Triple combination of motixafortide, pembrolizumab, and chemotherapy was safe and well tolerated, and showed signs of efficacy in a population with poor prognosis and aggressive disease.

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Purpose:Limited options exist for patients with advanced pancreatic cancer progressing after 1 or more lines of therapy. A phase II study in patients with previously treated metastatic pancreatic cancer showed that combining GVAX pancreas (granulocyte-macrophage colony-stimulating factor-secreting allogeneic pancreatic tumor cells) with cyclophosphamide (Cy) and CRS-207 (live, attenuated Listeria monocytogenes expressing mesothelin) resulted in median overall survival (OS) of 6.1 months, which compares favorably with historical OS achieved with chemotherapy. In the current study, we compared Cy/GVAX + CRS-207, CRS-207 alone, and standard chemotherapy in a three-arm, randomized, controlled phase IIb trial.Patients and Methods:Patients with previously treated metastatic pancreatic adenocarcinoma were randomized 1:1:1 to receive Cy/GVAX + CRS-207 (arm A), CRS-207 (arm B), or physician's choice of single-agent chemotherapy (arm C). The primary cohort included patients who had failed ≥2 prior lines of therapy, including gemcitabine. The primary objective compared OS between arms A and C in the primary cohort. The second-line cohort included patients who had received 1 prior line of therapy. Additional objectives included OS between all treatment arms, safety, and tumor responses.Results:The study did not meet its primary efficacy endpoint. At the final study analysis, median OS [95% confidence interval (CI)] in the primary cohort (N = 213) was 3.7 (2.9–5.3), 5.4 (4.2–6.4), and 4.6 (4.2–5.7) months in arms A, B, and C, respectively, showing no significant difference between arm A and arm C [P = not significant (NS), HR = 1.17; 95% CI, 0.84–1.64]. The most frequently reported adverse events in all treatment groups were chills, pyrexia, fatigue, and nausea. No treatment-related deaths occurred.Conclusions:The combination of Cy/GVAX + CRS-207 did not improve survival over chemotherapy. (ClinicalTrials.gov ID: NCT02004262)See related commentary by Salas-Benito et al., p. 5435

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Targeted therapies and immunotherapy have changed the face of multiple solid malignancies, including metastatic melanoma and lung cancer, but no such therapies exist for pancreatic ductal adenocarcinoma (PDAC) despite the knowledge of key mutations and an increasing understanding of the tumor microenvironment. Until now, most clinical studies have not been biomarker driven in this highly immunosuppressive and heterogeneous cancer. Ongoing basic and translational studies are better classifying the disease in hopes of identifying critical pathways that distinguish the unique PDAC subtypes, which will lead to personalized therapies. In this review, we discuss the current treatment options for metastatic pancreatic cancer and highlight current ongoing clinical trials, which aim to target the stroma and the immune microenvironment either alone or in combination with standard chemotherapy. Identifying biomarkers and key resistance pathways and targeting these pathways in a personalized manner in combination with chemotherapy are likely to yield a more immediate and durable clinical benefit. Clin Cancer Res; 23(7); 1670–8. ©2017 AACR.See all articles in this CCR Focus section, “Pancreatic Cancer: Challenge and Inspiration.”

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Supplementary Table S1: Additional PDAC trials

The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) is a complex ecosystem that drives tumor progression; however, in-depth single cell characterization of the PDAC TME and its role in response to therapy is lacking. We performed single-cell RNA sequencing on freshly collected human PDAC samples either before or after chemotherapy. Overall, we found a heterogeneous mixture of basal and classical cancer cell subtypes, along with distinct cancer-associated fibroblast and macrophage subpopulations. Strikingly, classical and basal-like cancer cells exhibited similar transcriptional responses to chemotherapy, and did not demonstrate a shift towards a basal-like transcriptional program among treated samples. We observed decreased ligand-receptor interactions in treated samples, particularly TIGIT on CD8+ T cells and its receptor on cancer cells, and identified TIGIT as the major inhibitory checkpoint molecule of CD8+ T cells. Our results suggest that chemotherapy profoundly impacts the PDAC TME and may promote resistance to immunotherapy.

Background: Perioperative therapy for locally advanced (LA) GC/GEJ adenocarcinoma is standard of care. Although immune checkpoint blockade (ICB) following chemoradiotherapy and resection significantly improves disease free survival (DFS) for esophageal cancer, the effectiveness of ICB together with chemotherapy in LA GC/GEJ cancer is unknown. Methods: This is a multicenter, single-arm, phase II clinical trial of pembrolizumab 200 mg every 3 weeks with capecitabine 625 mg/m2 twice daily and oxaliplatin 130 mg/m2 every 3 weeks (CAPOX) in patients with resectable GC/GEJ adenocarcinoma. Subjects with ECOG PS of 0-1 received CAPOX with pembrolizumab for 3 cycles prior to and 3 cycles following surgery with an additional cycle of pembrolizumab just prior to surgery and 12 months of maintenance pembrolizumab following adjuvant chemoimmunotherapy. The primary endpoint was pathologic complete response (pCR) rate. The study had 80% power to detect an increase in pCR rate from 3% to 15% with a one-sided alpha of 0.05. Secondary endpoints included overall response rate, DFS, and overall survival (OS). This study was registered with ClinicalTrials.gov (NCT02918162). Results: Between 02/10/2017 and 06/17/2021, 36 patients were enrolled with 34 (21 gastric and 13 GEJ) evaluable for efficacy. The median age was 65 years and 17 (50%) patients had an ECOG PS of 1. In total, 29 (85%) patients underwent resection. Seven patients achieved a pCR (20.6% of evaluable patients and 24.1% of those who underwent resection). An additional 6 (17.6%) patients achieved a near CR and 8 (23.5%) demonstrated a significant treatment effect on pathologic review. One patient was deemed unfit for surgery, 2 expired prior to surgery, and 2 were found to have metastatic disease during surgery. At the time of data cut-off, the median follow-up was 19 mo. Of those who underwent resection, 4 (13.7%) experienced disease recurrence and 5 (17.2%) expired. The probability of survival at 1 and 2 years was 0.91 (0.82-1.0) and 0.80 (0.64-0.99), respectively. The median DFS and OS have not been reached. Of the 35 patients who received treatment, treatment related adverse events (AEs) of grade greater than or equal to 3 were reported in 18 (51%) patients. Grade greater than or equal to 3 immune-related AEs were reported in 10 (29%) patients. Three grade 5 AEs occurred, two possibly treatment-related (gastric hemorrhage and gastric perforation) and one unrelated to treatment (cardiac arrest). Conclusion: In LA GC/GEJ adenocarcinoma, the combination CAPOX and pembrolizumab resulted in a pCR rate of 20.6%. The combination was well tolerated and 85.3% of patients underwent surgical resection. This trial met its primary endpoint supporting further investigation of this regimen as an alternative for patients who are unlikely to tolerate triple combination chemotherapy. Correlative studies are in progress. Citation Format: Alexander Grenander Raufi, Shing Lee, Michael May, Armando Del Portillo, Naomi Sender, Sarah Sta Ana, Katarzyna Gautier, Emily Alouani, Haeseong Park, Paul Oberstein, Manish Shah, Gulam A. Manji. Phase II trial of perioperative pembrolizumab plus capecitabine and oxaliplatin followed by adjuvant pembrolizumab for resectable gastric and gastroesophageal junction (GC/GEJ) adenocarcinoma [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 CT009.

Background: Most microsatellite stable/mismatch repair proficient (MSS/MMRp) stage IV colorectal cancers (CRC) do not respond to PD-1 inhibition. ATP128, based on the KISIMA platform, is a single chimeric fusion protein, composed of 3 elements essential to generate potent antitumoral cellular immunity: a proprietary cell-penetrating peptide (CPP) for antigen delivery, a proprietary Toll-like receptor (TLR)-peptide agonist with self-adjuvant properties and a modulable multi-antigenic domain (Mad), where the Mad for CRC includes 3 antigens: carcinoembryonic antigen (CEA), Survivin, Achaete-scute complex homolog 2 (ASCL2). VSV-GP128 is a recombinant vesicular stomatitis virus (VSV) carrying the glycoprotein (GP) of a non-neurotropic strain of lymphocytic choriomeningitis virus (LCMV) instead of the native VSV-GP. The GP of the LCMV abrogates neurotoxicity. As viral vector, VSV-GP128 expresses a Mad with identical sequence to ATP128 integrated in a linear, negative-sense, single-stranded RNA genome. Preclinical data have shown that priming with KISIMA vaccine followed by VSV-GP boost induced a large pool of polyfunctional and persistent antigen-specific cytotoxic T cells in the periphery as well as within the tumor in several tumor models. Combining heterologous vaccination with a PD-1 inhibitor further improved its therapeutic efficacy (Das et al., Nature Communication 2021). Methods: KISIMA-01 (NCT04046445) is an open-label, multi-center Phase 1b umbrella trial to investigate the safety, tolerability and immunogenicity of the heterologous prime-boost vaccine AT128/VSV-GP128 in combination with the anti-PD1 ezabenlimab in patients with stage IV MSS CRC. Two different patient cohorts are investigated: 1) maintenance setting (during a chemotherapy free period) after a minimum of 4 months of 1st line standard chemotherapy with clinical benefit (defined as PR or SD) (n=30); 2) resectable liver-limited disease (n=15). ATP128 is given subcutaneously on day 1 (prime); VSV-GP128 is administered intravenously on day 15 as the heterologous boost. ATP128 is again administered on day 29 (injection 3) and then every 4 weeks for the last 3 immunizations. Ezabenlimab is administered every 3 weeks starting with the first ATP128 administration. Blood and tissue samples are collected before, during and after ATP128/VSV-GP128 treatment to monitor the induction of a tumor associated antigen-specific immune response and immune-related changes. Immunogenicity will be analyzed in the peripheral blood using ELISpot, and in the tumor microenvironment by immunohistochemical assessment of tumor-infiltrating lymphocytes (TILs). Clearance of ctDNA is analyzed as an exploratory endpoint. The heterologous prime-boost cohorts (ATP128/VSV-GP128) of the KISIMA-01 trial are recruiting in the US, Switzerland and Belgium. Citation Format: Heinz-Josef Lenz, Thibaud Koessler, Paul Oberstein, Eric Van Cutsem, Sunnie Kim, Ralph Fritsch, Hans Prenen, Michael Morse, Delphine Gani, Madiha Derouazi, Thomas Bogenrieder, Scott Kopetz. KISIMA-01: A first-in-human trial of the heterologous prime-boost vaccine ATP128/VSV-GP128 with ezabenlimab (BI 754091) in patients with stage IV colorectal cancer [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 CT570.

PURPOSE To evaluate the efficacy and safety of pegvorhyaluronidase alfa (PEGPH20) plus nab-paclitaxel/gemcitabine (AG) in patients with hyaluronan-high metastatic pancreatic ductal adenocarcinoma (PDA). PATIENTS AND METHODS HALO 109-301 was a phase III, randomized, double-blind, placebo-controlled study. Patients ≥ 18 years of age with untreated, metastatic, hyaluronan-high PDA were randomly assigned 2:1 to PEGPH20 plus AG or placebo plus AG. Treatment was administered intravenously in 4-week cycles (3 weeks on, 1 week off) until progression or intolerable adverse events: PEGPH20 3.0 µg/kg twice per week for cycle 1 and once per week thereafter; nab-paclitaxel 125 mg/m2 once per week; and gemcitabine 1,000 mg/m2 once per week. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety. Response was independently assessed per RECIST v1.1. RESULTS At data cutoff, 494 patients were randomly assigned, with 492 (327 for PEGPH20 and 165 for placebo) included in intention-to-treat analyses. Baseline characteristics were balanced for PEGPH20 plus AG versus placebo plus AG. There were 330 deaths, with a median OS of 11.2 months for PEGPH20 plus AG versus 11.5 months for placebo plus AG (hazard ratio [HR], 1.00; 95% CI, 0.80 to 1.27; P = .97); median PFS was 7.1 months versus 7.1 months (HR, 0.97 [95% CI, 0.75 to 1.26]); ORR was 47% versus 36% (ORR ratio, 1.29 [95% CI, 1.03 to 1.63]). Grade ≥ 3 adverse events with a ≥ 2% higher rate with PEGPH20 plus AG than with placebo plus AG included fatigue (16.0% v 9.6%), muscle spasms (6.5% v 0.6%), and hyponatremia (8.0% v 3.8%). CONCLUSION The addition of PEGPH20 to AG increased the ORR but did not improve OS or PFS. The safety profile of PEGPH20 plus AG was consistent with that found in previous studies. These results do not support additional development of PEGPH20 in metastatic PDA.