Rodriguez, Luz M.

Abstract Globally, gastric adenocarcinoma is the fourth leading cause of cancer mortality and a major cancer disparity in the United States. Chemoprevention strategies are lacking for high-risk individuals with gastric premalignant conditions (GPMC). Curcumin, the principal curcuminoid in turmeric, exerts immunomodulatory effects in the epithelium and against Helicobacter pylori, and studies suggest chemoprevention potential. We conducted a double-blind, phase IIa randomized controlled trial in high-risk populations in Puerto Rico and Honduras. We investigated the utility of a bioavailable formulation of curcumin (Meriva) among individuals with H. pylori–negative GPMC, specifically, multifocal atrophic gastritis (MAG) or gastric intestinal metaplasia (GIM). Patients were 1:1 randomized to 1,000 mg Meriva daily or placebo for a 6-month intervention with endoscopy at baseline and 6 months. Outcomes included assessment of epithelial cytokine and chemokine levels, histology, and DNA damage as assessed by γ-H2AX phosphorylation IHC. Of the 110 subjects screened, 50 participants were randomized, and 48 completed the trial. A significant reduction in gastric mucosal IL1β levels from baseline in the gastric body, the primary endpoint, was observed in the Meriva group (P = 0.032). Changes in epithelial IL8, TNFα, and inducible protein 10 levels and gastric mucosal histology and DNA damage (secondary endpoints) were similar between arms. Curcumin (Meriva) was safe, well-tolerated, and showed potential as a curcuminoid chemoprevention agent in H. pylori–negative patients with GPMC. A potential reduction in gastric inflammation as measured by gastric mucosal IL1β levels was observed. Further studies are warranted, including studies in H. pylori–positive individuals, based upon the curcuminoid direct effects on H. pylori. Prevention Relevance: Gastric adenocarcinoma is a leading cause of cancer mortality worldwide. Chemoprevention candidates for GPMCs are limited. This randomized phase IIa trial evaluated a bioavailable curcumin formulation in high-risk individuals with MAG and GIM. The results support further study of curcuminoids for gastric cancer risk reduction. See related Spotlight, p. 387 See related article by Morgan et al., p. 391

Abstract Gastric adenocarcinoma (GAC) is the fourth leading global cause of cancer mortality and leading infection-associated cancer. High-incidence regions of GAC include Latin America and Eastern Asia. Immigrants from high-incidence regions maintain their GAC risk. GAC is a major U.S. cancer disparity, and its incidence rates are 2 to 10 times higher in non-White populations. Emerging guidelines recommend 3-year surveillance endoscopy for patients with high-risk gastric premalignant conditions (GPMC). Clinical trials of GPMC chemoprevention agents are lacking. We conducted a NCI Division of Cancer Prevention–funded, phase II placebo-controlled chemoprevention trial in patients with GPMCs (atrophic gastritis and intestinal metaplasia) with a highly bioavailable preparation of curcuminoids (Meriva). The trial sites in Puerto Rico and rural Honduras had important characteristics: (i) representative Caribbean and Mesoamerican populations, linked to large U.S. immigrant populations; (ii) high prevalence of Helicobacter pylori infection and GPMCs; (iii) the absence of turmeric and curcuminoids in local diets; and (iv) proven bidirectional collaboration with U.S. academic institutions. H. pylori–negative patients with GPMCs were randomized to the study drug (500 mg po bid) or placebo for 180 days (NCT02782949), with primary outcomes based upon histologic parameters. Principal study challenges included (i) an international regulatory environment; (ii) research infrastructure strengthening, particularly in Central America; (iii) participant recruitment in Honduras, wherein only 10% to 15% are H. pylori negative; (iv) the COVID-19 pandemic; and (v) natural disasters (three hurricanes). There were no losses to follow-up related to the pandemic or natural disasters. In conclusion, the south–south partnership provides a model for chemoprevention and translational studies in Latino populations with prevalent cancers, such as GAC.

Abstract Purpose: To assess whether MUC1 peptide vaccine produces an immune response and prevents subsequent colon adenoma formation. Patients and Methods: Multicenter, double-blind, placebo-controlled randomized trial in individuals age 40 to 70 with diagnosis of an advanced adenoma ≤1 year from randomization. Vaccine was administered at 0, 2, and 10 weeks with a booster injection at week 53. Adenoma recurrence was assessed ≥1 year from randomization. The primary endpoint was vaccine immunogenicity at 12 weeks defined by anti-MUC1 ratio ≥2.0. Results: Fifty-three participants received the MUC1 vaccine and 50 placebo. Thirteen of 52 (25%) MUC1 vaccine recipients had a ≥2-fold increase in MUC1 IgG (range, 2.9–17.3) at week 12 versus 0/50 placebo recipients (one-sided Fisher exact P < 0.0001). Of 13 responders at week 12, 11 (84.6%) responded to a booster injection at week 52 with a ≥2-fold increase in MUC1 IgG measured at week 55. Recurrent adenoma was observed in 31 of 47 (66.0%) in the placebo group versus 27 of 48 (56.3%) in the MUC1 group [adjusted relative risk (aRR), 0.83; 95% confidence interval (CI), 0.60–1.14; P = 0.25]. Adenoma recurrence occurred in 3/11 (27.3%) immune responders at week 12 and week 55 (aRR, 0.41; 95% CI, 0.15–1.11; P = 0.08 compared with placebo). There was no difference in serious adverse events. Conclusions: An immune response was observed only in vaccine recipients. Adenoma recurrence was not different than placebo, but a 38% absolute reduction in adenoma recurrence compared with placebo was observed in participants who had an immune response at week 12 and with the booster injection.

Abstract Chronic hepatitis C can lead to cirrhosis and hepatocellular carcinoma. We studied the safety and immunogenicity of a novel therapeutic hepatitis C virus (HCV) genotype 1a/1b consensus DNA vaccine, INO-8000, encoding HCV NS3, NS4A, NS4B, and NS5A proteins alone or co-administered with DNA-encoding IL12 (INO-9012), a human cytokine that stimulates cellular immune function, in individuals with chronic hepatitis C. This was a phase I, multisite dose-escalation trial with an expansion cohort evaluating doses of 0, 0.3, 1.0, and 3.0 mg of INO-9012 (IL12 DNA) as an addition to 6.0 mg of (INO-8000; HCV DNA vaccine). Vaccines were administered by intramuscular injection followed by electroporation at study entry and at weeks 4, 12, and 24. HCV-specific CD4+ and CD8+ T-cell immune responses were measured by IFNγ ELISpot and flow cytometry–based assays. Transient, mild-to-moderate injection site reactions unrelated to IL12 DNA dose were common. Increases in HCV-specific IFNγ production occurred in 15/20 (75%) participants. Increases in the frequency of HCV-specific CD4+ and CD8+ T cells occurred at all dose levels, with the greatest increases seen at 1.0 mg of INO-9012. HCV-specific CD8+ and CD4+ T-cell activities increased in 16/18 (89%) and 14/17 (82%) participants with available data, respectively. The vaccine regimen was safe and induced HCV-specific CD4+ and CD8+ cellular immune responses of modest magnitude in most HCV-infected participants. The addition of 1.0 mg of IL12 DNA provided the best enhancement of immune responses. The vaccine regimen had little effect on controlling HCV viremia. Prevention Relevance: The administration of IL12 DNA along with a hepatitis C viral antigen DNA vaccine enhanced the HCV-specific immune responses induced by the vaccine in individuals with chronic hepatitis C, an important cause of hepatocellular carcinoma. IL12 could be an effective adjuvant in vaccines targeting HCV and other oncogenic viruses.

Importance Patients with familial adenomatous polyposis (FAP) are at markedly increased risk for duodenal adenomas and cancer. Combination sulindac and erlotinib was previously shown to reduce duodenal polyp burden but was associated with a relatively high adverse event (AE) rate. Objective: To evaluate if a once weekly dosing schedule for erlotinib intervention improves the AE profile, while still providing efficacy with respect to reduced polyp burden, in participants with FAP. Design, setting and participants: Single-arm trial, enrolling 46 participants with FAP, conducted from October 2017 to September 2019 in eight academic cancer centres. Exposures Participants self-administered 350 mg of erlotinib by mouth, one time per week for 6 months. Main outcomes and measures: Duodenal polyp burden (sum of polyp diameters) was assessed in the proximal duodenum by esophagogastroduodenoscopy performed at baseline and 6 months, with mean per cent change defined as the primary efficacy outcome of interest. Rate of grade 2–3 AEs was evaluated as a co-primary outcome. Secondary outcomes included changes in total duodenal polyp count, along with changes in lower gastrointestinal (GI) polyp burden and count (for participants examined by optional lower endoscopy). Results Forty-six participants (mean age, 44.1 years (range, 18–68); women, 22 (48%)) were enrolled; 42 participants completed 6 months of intervention and were included in the per-protocol analysis. Duodenal polyp burden was significantly reduced after 6 months of weekly erlotinib intervention, with a mean per cent change of −29.6% (95% CI, −39.6% to −19.7%; p<0.0001). Similar results were observed in subgroup analyses defined by participants with advanced duodenal polyposis (Spigelman 3) at baseline (mean, −27%; 95% CI, −38.7% to −15.2%; p<0.0001). Post-intervention Spigelman stage was downstaged in 12% of the participants. Lower GI polyp number was also decreased after 6 months of intervention (median, −30.8%; IQR, −47.4% to 0.0%; p=0.0256). Grade 2 or 3 AEs were reported in 71.7% of subjects, with only two experiencing grade 3 toxicity at least possibly related to intervention. Conclusion In this single-arm, multi-centre trial of participants with FAP, erlotinib one time per week resulted in markedly lower duodenal polyp burden, and modestly reduced lower GI polyp burden, after 6 months of intervention. While AEs were still reported by nearly three-quarters of all participants, these events were generally lower grade and well-tolerated. These findings support further investigation of erlotinib as an effective, acceptable cancer preventive agent for FAP-associated GI polyposis. Trial registration number NCT02961374 .

Abstract Background: Immunoprevention via targeting antigens aberrantly expressed on colorectal cancers and adenomatous polyps offers the potential for a less invasive prevention strategy than endoscopic surveillance. Specificity of the immune response and long-term memory provide the potential for prolonged protection. Leveraging the infrastructure of the NCI-funded Cancer Prevention Network (CPN) consortium, we are conducting a double-blind randomized trial in individuals with a diagnosis of advanced colorectal adenomas within the previous year. We are evaluating MUC1 vaccine with the TLR-3 agonist polyICLC as an adjuvant, for its immunogenicity, ability to elicit immune memory and prevent recurrence of colorectal adenomas. Aims: We previously reported on the vaccine immunogenicity at week 12 (vaccine administered at 0, 2, and 10 weeks) compared to placebo. Here we report the ability of the vaccine to elicit long-term memory by measuring increase in anti-MUC1 antibody levels following a booster administered at one year. Methods: Subjects with endoscopically resected advanced adenoma (defined as ≥1cm, tubululovillous or villous histology, or with high grade dysplasia) were randomized. The primary endpoint was the response to the vaccine at week 12 assessed by monitoring anti-MUC1 IgG antibody titer ratio defined as t12/t0, where t0 was the titer pre-vaccination, and t12 was the titer at week 12. The key secondary endpoint was to assess anti-MUC1 IgG response at week 55 to a booster at week 52 in the vaccine arm compared to placebo. Results: 102 eligible subjects were randomized at 6 centers, 52 received MUC1 vaccine and 50 placebo. The mean age was 59.4±7.0 (range 40-70), 60.8% male, 88.2% white, and 18.6% Hispanic or Latino ethnicity. At 12 weeks the IgG ratio was ≥2.0 in 13/52 (25%) of individuals receiving vaccine (ratio range -0.5-17.3), vs. 0/50 in placebo group (2-sided p=.0001), and was ≥1.5 in 19/52 (36.5%) individuals receiving vaccine compared to 1/50 (2%) in placebo group (P&lt;.0001). To evaluate immune memory, 1-year booster data available for 95 patients (51-MUC1, 44-placebo) were analyzed. 10/13 (76.9%) of the week 12 vs. week 0 vaccine responders showed a response at week 52 vs. baseline and 11/13 (84.6%) at week 55 vs. week 52. Using an IgG ratio of 2 (per-protocol), the response rate was 33% for MUC1 vs. 5% for placebo (1-sided p=0.0003). Using a ratio of 1.5 yielded similar results (37% MUC1 vs. 9% Placebo (1-sided p=0.0008). The MUC1 arm had significantly higher IgG at week 52 (1-sided p=0.0294), week 55 (1-sided p=0.0048), and significantly higher week 55 to week 52 IgG ratio values (1-sided p=0.0293). Conclusions: Subjects with a recent history of advanced adenoma receiving a MUC1 vaccine compared with a placebo were significantly more likely to develop an immune response at week 12, confirming the vaccine’s immunogenicity, and to respond again at week 55 to a booster injection on week 52, confirming the vaccine’s ability to elicit immune memory. Follow-up colonoscopy to evaluate the vaccine’s potential to lower adenomatous polyp recurrence rates are in progress. Citation Format: Olivera J. Finn, Lisa Boardman, Marcia Cruz-Correa, Ajay Bansal, David Kastenberg, Chin Hurr, Sharon Kaufman, Colleen Akerley, Lynda Dzubinski, April Felt, Karrie Fursa, L.M. Rodriguez, Ellen Richmond, Asad Umar, Eva Szabo, John McKolanis, Ryan McMurray, Nathan Foster, Andres Salazar, Paul Limburg, Robert Schoen. Randomized, double-blind, placebo-controlled trial of preventative MUC1 vaccine in patients with newly diagnosed advanced adenomas: Results from one-year booster [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT236.

Abstract Background: Immunotherapy targeting tumor-associated antigens aberrantly expressed on colorectal cancers and adenomatous polyps offers the potential for a relatively non-invasive and non-toxic prevention strategy, and because of the specificity of the immune response and its long-term memory, the potential for prolonged protection. In a double-blind randomized trial in patients with a diagnosis of advanced colorectal adenomas within the previous year, we are evaluating MUC1 vaccine with the TLR-3 agonist polyICLC (Hiltonol®) as an adjuvant, for its immunogenicity and effect on colorectal adenoma recurrence at follow up colonoscopy. Aim: We report on a primary endpoint, MUC1 immunogenicity at week 12 (following vaccine or placebo administration at 0, 2, and 10 weeks), and on determinants of the immune response and vaccine toxicity. Methods: Subjects with an advanced adenoma (defined as ≥1cm, tubulovillous or villous histology, or with HGD) were randomized. Response to the vaccine was assessed by monitoring IgG anti-MUC1 antibody titer ratio; defined as t12/t0, where t0 is the initial titer measured prior to vaccination, and t12 is the titer drawn at 12 weeks. A ratio of 2.0 was used as the primary definition of a significant immune response. T Regulatory and myleoid derived suppressor cell (MDSC) levels at baseline were assessed in relation to vaccine response. Adverse events (AEs) were recorded according to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Results: 102 subjects were randomized at 6 centers, 52 received MUC1 vaccine and 50 placebo. Subjects had a mean age of 59.4±7.0 (range 40-70) years, 60.8% were male, 88.2% were white, and 18.6% Hispanic or Latino. At 12 weeks the IgG ratio was ≥2.0 in 13/52 (25%) of patients receiving vaccine (ratio range 2.9-17.3), vs. 0/50 in placebo group (P=.0001), and was ≥1.5 in 19/52 (36.5%) of patients receiving vaccine compared to 1/50 (2%) in placebo group (P&lt;.0001). In the vaccinated group, the IgG ratio was ≥2.0 in 45% of women (9/20) vs. 12.5% of men (4/32) (P=0.009) and ≥1.5 in 55% of women (11/20) vs. 25% of men (8/32) (P=0.03). In the vaccinated group, reduced levels of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) pre-vaccination were associated with response, 0.2±0.1 among responders (n=13) vs. 0.8±1.1 among non-responders (N=39) (p=0.0006) whereas monocytic MDSC and T regulatory cells (CD4+CD25, Foxp3) were not. There were no grade 3 adverse events (AE) possibly or probably related to the vaccine. The most common AE was an injection site reaction (grade 1 or 2) which occurred in 80.8% (n=42/52) in vaccine group vs. 6.0% in the placebo group (3/50). Conclusions: Subjects with an advanced adenoma receiving MUC1 vaccine compared with a placebo are significantly more likely to develop an anti-IgG MUC1 immune response at 12 weeks. Women and subjects with lower circulating PMN-MDSC levels at baseline were more likely to respond. The vaccine was well tolerated. Follow up for the effect of the vaccine on adenomatous polyp recurrence is ongoing. Citation Format: Robert E. Schoen, Lisa A. Boardman, Marcia Cruz-Correa, Ajay Bansal, Pamela L. Beatty, David Kastenberg, Chin Hur, Lynda Dzubinski, Luz Rodriguez, Andres Salazar, John McKolanis, Drew Seisler, Nathan R. Foster, May-Yin Polley, Paul J. Limburg, Olivera J. Finn. Randomized, double-blind, placebo-controlled immunoprevention trial with MUC1 vaccine in patients with newly diagnosed advanced adenomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-305.

Abstract Sulindac, atorvastatin, or prebiotic dietary fiber may reduce colorectal cancer (CRC) risk. However, clinical trial data are currently limited. We conducted a randomized, phase II chemoprevention trial involving subjects 40 years or older, with previously resected colon cancer or multiple/advanced colorectal adenomas. Magnification chromoendoscopy (MCE) was performed to identify and characterize rectal aberrant crypt foci (ACF); eligibility criteria required five or more rectal ACFs at baseline. Intervention assignments were as follows: (a) atorvastatin 20 mg qd; (b) sulindac 150 mg bid; (c) oligofructose-enriched inulin (as ORAFTI®Synergy1) 6 gm bid; or (d) control (maltodextrin) 6 gm bid, for 6 months. Percent change in rectal ACF number (%ΔACF) within arm was the primary endpoint. Secondary endpoints included changes in proliferation (Ki67) and apoptosis (caspase-3), as measured from normal mucosa biopsy samples. Among 85 eligible randomized subjects, 76 (86%) completed the trial per protocol. The median (range) of rectal ACF was 9 (5–34) and 8 (0–37) at baseline and postintervention, respectively. The median (SD) for %ΔACF was 5.6 (−69% to 143%), −18.6 (−83% to 160%), −3.6 (−88% to 83%), and −10.0 (−100% to 117%) in the atorvastatin, sulindac, ORAFTI®Synergy1 and control arms, respectively. Neither within-arm (P = 0.12–0.59) nor between-arm (P = 0.30–0.92) comparisons of %ΔACF were statistically significant. The active and control interventions also seemed to have similar effects on mucosal proliferation and apoptosis (P &gt; 0.05 for each comparison). Data from this multicenter, phase II trial do not provide convincing evidence of CRC risk reduction from 6-month interventions with atorvastatin, sulindac, or ORAFTI®Synergy1, although statistical power was limited by the relatively small sample size. Cancer Prev Res; 4(2); 259–69. ©2011 AACR.