Mark O. Hardin

Standard vs Expanded Indications for Esophageal Magnetic Sphincter Augmentation for Reflux Disease

PACIFIC COAST SURGICAL ASSOCIATION Standard vs Expanded Indications for Esophageal Magnetic Sphincter Augmentation for Reflux Disease Magnetic sphincter augmentation (MSA) has proven to be safe and effective for appropriate candidates with gastroesophageal refluxdisease(GERD).1 Standardindicationsincludepatientswith GERD, normal motility, body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) <35, no prior foregut surgery, and no or small (<3 cm) hiatal defect. Although many surgeons are now offering MSA to candidates with expanded criteria, there are scant data on outcomes in these patients. Our aim was to evaluate the postoperative outcomes associated with MSA for expanded indications.

Interim analysis of a phase I/IIa trial assessing E39+GM-CSF, a folate binding protein vaccine, to prevent recurrence in ovarian and endometrial cancer patients

BACKGROUND Folate binding protein(FBP) is an immunogenic protein over-expressed in endometrial(EC) and ovarian cancer(OC). We are conducting a phase I/IIa trial of E39 (GALE 301)+GM-CSF, an HLA-A2-restricted, FBP-derived peptide vaccine to prevent recurrences in disease-free EC and OC patients. This interim analysis summarizes toxicity, immunologic responses, and clinical outcomes to date. METHODS HLA-A2+ patients were vaccinated(VG), and HLA-A2- or -A2+ patients were followed as controls(CG). Six monthly intradermal inoculations of E39+250mcg GM-CSF were administered to VG. Demographic, safety, immunologic, and recurrence rate(RR) data were collected and evaluated. RESULTS This trial enrolled 51 patients; 29 in the VG and 22 in the CG. Fifteen patients received 1000mcg E39, and 14 received <1000mcg. There were no clinicopathologic differences between groups(all p = 0.1). E39 was well-tolerated regardless of dose. DTH increased pre- to post-vaccination (5.71.5 mm vs 10.33.0 mm, p = 0.06) in the VG, and increased more in the 1000mcg group (3.82.0 mm vs 9.53.5 mm, p = 0.03). With 12 months median follow-up, the RR was 41% (VG) vs 55% (CG), p = 0.41. Among the 1000mcg patients, the RR was 13.3% vs 55% CG, p = 0.01. Estimated 2-year DFS was 85.7% in the 1000mcg group vs 33.6% in the CG (p = 0.021). CONCLUSIONS This phase I/IIa trial reveals that E39+GM-CSF is well-tolerated and elicits a strong, dose-dependent in vivo immune response. Early efficacy results are promising in the 1000 mcg dose cohort. This study proves the safety and establishes the dose of E39 for a larger prospective, randomized, controlled trial in HLA-A2+ EC and OC patients to prevent recurrence.

The true impact of breast magnetic resonance imaging on the management of in situ disease: more is not better.

BACKGROUND The optimal role of breast magnetic resonance imaging (MRI) in the management of ductal carcinoma in situ (DCIS) remains controversial. We sought to better define the impact of breast MRIs when utilized during the workup of DCIS. METHODS Patients with biopsy-proven DCIS without any additional invasive disease were prospectively enrolled in the multidisciplinary breast cancer pathway and comprised the study group. Patients who met any additional criteria for MRI screening were excluded. RESULTS From 2008 to 2014, 93 women met the inclusion criteria. 81 patients underwent MRI as part of their workup. One patient benefited from MRI via identification of occult malignancy not previously identified. 35 MRIs identified no additional information whereas 46 had additional findings. These findings led to 23 procedures and 16 negative biopsies; recommendations for 16 radiographic studies that were normal; and influenced nodal sampling in 7 women with 1 positive metastatic focus. CONCLUSIONS The routine use of breast MRI for women diagnosed with DCIS has limited benefit. Often, it leads to multiple procedures and studies that are clinically insignificant and delays surgical treatment.

Tumor lysate particle loaded dendritic cell vaccine: preclinical testing of a novel personalized cancer vaccine

AIM We developed a novel approach to efficiently deliver autologous tumor antigens to the cytoplasm of dendritic cells (DC) using yeast cell wall particles (YCWP). MATERIALS AND METHODS Loading of YCWP, leakage of protein from loaded YCWP and cytoplasmic delivery of YCWP content was assessed using fluorescent-tagged experiments. Spectrophotometric analysis compared the epitope-specific T-cell responses following antigen presentation via YCWP versus exogenous loading. The in vivo effectiveness of tumor lysate (TL) particle loaded DC (TLPLDC) vaccine was assessed using murine melanoma models. RESULTS In fluorescence-tagged experiments, YCWP efficiently delivered antigen to the cytoplasm of DC. TLPLDC loading was more effective than conventional exogenous loading of DC. Finally, in murine melanoma models, TLPLDC outperformed an analogous dendritoma vaccine. CONCLUSION The TLPLDC vaccine is commercially scalable and holds the potential of producing personalized vaccines.

Initial phase I/IIa trial results of an autologous tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine in patients with solid tumors

INTRODUCTION Tumor vaccines use various strategies to generate immune responses, commonly targeting generic tumor-associated antigens. The tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine is produced from DC loaded with autologous tumor antigens, creating a patient-specific vaccine. Here, we describe initial phase I/IIa trial results. METHODS This trial includes patients with any stage solid tumors, ECOG ≤1, and >4 months life-expectancy. A personalized vaccine is created using 1 mg of tumor and 120 ml blood (to isolate DC). Primary vaccination series (PVS) is four monthly inoculations. Patients are followed per standard of care (SOC). Endpoints include safety and tumor response (RECIST v1.1). RESULTS 44 patients were enrolled and vaccinated consisting of 31 late stage patients with residual/measurable disease, and 13 disease-free patients after SOC therapies. While 4 patients progressed before completing the PVS, 12/31 (39%) demonstrated clinical benefit (2 complete responses, 4 partial responses, 6 stable disease). In the adjuvant setting, 46% of late stage patients remain disease free at a median of 22.5 months. CONCLUSIONS The TLPLDC vaccine is scalable, generates a personalized DC vaccine, and requires little autologous tumor tissue and few DC. The vaccine is safe, with primarily grade 0-2 toxicities, and nearly 40% clinical benefit rate in varied tumors, warranting further study. TRIAL REGISTRATION ISRCTN81339386, Registered 2/17/2016.

Abstract CT162: Pre-specified interim analysis in a prospective, randomized phase II trial of trastuzumab vs trastuzumab + NeuVax to prevent breast cancer recurrence in HER2+ breast cancer patients

Introduction: The HER2-targeted monoclonal antibody, trastuzumab (Tz), is standard of care (SOC) for HER2-positive (HER2+) breast cancer (BCa) and has been shown to reduce recurrence. We have previously shown that NeuVax (E75 peptide + GM-CSF), a HER2-targeted peptide vaccine, is safe, immunogenic, and may have synergistic clinical efficacy when combined with Tz. Given the known cardiac toxicity of Tz, there is concern that adding a HER2-directed vaccine to Tz therapy may exacerbate this effect. We are currently enrolling patients (pts) in a multi-center, prospective, randomized, single-blinded, placebo-controlled phase II trial combining Tz and Neuvax in the adjuvant setting to prevent recurrence in HER2+ BCa pts. Here, we present the initial safety data. Methods: HLA-A2/A3+ BCa pts with stage I-III HER2+ disease at high risk for recurrence (pts not achieving complete response after Tz-containing neoadjuvant therapy or those undergoing up-front surgery with any node-positive disease if ER/PR- or ≥4 positive nodes if ER/PR+) were enrolled after SOC surgery, radiation and neo-adjuvant/adjuvant chemotherapy with approved Tz-containing regimen. Pts were randomized to receive Tz and NeuVax in the vaccine group (VG) or Tz and GM-CSF only in the control group (CG). Pts received vaccinations of NeuVax or GM-CSF intradermally every 3 weeks for 6 total vaccinations (primary vaccine series, PVS) starting with the third dose of Tz maintenance therapy. Starting 6 months after the completion of the PVS, pts received four booster inoculations, one every 6 months. Cardiac ejection fraction (EF) was assessed by either echo or MUGA at baseline and serially during treatment. Demographic and safety data were collected and analyzed. Safety analysis was initiated after enrollment of the 50th patient. Results: To date, we have enrolled 50 pts (VG n=22, CG n=28). There were no significant clinicopathologic differences between groups. There were no related grade 4 or 5 toxicities and no differences in related toxicities between the VG and CG (Grade 1: 96% vs 98.5%; Grade 2: 3.2% vs 1.5%; Grade 3: 0.8% vs 0%, p=0.14). There was no significant reduction in EF pre- to post-treatment in either group (VG: 61.1±5.4% vs 60.1±4.8%, p=0.55; CG: 62.3±5.7% vs 61.9±4.0%, p=0.74) and there was no difference in change between groups (p=0.54). Conclusion: The combination of Tz and Neuvax in HER2+ BCa pts is well tolerated and the cardiac effects from Tz are not worsened by the addition of NeuVax. We will continue to enroll up to our goal of 100 pts in this ongoing trial, and will report immunologic and clinical outcomes in the planned primary analysis after 24-months follow-up. Citation Format: Kaitlin M. Peace, Jennifer K. Litton, Rashmi Murthy, Timothy J. Vreeland, Diane F. Hale, Doreen O. Jackson, John S. Berry, Alfred F. Trappey, Garth S. Herbert, Guy T. Clifton, Mark O. Hardin, George E. Peoples, Elizabeth A. Mittendorf. Pre-specified interim analysis in a prospective, randomized phase II trial of trastuzumab vs trastuzumab + NeuVax to prevent breast cancer recurrence in HER2+ breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT162. doi:10.1158/1538-7445.AM2017-CT162

Abstract B007: Improved disease-free survival in endometrial and ovarian cancer patients with low folate binding protein expression after treatment with the E39 peptide vaccine in a Phase I/IIa trial

Introduction: One of the most encouraging examples of targeted therapy for cancer is trastuzumab, but its success is dependent on levels of expression of its target, HER2. We have found that HER2 expression levels also have a significant impact on the efficacy of HER2-directed peptide vaccines. Analogous to HER2 in breast cancer, Folate Binding Protein (FBP) is over-expressed on ovarian and endometrial cancer cells (up to 80 - 90-fold higher) and increased FBP expression is associated with aggressive disease. As a result, multiple FBP-directed therapies are being developed. We are investigating E39 + GM-CSF, which is an HLA-A2-restricted FBP-derived peptide vaccine used to prevent recurrence in disease-free endometrial and ovarian cancer patients (pts) after standard of care (SOC), multi-modality therapy. We have shown that E39 is safe, effectively generates E39-specific immune responses, and may improve DFS when optimally dosed in a phase I/IIa trial.1 Little is known about the effects of FBP expression levels on FBP-directed therapies, including our E39 vaccine. Purpose: Here, we report clinical outcomes of patients based on FBP expression levels from a phase I/IIa trial of the E39+GM-CSF vaccine given for the prevention of recurrence in disease-free endometrial and ovarian cancer patients. Methods: Disease-free, HLA-A2+ pts were vaccinated (VG), while HLA-A2- pts were followed as untreated controls (CG). The VG received 6 monthly inoculations of E39+GM-CSF, including either 100, 500, or 1000mcg of peptide and 250mcg of GM-CSF. FBP expression testing was performed by immunohistochemistry and the results were graded 0-4+ based on the percentage of positively staining cells. Patient9s tumors were then categorized as low expression (FBPlo) if scored 0-1+ or high expression (FBPhi) if 2-4+. The pts were monitored for evidence of clinical recurrence through the SOC follow-up by their treating oncology team. Demographics, FBP expression and disease-free survival (DFS) were analyzed using appropriate statistical tests. Results: Thirty-eight enrolled pts underwent FBP expression testing (CG n = 20; VG n = 18). There were no clinicopathologic differences between groups (p≥0.1). Nineteen pts were found to be FBPlo (CG, n = 11; VG, n = 8) and 19 were FBPhi (CG, n = 9; VG, n = 10). Median follow up was 16.3 months. There was no significant difference in overall DFS between the CG and the VG (34.6% vs. 34.6%, p = 0.208). In FBPlo pts, there was improved DFS in the VG vs. CG (85.7% vs. 17.5%, p = 0.01) while there was no such difference in FBPhi pts (VG:13.9% vs. CG:44.4%, p = 0.83). Though groups were small, there was a dose-dependent effect on DFS; pts receiving 1000mcg (n = 4) had improved DFS compared to the Conclusion: This phase I/IIa trial has previously demonstrated that E39 is well-tolerated, elicits a strong, dose-dependent in vivo immune response and may improve DFS when properly dosed. This focused analysis based on FBP expression level revealed a DFS benefit in FBPlo, but not FBPhi, endometrial and ovarian cancer pts treated with E39. This may be due to immunotolerance from significantly higher endogenous exposure to the FBP antigen. This is concordant with findings in our trials of HER2-directed peptide vaccines in breast cancer pts. These findings warrant further study as they may have important implications regarding the target population for future E39 peptide vaccine trials. 1. Jackson DO, et al. Interim analysis of a phase I/IIa trial assessing E39+GM-CSF, a folate binding protein vaccine, to prevent recurrence in ovarian and endometrial cancer patients. In Press. Citation Format: Kaitlin M. Peace, Diane F. Hale, Timothy J. Vreeland, Doreen O. Jackson, Julia M. Greene, John S. Berry, IV, Alfred F. Trappey, Garth S. Herbert, Guy T. Clifton, Mark O. Hardin, Kathleen M. Darcy, Chad A. Hamilton, G. Larry Maxwell, George E. Peoples. Improved disease-free survival in endometrial and ovarian cancer patients with low folate binding protein expression after treatment with the E39 peptide vaccine in a Phase I/IIa trial [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B007.