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Purpose: Immunotherapy is currently ineffective for nearly all pancreatic ductal adenocarcinomas (PDAC), largely due to its tumor microenvironment (TME) that lacks antigen-experienced T effector cells (Teff). Vaccine-based immunotherapies are known to activate antigen-specific Teffs in the peripheral blood. To evaluate the effect of vaccine therapy on the PDAC TME, we designed a neoadjuvant and adjuvant clinical trial of an irradiated, GM-CSF-secreting, allogeneic PDAC vaccine (GVAX). Patients and Methods: Eighty-seven eligible patients with resectable PDAC were randomly assigned (1:1:1) to receive GVAX alone or in combination with two forms of low-dose cyclophosphamide. Resected tumors following neoadjuvant immunotherapy were assessed for the formation of tertiary lymphoid aggregates (TLA) in response to treatment. The clinical endpoints are disease-free survival (DFS) and overall survival (OS). Results: The neoadjuvant treatment with GVAX either alone or with two forms of low-dose cyclophosphamide is safe and feasible without adversely increasing the surgical complication rate. Patients in Arm A who received neoadjuvant and adjuvant GVAX alone had a trend toward longer median OS (35.0 months) than that (24.8 months) in the historical controls who received adjuvant GVAX alone. However, Arm C, who received low-dose oral cyclophosphamide in addition to GVAX, had a significantly shorter DFS than Arm A. When comparing patients with OS > 24 months to those with OS < 15 months, longer OS was found to be associated with higher density of intratumoral TLA. Conclusions: It is safe and feasible to use a neoadjuvant immunotherapy approach for PDACs to evaluate early biologic responses. In-depth analysis of TLAs is warranted in future neoadjuvant immunotherapy clinical trials.

TPS758 Background: KRAS mutations are identified in the majority of premalignant lesions that precede pancreatic ductal adenocarcinoma (PDAC). Arising during tumorigenesis, mutant KRAS (mKRAS) neoantigens are less susceptible to central tolerance mechanisms and serve as ideal vaccine targets. Indeed, targeting mKRAS neoantigens with vaccines has shown promising anti-tumor activity in the preclinical setting. For instance, our group previously demonstrated that a Listeria-based vaccine targeting mKRAS G12D combined with Treg-depleting agents can prevent the progression of early pancreatic intraepithelial neoplasia to overt PDAC in a mouse model (Keenan et al, 2014). Building upon this work, the current study aims to determine the safety and immunogenicity of a pooled synthetic long peptide (SLP) mKRAS vaccine in patients identified as high risk for developing PDAC based on family history and germline mutation testing. Methods: This is a single-arm, open-label phase I trial evaluating a pooled SLP mKRAS vaccine in patients at high risk of developing PDAC ( n = 20). The vaccine consists of poly-ICLC adjuvant admixed with SLPs corresponding to six common mKRAS subtypes: G12D, G12R, G12V, G12A, G12C, and G13D. A four-dose series of the mKRAS vaccine is administered on weeks 1, 3, 4, and 17. Following completion of the treatment phase, all patients have the option to continue annual follow-up visits until study closure. Eligible patients must have radiographic evidence of a premalignant pancreatic lesion and fall under at least one of the following three high-risk groups: 1) ≥ 2 familial pancreatic cancer relatives, 2) germline mutation carriers with ≥ 10% lifetime PDAC risk and 3) germline mutation carriers with ~5% lifetime PDAC risk. The co-primary endpoints of this study are safety and T cell response. Safety will be assessed by the frequency and grading of adverse events per NCI CTCAE v5.0. T cell response will be determined by the maximal percent change in IFNγ-producing mKRAS-specific T cell density within 16 weeks post-vaccination compared to baseline. Correlative studies will explore vaccine-associated changes in T cell quality (e.g., memory, exhaustion, poly-functionality, and activation) using mass cytometry analysis of peripheral blood samples. Patient accrual began in April 2022 and is currently ongoing. Clinical trial information: NCT05013216 .

Recent research on genomic profiling of pancreatic ductal adenocarcinoma (PDAC) has identified many potentially actionable alterations. However, the feasibility of using genomic profiling to guide routine clinical decision making for PDAC patients remains unclear. We retrospectively reviewed PDAC patients between October 2013 and December 2017, who underwent treatment at the Johns Hopkins Hospital and had clinical tumor next-generation sequencing (NGS) through commercial resources. Ninety-two patients with 93 tumors tested were included. Forty-eight (52%) patients had potentially curative surgeries. The median time from the tissue available to the NGS testing ordered was 229 days (interquartile range 62–415). A total of three (3%) patients had matched targeted therapies based on genomic profiling results. Genomic profiling guided personalized treatment for PDAC patients is feasible, but the percentage of patients who receive targeted therapy is low. The main challenges are ordering NGS testing early in the clinical course of the disease and the limited evidence of using a targeted approach in these patients. A real-time department level genomic testing ordering system in combination with an evidence-based flagging system for potentially actionable alterations could help address these shortcomings.

Epigenetic therapies may modulate the tumor microenvironment. We evaluated the safety and optimal sequence of combination DNA methyltransferase inhibitor guadecitabine with a granulocyte macrophage-colony-stimulating-factor (GM-CSF) secreting colon cancer (CRC) vaccine (GVAX) using a primary endpoint of change in CD45RO + T cells. 18 patients with advanced CRC enrolled, 11 underwent paired biopsies and were evaluable for the primary endpoint. No significant increase in CD45RO + cells was noted. Grade 3–4 toxicities were expected and manageable. Guadecitabine + GVAX was tolerable but demonstrated no significant immunologic activity in CRC. We report a novel trial design to efficiently evaluate investigational therapies with a primary pharmacodynamic endpoint.Trial registry Clinicaltrials.gov: NCT01966289. Registered 21 October, 2013.

Background Data analysis of specimens from prior clinical trials identified the immune co-simulatory molecule CD137 within the tumor microenvironment(TME) of pancreatic ductal adenocarcinoma(PDAC) that remain to be activated following vaccine induced T cell and PD-1 inhibitory treatments. The requirement of CD137 was subsequently supported by preclinical studies. Therefore, we conducted a clinical trial of combining anti-CD137 agonist antibody urelumab, anti-PD-1 antagonist antibody nivolumab and a GM-CSF-secreting allogeneic tumor cell vaccine(GVAX) as neoadjuvant and adjuvant therapy for resectable PDAC. Methods Patients of >=18 years old with radiographic evidence of resectable PDACs were eligible for Arm C of this trial(NCT02451982) with an accrual goal of 10 evaluable subjects. The primary objective was to evaluate changes in numbers of tumor infiltrating CD137+CD8+ T cells. Secondary objectives were safety, overall survival, disease free survival, and other immune parameters. Patients who underwent R0/R1 resection were considered evaluable. All subjects received 480mg nivolumab and 8 mg urelumab both intravenously one day prior to receiving GVAX intradermally and two weeks before surgical resection (figure 1). After surgery, eligible patients continued to receive 5 combination immunotherapy cycles in addition to standard of care chemotherapy. Treatment-related toxicity and perioperative complications are monitored. Results Between February 2019 and August 2020, we completed planned enrollment and treated 10 evaluable patients, who underwent R0 surgical resection of their PDACs. Nausea is the most common adverse event attributed to urelumab (table 1). Other adverse events and perioperative complication were observed in a type, frequency and degree similar to other treatment arms. After repeated dosing, 1 patient demonstrated grade 1 arthritis; 1 patient demonstrated self-limited, transient grade 2 elevated LFTs; 1 patient developed grade 3 rashes, which responded quickly to oral steroid and did not recur after re-dosing. Interestingly, two out of 10 resected patients demonstrated CAP grade 2 pathologic responses in the resected PDACs after a single neoadjuvant treatment; this was not observed with other treatment cohorts(GVAX alone or GVAX+nivolumab) in this neoadjuvant platform trial. Nine out of 10 resected patients remain disease free after a median follow up of 12 months. Immunology endpoints are being analyzed by multiplex immunohistochemistry, DNA sequencing for neoantigen loads, and RNA/TCR sequencing. Conclusions Previous observations of liver toxicity with urelumab or other T cells agonists and severe immune-related adverse events were not observed in this trial, suggesting urelumab(8 mg) is safe as neoadjuvant/adjuvant therapy in this resectable PDAC patient population. Immune and clinical efficacy of anti-CD137 agonist-based combinations warrant further investigation. Acknowledgements This is an investigator initiated clinical trial and supported by the funding from the Rare Disease Program at Bristol-Myers Squibb. Trial Registration NCT02451982 Ethics Approval The study was approved by the Johns Hopkins Medical Institution Institutional Review Board, approved number IRB00050517

558 Background: Utilizing a vaccine that induces and activates host effector T cells and co-administering it with immune modulating agents that enhance anti-tumor T cell activity is a potential strategy for overcoming pancreatic adenocarcinoma’s (PDA) resistance to immunotherapy. Our prior clinical trial demonstrated a GM-CSF-secreting, allogeneic tumor cell vaccine (GVAX) increases infiltrating CD8+ T cells in PDA. Follow up preclinical work demonstrated therapeutic synergy between GVAX and PD-1inhibition (PD1) with efficacy further enhanced by CD137 agonism (CD137). Methods: This was a 3-arm trial of neoadjuvant & adjuvant GVAX-based therapy in resectable (r) PDA patients (pts). Adults with clinically resectable, untreated PDA were enrolled in 1 of 3 study treatments: Arm A (GVAX alone), Arm B (GVAX + PD1 [Nivolumab]), or arm C (GVAX + PD1 + CD137 [Urelumab]). Treatment was given as follows: Day 1 - Cyclophosphamide 200mg/m2 IV (All Arms), Nivolumab 480mg IV (Arms B, C), Urelumab 8mg IV (Arm C); Day 2 – GVAX ID (All Arms). Pts were treated at 3 timepoints: 1) once 2 weeks prior to surgery; 2) once post-surgical recovery prior to standard of care adjuvant chemotherapy (SOC); 3) every month (up to 4 mo) following completion of SOC (if disease-free). SOC regimes included (m)FOLFIRINOX, Gem +/- Cap/NAB-Paclitaxel. The study was powered for a primary biologic endpoint: treatment-related change in intratumoral CD8+CD137+ T cells. Clinical endpoints included disease-free survival (DFS: time from surgery to recurrence), overall survival (OS: time from surgery to death), and safety. Results: 38 pts (N = 15 [Arm A], N = 13 [Arm B], N = 10 [Arm C]) were eligible for efficacy analysis (had R0/R1 resection) and 45 pts (N = 17 [A], N = 17 [B], N = 11 [C]) were eligible for safety analysis (had ≥1 dose of study treatment). Demographics, surgical pathology features, and SOC durations were similar in all Arms. At median follow up of 23 mo [A], 26 mo [B], and 22 mo [C], median DFS (95% CI) was 14.82 mo (6.0, NA), 16.23 mo (7.49, NA) and not reached (16.33, NA) for Arms A, B, C, respectively. There was no DFS benefit to adding PD1 compared to GVAX alone (HR 0.98 [95% CI 0.42, 2.27], p = 0.96). Combination CD137 + PD1 + GVAX was associated with marginally significant improved DFS compared to GVAX alone (HR 0.38 [95%CI 0.12, 1.19], p = 0.097) and GVAX + PD1 (HR 0.38 [95%CI 0.12, 1.21], p = 0.103). Median OS (95% CI) was 25.0 mo (18.8, NA), 26.4 mo (20.3, NA), and not yet reached for Arms A, B, C, respectively. There were no serious adverse events. In Arm C, 1 pt had grade 3 rash that delayed treatment and there was 1 instance of grade 2 AST/ALT elevation. The biologic endpoint will be reported at the meeting. Conclusions: Despite a small sample size, combining GVAX with dual immune-targeting of PD-1 blockade and CD137 agonism was safe and may enhance DFS in rPDA pts treated in the perioperative and post-adjuvant settings. Clinical trial information: NCT02451982.

Despite recent advances in earlier detection and improvements in chemotherapy, the 5-year survival rate of patients with metastatic colorectal carcinoma remains poor. Immunotherapy is a potentially effective therapeutic approach to the treatment of colorectal carcinoma. Preclinical studies have supported the antitumor activity of immunization with a granulocyte–macrophage colony-stimulating factor (GM-CSF) producing murine colon tumor cell vaccine. A novel colorectal cancer vaccine composed of irradiated, allogeneic human colon cancer cells and GM-CSF-producing bystander cells was developed and tested in combination with a single intravenous low dose of cyclophosphamide in a phase 1 study of patients with metastatic colorectal cancer. A total of nine patients were enrolled onto and treated in this study. Six patients had a history of colorectal adenocarcinoma hepatic metastases and underwent curative metastasectomy, while three other patients had unresectable stage IV disease. This study demonstrates the safety and feasibility of this vaccine administered in patients with metastatic colorectal cancer. At last follow-up, the six patients who underwent curative metastasectomy survived longer than 36 months, and four of these six patients were without disease recurrence. Immunologic correlate results suggest that the GM-CSF-producing colon cancer vaccine enhances the production of anti-MUC1 antibodies. This vaccine is feasible and safe. Future investigation of the efficacy and antitumor immunity of this vaccine is warranted.