Aimee Murphy

Safety and Survival With GVAX Pancreas Prime and Listeria Monocytogenes–Expressing Mesothelin (CRS-207) Boost Vaccines for Metastatic Pancreatic Cancer

PURPOSE GVAX pancreas, granulocyte-macrophage colony-stimulating factor-secreting allogeneic pancreatic tumor cells, induces T-cell immunity to cancer antigens, including mesothelin. GVAX is administered with low-dose cyclophosphamide (Cy) to inhibit regulatory T cells. CRS-207, live-attenuated Listeria monocytogenes-expressing mesothelin, induces innate and adaptive immunity. On the basis of preclinical synergy, we tested prime/boost vaccination with GVAX and CRS-207 in pancreatic adenocarcinoma. PATIENTS AND METHODS Previously treated patients with metastatic pancreatic adenocarcinoma were randomly assigned at a ratio of 2:1 to two doses of Cy/GVAX followed by four doses of CRS-207 (arm A) or six doses of Cy/GVAX (arm B) every 3 weeks. Stable patients were offered additional courses. The primary end point was overall survival (OS) between arms. Secondary end points were safety and clinical response. RESULTS A total of 90 patients were treated (arm A, n = 61; arm B, n = 29); 97% had received prior chemotherapy; 51% had received ≥ two regimens for metastatic disease. Mean number of doses (± standard deviation) administered in arms A and B were 5.5 ± 4.5 and 3.7 ± 2.2, respectively. The most frequent grade 3 to 4 related toxicities were transient fevers, lymphopenia, elevated liver enzymes, and fatigue. OS was 6.1 months in arm A versus 3.9 months in arm B (hazard ratio [HR], 0.59; P = .02). In a prespecified per-protocol analysis of patients who received at least three doses (two doses of Cy/GVAX plus one of CRS-207 or three of Cy/GVAX), OS was 9.7 versus 4.6 months (arm A v B; HR, 0.53; P = .02). Enhanced mesothelin-specific CD8 T-cell responses were associated with longer OS, regardless of treatment arm. CONCLUSION Heterologous prime/boost with Cy/GVAX and CRS-207 extended survival for patients with pancreatic cancer, with minimal toxicity.

A Live-Attenuated Listeria Vaccine (ANZ-100) and a Live-Attenuated Listeria Vaccine Expressing Mesothelin (CRS-207) for Advanced Cancers: Phase I Studies of Safety and Immune Induction

Purpose: Listeria monocytogenes (Lm)-based vaccines stimulate both innate and adaptive immunity. ANZ-100 is a live-attenuated Lm strain (Lm ΔactA/ΔinlB). Uptake by phagocytes in the liver results in local inflammatory responses and activation and recruitment of natural killer (NK) and T cells, in association with increased survival of mice bearing hepatic metastases. The Lm ΔactA/ΔinlB strain, engineered to express human mesothelin (CRS-207), a tumor-associated antigen expressed by a variety of tumors, induces mesothelin-specific T-cell responses against mesothelin-expressing murine tumors. These two phase I studies test ANZ-100 and CRS-207 in subjects with liver metastases and mesothelin-expressing cancers, respectively. Experimental Design: A single intravenous injection of ANZ-100 was evaluated in a dose escalation study in subjects with liver metastases. Nine subjects received 1 × 106, 3 × 107, or 3 × 108 colony-forming units (cfu). CRS-207 was evaluated in a dose-escalation study in subjects with mesothelioma, lung, pancreatic, or ovarian cancers. Seventeen subjects received up to 4 doses of 1 × 108, 3 × 108, 1 × 109, or 1 × 1010 cfu. Results: A single infusion of ANZ-100 was well tolerated to the maximum planned dose. Adverse events included transient laboratory abnormalities and symptoms associated with cytokine release. Multiple infusions of CRS-207 were well tolerated up to 1 × 109 cfu, the determined maximum tolerated dose. Immune activation was observed for both ANZ-100 and CRS-207 as measured by serum cytokine/chemokine levels and NK cell activation. In the CRS-207 study, listeriolysin O and mesothelin-specific T-cell responses were detected and 37% of subjects lived ≥15 months. Conclusions: ANZ-100 and CRS-207 administration was safe and resulted in immune activation. Clin Cancer Res; 18(3); 858–68. ©2011 AACR.

Phase I study of safety and immunogenicity of ADU-623, a live-attenuated listeria monocytogenes vaccine (ΔactA/ΔinlB) expressing EGFRVIII and NY-ESO-1, in patients with who grade III/IV astrocytomas

Meeting abstracts The neo-antigen EGFRvIII is expressed in multiple tumor types, including high-grade astrocytomas. It is associated with a poor prognosis and resistance to conventional therapies such as chemotherapy and radiation that are part of the standard treatment. We propose that

Randomized Phase II study of the safety, efficacy and immune response of GVAX pancreas (with cyclophosphamide) and CRS-207 with or without nivolumab in patients with previously treated metastatic pancreatic adenocarcinoma (STELLAR)

Meeting abstracts A heterologous prime-boost vaccination strategy using GVAX pancreas vaccine and CRS-207 is showing promise in patients with pancreatic adenocarcinoma (PDA) (Le, JCO 2015). Furthermore, blockade of the immune checkpoint programmed death-1 (PD-1) is active in some cancers.

Clinical experience with live-attenuated, double-deleted (LADD) listeria monocytogenes targeting mesothelin-expressing tumors

Immune-based cancer therapies have demonstrated benefit in multiple clinical trials. The interest in using recombinant bacteria as vaccine vectors for active cancer immunotherapy derives in part from their ability to stimulate multiple innate immune pathways and, at the same time, to effectively deliver antigen for presentation to the adaptive immune system. We have developed a vaccine platform based on LADD Listeria monocytogenes (Lm) in which two virulence genes (actA and inlB) have been deleted from the Lm chromosome which leads to a 1,000-fold attenuation without loss of its ability to induce potent innate and adaptive cellular immunity. Our lead therapeutic, CRS-207, engineered to express the tumorassociated antigen mesothelin, has been tested in 3 clinical studies to date. In a Phase 1 study in 17 patients with advanced cancers that express mesothelin, CRS-207 appeared to be well-tolerated at several dose levels and induced mesothelin-specific CD8+ T cell immunity (Le D Clin. Cancer Res 2012). CRS-207 is currently being tested at a dose level of 1×10 CFU in clinical trials with patients with metastatic pancreatic ductal adenocarcinoma (PDA) and in frontline unresectable malignant pleural mesothelioma (MPM). Importantly, no serious adverse events (AEs) related to CRS-207 have been reported in these studies. In the study with metastatic PDA patients, the most common AEs related to administration of the combination immunotherapy treatment (immunomodulatory doses of cyclophosphamide, GVAX pancreas vaccine and CRS-207) were nausea, vomiting, chills, fatigue, fever and injection site reactions (related to intradermal GVAX injections). No accumulative toxicities in subsequent administrations have been observed. Encouragingly, in this randomized, Phase 2 study, PDA patients receiving the immunotherapy combination of cyclophosphamide, GVAX pancreas vaccine and CRS-207 survived significantly longer than subjects receiving cyclophosphamide and GVAX pancreas vaccine alone. The study was stopped for efficacy at the interim analysis based on recommendation by the independent data monitoring committee. Additionally, in the Phase 1b study in MPM patients where CRS-207 is sequenced with chemotherapy, encouraging anti-tumor activity has been observed, with two minor and two partial responses (PRs) in the first 4 patients. Based on these studies, it appears that CRS-207 can be safely administered intravenously to patients with late-stage metastatic disease at doses up to 1×10 CFU, vaccination can induce the intended immune response and may contribute to extended survival in advanced cancer patients.

Anti-mesothelin vaccine CRS-207 with or without low-dose cyclophosphamide plus chemotherapy as front-line treatment for malignant pleural mesothelioma (MPM)

Meeting abstracts CRS-207 is live-attenuated, double-deleted Listeria monocytogenes (LADD) engineered to express the tumor-associated antigen mesothelin which is highly expressed in malignant pleural mesothelioma (MPM). CRS-207 stimulates potent innate and adaptive immunity and in combination with

Long term survivors and immune biomarker analysis of Phase IIa, randomized study of GVAX pancreas and crs-207 immunotherapy in patients with metastatic pancreatic cancer

Meeting abstracts Non-clinical and clinical combination studies with GVAX and live-attenuated, double-deleted (LADD) Listeria monocytogenes strains engineered to express tumor-associated antigens resulted in survival benefit and induction of cellular mediated immune responses. In a Phase IIa

A Phase IIb, randomized, multicenter study of the efficacy of GVAX pancreas vaccine and CRS-207 compared to chemotherapy or to CRS-207 alone in adults with previously-treated metastatic pancreatic adenocarcinoma (eclipse study)

Meeting abstracts A heterologous prime-boost vaccination strategy using GVAX pancreas vaccine and CRS-207 is showing promise in patients with metastatic pancreatic adenocarcinoma (PDA). GVAX is composed of lethally-irradiated, allogeneic pancreatic cancer cells modified to express GM-CSF and