Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer

Abstract

Preclinical reports support the concept of synergy between cancer vaccines and immune checkpoint blockade in nonimmunogenic tumors. In particular, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) antibodies have been successfully combined with GM-CSF cell-based vaccines (GVAX). Ipilimumab (anti-CTLA-4) has been tested as a single agent in patients with pancreatic ductal adenocarcinoma (PDA) resulting in a delayed response at a dose of 3 mg/kg. Our study evaluated ipilimumab 10 mg/kg (arm 1) and ipilimumab 10 mg/kg + GVAX (arm 2). A total of 30 patients with previously treated advanced PDA were randomized (1:1). Induction doses were administered every 3 weeks for a total of 4 doses followed by maintenance dosing every 12 weeks. Two patients in arm 1 showed evidence of stable disease (7 and 22 wk) but none demonstrated CA19-9 biochemical responses. In contrast, 3 patients in arm 2 had evidence of prolonged disease stabilization (31, 71, and 81 wk) and 7 patients experienced CA19-9 declines. In 2 of these patients, disease stabilization occurred after an initial period of progression. The median overall survival (OS) (3.6 vs. 5.7 mo, hazards ratio: 0.51, P = 0.072) and 1 year OS (7 vs. 27%) favored arm 2. Similar to prior ipilimumab studies, 20% of patients in each arm had grade 3/4 immune-related adverse events. Among patients with OS > 4.3 months, there was an increase in the peak mesothelin-specific T cells (P = 0.014) and enhancement of the T-cell repertoire (P = 0.031). In conclusion, checkpoint blockade in combination with GVAX has the potential for clinical benefit and should be evaluated in a larger study.

Figure 1. Survival

Kaplan-Meier overall survival curve as of 1/27/2013. One patient in arm 2 (Ipilimumab + GVAX) is still alive.

Figure 2. Longer survival is associated with an induction of CD8⁺mesothelinspecific T cell responses

Mesothelin peptide-specific CD8⁺ T cells were quantitated in pre- and post-treatment PBL using IFNγ ELISPOT assays. A) Mesothelin-specific T cell frequencies measured at baseline, following the first treatment, and at the peak of induction in 19 HLA-A1⁺ and/or HLA-A2⁺ patients receiving at least one treatment. B) Mesothelin-specific T cell frequencies measured at baseline, following the first treatment, at the peak of induction, and following the final treatment in 14 of the 19 patients who received at least two treatments. Patients in both treatment arms (Ipilimumab alone = open triangles; Ipilimumab + GVAX = solid circles) were grouped together based on survival of greater than or less than 4.3 months. Post-treatment T cell levels were compared to baseline levels using Wilcoxon sign-rank tests.

Figure 3. Increased levels of peak and post-induction dose 2 mesothelin-specific T cells are associated with longer survival

Frequencies of mesothelin-specific T cells measured by IFNγ ELISPOT in PBL isolated A) prior to treatment, B) following the initial treatment, C) following the second treatment and D) at the time of peak induction are plotted against overall survival. Linear regressions were performed and respective p values are shown for each timepoint.

Figure 4. Longer survival is associated with post-treatment expansion of the mesothelin-specific CD8⁺ T cell repertoire

The percentage of mesothelin peptides for which enhanced T cell responses were measured following the first (Post Tx1) and final treatments (Post Final Tx) are shown for 14 patients receiving two or more treatments with Ipilimumab alone (open triangles) or Ipilimumab + GVAX (solid circles). A) T cell repertoires in patients grouped based on survival of less than or greater than 4.3 months. Comparisons between group T cell repertoires were made using Mann Whitney tests. B) Changes in mesothelin-specific T cell repertoires in patients surviving 4.3 months or less (left) and greater than 4.3 months (right).

Figure 5. Delayed tumor responses both radiographically and by CA 19-9 tumor marker kinetics in arm 2 only

A) Baseline scan. B) Week 7 scan shows growth from baseline. C) Week 14 (4 weeks post dose 3) scan shows minor response maintained until week 31. D) CA 19-9 responses paralleled clinical response in the same patient. Small arrows denote treatment administration. E) Delayed CA 19-9 response in a patient with localized disease who received steroids (*) for hypophysitis. F) Patient with localized disease that was progressive on CT at week 7 (local progression and new omental lesion) and 14 and then stabilized from week 22 to 81.