A phase I study of IMP321 and gemcitabine as the front-line therapy in patients with advanced pancreatic adenocarcinoma

Abstract

Purpose This phase I study was conducted to determine the safety profile and maximum tolerated dose (MTD) of IMP321, a soluble lymphocyte activation gene-3 (LAG-3) Ig fusion protein and MHC Class II agonist, combined with gemcitabine in patients with advanced pancreatic adenocarcinoma. Patients and methods Patients with advanced pancreatic adenocarcinoma were treated with gemcitabine (1,000 mg/m2)(level 1), gemcitabine (1,000 mg/m2) plus IMP 321 at 0.5 mg (level 2) and 2.0 mg (level 3), respectively. Safety, toxicity, and immunological markers at baseline and post treatment were assessed. Results A total of 18 patients were enrolled to the study, and 17 were evaluable for toxicity. None of the 6 patients who received 0.5 mg IMP321 experienced IMP321-related adverse events. Of the 5 patients who received IMP321 at the 2 mg dose level, 1 experienced rash, 1 reported hot flashes and 2 had mild pain at the injection sites. No severe adverse events previously attributed to IMP321 were observed. No significant differences were observed when comparing pre- and post-treatment levels of monocytes (CD11b+CD14+), conventional dendritic cells (CD11c+) or T cell subsets (CD4, CD8). Conclusions IMP321 in combination with gemcitabine is a well-tolerated regimen. IMP321 did not result in any severe adverse events. No incremental activity observed for the additional IMP 321 to gemcitabine at the dose levels evaluated, likely due to sub-optimal dosing. Immunological markers suggested that higher dose levels of IMP321 are needed for future clinical studies.

Immunotherapy against endocrine malignancies: immune checkpoint inhibitors lead the way

“…Inspired by the success of checkpoint inhibitors, several other checkpoints are now under investigation as targets for monotherapy or as combination therapy, including lymphocyte activation gene-3 (LAG-3), T-cell immunoglobulin mucin-3 (TIM-3) and indoleamine-2,3-dioxygenase (IDO) (Brignone et al 2010, Wang-Gillam et al 2013, Beatty et al 2017). (Grosso et al 2007, Assal et al 2015.…”

“…In the last few years, studies have investigated the use of IMP321, a LAG-3-Ig recombinant fusion protein that antagonizes the normal function of LAG-3. These studies were focused on renal cell carcinoma (Brignone et al 2009), metastatic breast carcinoma (Brignone et al 2010) and advanced pancreatic adenocarcinoma (Wang-Gillam et al 2013). All these studies showed promising results regarding the effect of LAG-3 in reducing tumor size.…”

Emerging immune checkpoints for cancer therapy

“…When combined with paclitaxel, iMP321 has exerted immune enhancement and tumor inhibition with no significant iMP321-related adverse events [63]. in addition, in a phase i study focusing on pancreatic adenocarcinoma [19], iMP321 was tested combined with gemcitabine, appearing to be a safe regimen but only with limited antitumor responses possibly due to low doses of iMP321. So doses larger than 6 mg has been recommended in future US trials [19].…”

“…in addition, in a phase i study focusing on pancreatic adenocarcinoma [19], iMP321 was tested combined with gemcitabine, appearing to be a safe regimen but only with limited antitumor responses possibly due to low doses of iMP321. So doses larger than 6 mg has been recommended in future US trials [19]. Besides, a small trial combining iMP321 and melanoma-associated antigen immunization in melanoma patients is still ongoing (nCT01308294).…”

“…A few other checkpoints also have potential for anticancer immunotherapy, such as lymphocyte activation gene-3 (LAg-3) [19], T-cell membrane protein-3 (TiM-3) [20], signal transducer and activator of transcription 3 (STAT3) [21], and glucocorticoid-induced tumor necrosis factor receptor (TnFR) family related protein (giTR) [22] have also entered the clinical trials arena. Here, we review the role and application of LAg-3 and TiM-3 for cancer immunotherapy.…”