TG01/GM-CSF and adjuvant gemcitabine in patients with resected RAS-mutant adenocarcinoma of the pancreas (CT TG01-01): a single-arm, phase 1/2 trial

Abstract

Background TG01 is the first cancer immunotherapy targeting KRAS oncogenic mutations. This study assessed the safety and efficacy of TG01/GM-CSF in patients with resected pancreatic adenocarcinoma. Methods Patients with stage I or II pancreatic adenocarcinoma who had undergone surgical resection (R0 or R1) received adjuvant gemcitabine with TG01/GM-CSF using two schedules of vaccination. Immune response was defined as a positive delayed-type hypersensitivity (DTH) response and/or positive T-cell proliferation assay. Results Thirty-two patients were enrolled between February 2013 and May 2016. Nineteen were treated with the high antigen burden, with four serious adverse reactions considered possibly related to TG01 treatment, including three allergic reactions. On this basis, a further 13 patients received a modified vaccination schedule with reduced antigen burden, with no serious adverse events related to TG01. Ninety-five percent patients in the main cohort and 92% in the modified cohort had a positive immune response. Median overall survival (OS) was 33.1 months, and median disease-free survival (DFS) was 13.9 months for the main cohort. For the modified cohort, the median OS was 34.3 months and median DFS was 19.5 months. Conclusions TG01/GM-CSF with gemcitabine was well tolerated, with high levels of immune activation. OS and DFS compare favourably with published data for adjuvant gemcitabine. Clinical trial registration This clinical trial was registered at ClinicalTrials.gov (NCT02261714).

Pancreatic Cancer and Immunotherapy: A Clinical Overview

“…Immune stimulatory cytokines, such as IL-2, IL-15, GM-CSF and IFN-α, have been utilized as a subsidiary component in broader immunotherapy approaches in PDAC [57,[108][109][110][111][112][113][114][115]. Solitary cytokine therapy had initial success in PDAC when used in the peri-operative phase [116,117].…”

“…In more than 90% of PDAC patients the KRAS proto-oncogene is mutated, its expression being associated with overall worse prognosis and treatment insensitivity [208]. In clinical trials, a mutant KRAS vaccine has been utilized through an Epstein Barr Virus-transformed lymphoblastoid cell line (CLC) [183] or combined with adjuvant GM-CSF [113,114] in PDAC patients with a confirmed KRAS mutation. Mutant KRAS vaccines combined with gemcitabine as adjuvant therapy have demonstrated encouraging initial results in resected PDAC patients.…”

“…Mutant KRAS vaccines combined with gemcitabine as adjuvant therapy have demonstrated encouraging initial results in resected PDAC patients. Palmer et al [114] published data from a phase 1/2 clinical trial, in which 32 PDAC patients with resected primary tumors received an intradermal injection of a seven-peptide vaccine covering most known mutations of KRAS (TG01), co-administered with recombinant GM-CSF (TG01/GM-CSF), and combined with gemcitabine. Their survival outcomes (mOS 33.1-34.3 months; mPFS 13.9-19.5 months) compared favorably with current literature reporting survival after resection followed by adjuvant gemcitabine (mOS 17-27 months) [209][210][211][212].…”

Challenges and Future Perspectives of Immunotherapy in Pancreatic Cancer

“…Accordingly, multiple peptides or whole cell-based tumour vaccines applied as single agents or in combination with conventional chemotherapy or additional treatment modalities have been explored for the treatment of PDAC. Antigens used for vaccination purposes have been, i.e., Mesothelin, mutated KRAS, Vascular Endothelial Growth Factor Receptors 1 and 2 (VEGFR1, VEGFR2), Kinesin-like Protein KIF20A and Wilms Tumour Protein 1 (WT1) [23][24][25].…”

Targeting neoantigens for cancer immunotherapy

“…The results showed that a lower dose resulted in good safety outcomes, whereas a few severe adverse reactions were observed in the higher-dose group, possibly related to the treatment. Both doses produced strong cellular immunological responses, and subject survival rates at two and three years were approximately 72 and 37 %, respectively [ 64 ]. Taken together, public neoantigen vaccines have proven their great value as therapeutic targets in cancer treatment.…”