A phase I clinical trial of dTCApFs, a derivative of a novel human hormone peptide, for the treatment of advanced/metastatic solid tumors

Abstract

The aim of the present phase I first-in-human study was to investigate the safety/efficacy of dTCApFs (a novel hormone peptide that enters cells through the T1/ST2 receptor), in advanced/metastatic solid tumors. The primary objective of this open-label dose-escalation study was to determine the safety profile of dTCApFs. The study enrolled patients (aged ≥18 years) with pathologically confirmed locally advanced/metastatic solid malignancies, who experienced treatment failure or were unable to tolerate previous standard therapy. The study included 17 patients (64% male; median age, 65 years; 47% colorectal cancer, 29% pancreatic cancer). The patients received 1–3 cycles of escalating dTCApFs doses (6–96 mg/m2). The mean number ± standard deviation of treatment cycles/patient was 3.2±1.4; no dose-limiting toxicities were observed up to a dose of 96 mg/m2, and the maximum tolerated dose was not reached. Half-life, maximal plasma concentration, and dTCApFs exposure were found to be linearly correlated with dose. Five patients were treated for ≥3 months (12, 24, 48 mg/m2) and experienced stable disease throughout the treatment period, and 1 experienced pathological complete response. Analysis of serum biomarkers revealed decreased levels of angiogenic factors at dTCApFs concentrations of 12–48 mg/m2, increased levels of anticancer cytokines, and induction of the endoplasmic reticulum (ER) stress biomarker GRP78/BiP. Efficacy and biomarker data suggest that patients whose tumors were T1/ST2-positive exhibited a better response to dTCApFs. In conclusion, dTCApFs was found to be safe/well-tolerated, and potentially efficacious, with linear pharmacokinetics. Consistent with preclinical studies, the mechanism through which dTCApFs exerts anticancer effects appears to involve induction of ER stress, suppression of angiogenesis, and activation of the innate immune response. However, further studies are warranted.

Anticancer peptide: Physicochemical property, functional aspect and trend in clinical application (Review)

“…For example, dTCApFs, a natural hormone peptide for the treatment of advanced or metastatic solid tumors, enters the cells via the Toll/interleukin-1 receptor superfamily, suppresses angiogenic factors and induces anticancer cytokine production and ER stress, leading to cancer cell apoptosis (208). dTCApFs anticancer activity in humans was firstly studied in a phase I clinical trial by investigating the safety and efficacy with regards to both pharmacokinetics and pharmacodynamics, with intravenous dTCApFs (6-96 mg/m 2 ; 3 times/week; in consecutive 28-day cycles) (209). The intravenous dTCApFs is decreased at lower limit of detection in serum after 24-h administration and its concentration in serum is present in dose-dependent manner (209).…”

“…dTCApFs anticancer activity in humans was firstly studied in a phase I clinical trial by investigating the safety and efficacy with regards to both pharmacokinetics and pharmacodynamics, with intravenous dTCApFs (6-96 mg/m 2 ; 3 times/week; in consecutive 28-day cycles) (209). The intravenous dTCApFs is decreased at lower limit of detection in serum after 24-h administration and its concentration in serum is present in dose-dependent manner (209). Furthermore, ACPs have been combined with immunogens for clinical therapeutic improvement (210).…”

Transformation of immunosuppressive mtKRAS tumors into immunostimulatory tumors by Nerofe and Doxorubicin

“…It has been previously reported in a Phase I clinical trial that Nerofe increases the levels of NK cell activators (IL-21 and IL12p70) and dendritic cell (DC) activators (IL-2 and GM-CSF). This effect was accompanied by the recruitment of NK and DC cells to the tumors, indicating that Nerofe treatment activates the innate immune response [ 21 ]. DOX has previously been associated with myeloid-derived suppressor cell (MDSC) depletion and the induction of immunogenic death [ 11 ].…”

“…Specifically, Nerofe at mid-range doses of 12–48 mg/m2 reduced the expression of multiple angiogenic factors and increased the expression of anticancer cytokines in the serum of treated patients. Furthermore, a retrospective biomarker analysis showed that patients whose tumors expressed higher levels of the Nerofe receptor T1/ST2 exhibited a better response to Nerofe [ 21 ].…”

Bioactive peptides: an alternative therapeutic approach for cancer management

“…For example, dTCAPF, a novel hormonal peptide that enters cells through the toll/interleukin-1 receptor, has been shown to be safe and effective in treating patients with prostate cancer, liver cancer/metastatic cancer. Its anticancer activity appears to be associated with the inhibition of angiogenic factors, induction of anticancer cells activity and proliferation, and endoplasmic reticulum stress ( 34 ). The relationship between antigenic peptides and correlation structure showed that most antigenic peptides have short segments of 3 to 25 amino acids.…”