Cytokine-induced killer (CIK) cells, successes and challenges: report on the first international conference dedicated to the clinical translation of this unique adoptive cell immunotherapy.

On August 30, 2023, experts from Germany and abroad met to discuss the successes and challenges of cytokine-induced killer cell (CIK) therapy, that recently celebrated its 30th anniversary providing treatment for cancer. This first virtual conference was hosted by CIO Bonn, a certified Comprehensive Cancer Center (CCC) funded by German Cancer Aid (DKH). In addition to keynote speakers involved in CIK cell clinical trials or optimized preclinical models to improve this adoptive cell immunotherapy, more than 100 attendees from around the world also participated in this event. Initiatives to establish the International Society of CIK Cells (ISCC) and a stronger CIK cell network guiding preclinical research and future clinical trials were also announced.

Safety and effectiveness of pembrolizumab combined with paclitaxel and cisplatin as neoadjuvant therapy followed by surgery for locally advanced resectable (stage III) esophageal squamous cell carcinoma: a study protocol for a prospective, single-arm, single-center, open-label, phase-II trial (Keystone-001).

Background: Esophageal squamous cell carcinoma (ESCC) is one of the most refractory malignant tumors. Esophageal cancer (EC) is a malignant tumor with a high incidence worldwide, and over 50% of EC cases occur in China. Under the National Comprehensive Cancer Network (NCCN) guidelines, concurrent chemoradiotherapy is the only standard neoadjuvant treatment for locally advanced ESCC. In the first-line treatment of advanced ESCC, the efficacy of immune checkpoint inhibitors (ICIs) combined with systemic chemotherapy is significantly better than that of chemotherapy alone. Paclitaxel and cisplatin (TP), as one of the neoadjuvant chemotherapy regimens for locally advanced ESCC, have been widely used in China in recent years. ICIs combined with TP as neoadjuvant therapy seems promising. Methods: This is an open-label, single-arm, single-center, phase-II trial. Locally advanced resectable (stage III) ESCC patients who have not undergone previous systemic treatments will be enrolled in this study. All the subjects will intravenously receive 3 cycles of pembrolizumab (200 mg) on day 1, paclitaxel (135 mg/m2) on day 2, and cisplatin (20 mg/m2) on days 2-4, every 3 weeks. After an efficacy evaluation, the subjects will undergo Da Vinci robot-assisted radical resection. If the postoperative pathologic results do not reveal a complete response, pembrolizumab will be administrated for at least 6 cycles as an adjuvant therapy with the same usage as before. The primary endpoints are the major pathological response and safety. The secondary endpoints include the objective response rate (ORR), overall survival (OS), disease-free survival (DFS), the R0 resection rate, and perioperative complications. The exploratory endpoint is to examine the correlation between related biomarkers and tumor responses to this neoadjuvant treatment regimen. Discussion: This trial is the first enrolled study to evaluate the safety and efficacy of pembrolizumab combined with TP as neoadjuvant therapy for locally advanced ESCC. Currently, under the NCCN guidelines, neoadjuvant chemoradiotherapy (nCRT) is the only recommended treatment for locally advanced ESCC. This phase-II study will provide preliminary evidence of the efficacy of pembrolizumab combined with TP as novel neoadjuvant therapy for patients with locally advanced ESCC. Trial Registration: Clinicaltrials.gov (Identifier: NCT04389177).

Cereblon harnesses Myc-dependent bioenergetics and activity of CD8+ T lymphocytes.

Immunomodulatory drugs, such as thalidomide and related compounds, potentiate T-cell effector functions. Cereblon (CRBN), a substrate receptor of the DDB1-cullin-RING E3 ubiquitin ligase complex, is the only molecular target for this drug class, where drug-induced, ubiquitin-dependent degradation of known "neosubstrates," such as IKAROS, AIOLOS, and CK1α, accounts for their biological activity. Far less clear is whether these CRBN E3 ligase-modulating compounds disrupt the endogenous functions of CRBN. We report that CRBN functions in a feedback loop that harnesses antigen-specific CD8+ T-cell effector responses. Specifically, Crbn deficiency in murine CD8+ T cells augments their central metabolism manifested as elevated bioenergetics, with supraphysiological levels of polyamines, secondary to enhanced glucose and amino acid transport, and with increased expression of metabolic enzymes, including the polyamine biosynthetic enzyme ornithine decarboxylase. Treatment with CRBN-modulating compounds similarly augments central metabolism of human CD8+ T cells. Notably, the metabolic control of CD8+ T cells by modulating compounds or Crbn deficiency is linked to increased and sustained expression of the master metabolic regulator MYC. Finally, Crbn-deficient T cells have augmented antigen-specific cytolytic activity vs melanoma tumor cells, ex vivo and in vivo, and drive accelerated and highly aggressive graft-versus-host disease. Therefore, CRBN functions to harness the activation of CD8+ T cells, and this phenotype can be exploited by treatment with drugs.

First-line axitinib versus sorafenib in Asian patients with metastatic renal cell carcinoma: exploratory subgroup analyses of Phase III data.

AIM: Efficacy/safety of first-line axitinib in Asian patients with metastatic renal cell carcinoma. METHODS: Patients were assigned (2:1) to 5-mg axitinib (n = 48) or 400-mg sorafenib (n = 24) twice daily. Primary end point was progression-free survival. Objective response rate, overall survival and adverse events were also assessed. RESULTS: For axitinib versus sorafenib, hazard ratio for progression-free survival was 0.652 (95% CI: 0.340-1.252; p = 0.0989), objective response rate was higher (35.4 vs 16.7%; p = 0.0495), overall survival longer (hazard ratio: 0.739; 95% CI: 0.397-1.375; p = 0.1683). Palmar-plantar erythrodysesthesia (57.4%), diarrhea (55.3%), hypertension (51.1%) were commonest adverse events with axitinib; palmar-plantar erythrodysesthesia (50.0%) with sorafenib. CONCLUSION: Axitinib improved efficacy in Asian patients with metastatic renal cell carcinoma; adverse events were consistent with previous findings.

Inhibitory effect of Dendrobium officinale polysaccharide on human gastric cancer cell xenografts in nude mice

Abstract This study investigated the inhibitory effect of Dendrobium officinale polysaccharide (DOPA) on human gastric cancer cell SGC-7901 xenografts in nude mice. The nude mice with SGC-7901 xenografts were randomly divided into model, 5-fluorouracil (5-Fu), low-dose DOPA, middle-dose DOPA and high-dose DOPA group. The later four groups were intragastrically administrated with 100, 200 and 400 mg·kg-1·day-1 DOPA, 400 mg·kg-1·day-1 5-Fu and normal saline, respectively. After treatment for 20 days, the tumor inhibition rate of in high-dose DOPA group was basically equivalent to 5-Fu group. Compared with 5-Fu, DOPA had no obvious toxic side effect on spleen or thymus indexes, routine blood indexes or liver and kidney functions of nude mice. Compared with model group, the serum tumor necrosis factor-α and interleukin-2 levels in middle- and high-dose DOPA group were significantly increased (P < 0.05), Bax protein expression was significantly increased (P < 0.05), and Bcl-2 protein expression was significantly decreased (P < 0.05). DOPA can inhibit the growth of SGC-7901 cell xenografts in nude mice. The mechanism may be related to its increase of serum TNF-α and IL-2 levels, up-regulation of Bax protein expression and down-regulation of Bcl-2 protein expression.

Effects of ulinastatin on early postoperative cognitive function after one-lung ventilation surgery in elderly patients receiving neoadjuvant chemotherapy.

We investigated the effects of ulinastatin on early postoperative cognitive dysfunction (POCD) after one-lung ventilation (OLV) surgery in elderly patients receiving neoadjuvant chemotherapy. Eighty elderly patients with preoperative neoadjuvant chemotherapy scheduling for radical esophagectomy under OLV were recruited. They were randomly divided into an ulinastatin pretreatment group (U group, n = 40) and a control group (C group, n = 40). The U group received 10,000 U/kg ulinastatin before anesthesia and 5000 U/kg daily on postoperative days 1 to 3, while C group received saline. Levels of interleukin (IL)-6, IL-10, C-reactive protein (CRP), and S-100ß protein were assayed before surgery, at the end of surgery, and on postoperative days 1 and 3. Patients underwent cognitive assessment 1 day before and 7 days after surgery. 38 patients in U group and 37 patients in C group completed the neuropsychological tests. The U group had a lower incidence of POCD than C group (23.7 % versus 45.9 %, P = 0.043). The levels of S-100ß protein, IL-6, IL-10, and CRP in both groups increased after surgery. The postoperative concentrations of S-100ß protein, IL-6, and CRP in U group were lower than those in C group. On postoperative day 3, compared with C group, the level of CRP in U group was lower, while that of IL-10 was higher. These findings demonstrate that ulinastatin can attenuate the elevation of S100ß protein levels and the incidence of POCD, most likely by the mechanism of reducing serum IL-6 and CRP levels and increasing IL-10 levels.

Berberine induces caspase-independent cell death in colon tumor cells through activation of apoptosis-inducing factor.

Berberine, an isoquinoline alkaloid derived from plants, is a traditional medicine for treating bacterial diarrhea and intestinal parasite infections. Although berberine has recently been shown to suppress growth of several tumor cell lines, information regarding the effect of berberine on colon tumor growth is limited. Here, we investigated the mechanisms underlying the effects of berberine on regulating the fate of colon tumor cells, specifically the mouse immorto-Min colonic epithelial (IMCE) cells carrying the Apc(min) mutation, and of normal colon epithelial cells, namely young adult mouse colonic epithelium (YAMC) cells. Berberine decreased colon tumor colony formation in agar, and induced cell death and LDH release in a time- and concentration-dependent manner in IMCE cells. In contrast, YAMC cells were not sensitive to berberine-induced cell death. Berberine did not stimulate caspase activation, and PARP cleavage and berberine-induced cell death were not affected by a caspase inhibitor in IMCE cells. Rather, berberine stimulated a caspase-independent cell death mediator, apoptosis-inducing factor (AIF) release from mitochondria and nuclear translocation in a ROS production-dependent manner. Amelioration of berberine-stimulated ROS production or suppression of AIF expression blocked berberine-induced cell death and LDH release in IMCE cells. Furthermore, two targets of ROS production in cells, cathepsin B release from lysosomes and PARP activation were induced by berberine. Blockage of either of these pathways decreased berberine-induced AIF activation and cell death in IMCE cells. Thus, berberine-stimulated ROS production leads to cathepsin B release and PARP activation-dependent AIF activation, resulting in caspase-independent cell death in colon tumor cells. Notably, normal colon epithelial cells are less susceptible to berberine-induced cell death, which suggests the specific inhibitory effects of berberine on colon tumor cell growth.