Sintilimab maintenance therapy post first-line cytokine-induced killer cells plus chemotherapy for extensive-stage small cell lung cancer.

Despite recent progress in treating advanced non-small cell lung cancer, clinical intervention in extensive-stage small-cell lung cancer (ES-SCLC) remains stagnant. The purpose of this study was to evaluate the clinical efficacy of cytokine-induced killer (CIK) cells combined with cytotoxic chemotherapy, followed by anti-programmed death 1 antibody (sintilimab) maintenance, in ES-SCLC patients. To explore a new method for safe treatment of ES-SCLC patients, thirteen ES-SCLC patients were enrolled between June 2019 and December 2021. All patients received first-line chemotherapy (etoposide plus platinum) combined with CIK cell therapy. Patients who reached a stable disease state or responded well to treatment received sintilimab maintenance treatment. The primary objective of this study was to determine the median overall survival (OS); the secondary objective was to assess the objective response rate (ORR), progression-free survival 1 and 2 (PFS1 was defined as the duration from the signing of informed consent to the date of tumor progression, or death, or the last follow-up. PFS2 was defined as the duration from the first day of sintilimab treatment to the date of tumor progression, death, or the last follow-up.), and adverse reactions. At a 24.1-month follow-up, the median OS was 11.8 (95% confidence interval [CI]: 10.6-13.0) months, median PFS1 was 5.5 (95% CI: 5.0-6.0) months, and the median PFS2 was 2.3 (95% CI: 0.5-4.1) months. The ORR was 76.9% (10/13), the disease control rate was 100% (13/13), and the 20-month survival rate was 41.7%. Eight participants exhibited grade 3 or 4 adverse events after combination therapy. During maintenance treatment with sintilimab, level 3 adverse events occurred in 1 patient (1/9). In conclusion, adding CIK cells to standard chemotherapy regimens, followed by maintenance therapy with sintilimab, may represent a new safe and effective treatment strategy. Clinical trial registration: ClinicalTrials.gov (NCT03983759).

The Sequence of Chemotherapy and Toripalimab Might Influence the Efficacy of Neoadjuvant Chemoimmunotherapy in Locally Advanced Esophageal Squamous Cell Cancer-A Phase II Study.

Background: There is no standard neoadjuvant therapy for locally advanced esophageal cancer in China. The role of neoadjuvant chemotherapy plus immunotherapy for locally advanced esophageal cancer is still being explored. Methods: This open-label, randomized phase II study was conducted at a single center between July 2019 and September 2020; 30 patients with locally advanced esophageal squamous cell carcinoma (ESCC) (T3, T4, or lymph-node positive) were enrolled. Patients were randomized according to the enrollment order at a 1:1 ratio to receive chemotherapy on day 1 and toripalimab on day 3 (experimental group) or chemotherapy and toripalimab on day 1 (control group). The chemotherapeutic regimen was paclitaxel and cisplatin. Surgery was performed 4 to 6 weeks after the second cycle of chemoimmunotherapy. The primary endpoint was pathological complete response (pCR) rate, and the secondary endpoint was safety and disease-free survival. Results: Thirty patients completed at least one cycle of chemoimmunotherapy; 11 in the experimental group and 13 in the control group received surgery. R0 resection was performed in all these 24 patients. Four patients (36%) in the experimental group and one (7%) in the control group achieved pCR. The experimental group showed a statistically non-significant higher pCR rate (p = 0.079). PD-L1 combined positive score (CPS) examination was performed in 14 patients; one in the control group had a PD-L1 CPS of 10, and pCR was achieved; the remaining 13 all had ≤1, and 11 of the 13 patients received surgery in which two (in the experimental group) achieved pCR. Two patients endured ≥grade 3 adverse events, and one suffered from grade 3 immune-related enteritis after one cycle of chemoimmunotherapy and dropped off the study. Another patient died from severe pulmonary infection and troponin elevation after surgery. Conclusions: Although the primary endpoint was not met, the initial results of this study showed that delaying toripalimab to day 3 in chemoimmunotherapy might achieve a higher pCR rate than that on the same day, and further large-sample clinical trials are needed to verify this. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03985670.

Long-term survival of a patient with microsatellite-stable refractory colorectal cancer with regorafenib and PD-1 inhibitor sintilimab: a case report and review of literature.

BACKGROUND: Colorectal cancer (CRC) is the third most prevalent cancer worldwide and poses a serious challenge for clinicians. Previous studies have shown promising results in patients with Microsatellite Stable microsatellite-stable CRC refractory to chemotherapy upon treating with (Programmed Cell Death Protein 1) PD-1 inhibitor combined with regorafenib. Herein, we report a unique case of a patient for whom the conventional chemotherapy and radiotherapy were ineffective, but showed a prolonged stable disease with third-line treatment with regorafenib and PD-1 inhibitor, sintilimab. CASE PRESENTATION: A 64-year-old East Asian female patient was admitted to a regional cancer hospital presenting with abdominal unease due to increased stool frequency and bloody stool. Digital anal examination revealed adenocarcinoma, while genetic profiling of the tumor resections detected wild-type KRAS mutations in codon 12 and 13. Microsatellite instability (MSI) analysis for detecting germline mutations of (Mismatch-repair) MMR genes showed stable phenotype. In December 2016, Miles' resection for intestinal adhesion release and iliac vessel exploration in the rectum was performed (Tumor, Node, Metastasis [TNM]: T3N0M0; stage IIA). The adjuvant chemotherapeutic regimen consisted of a combination of capecitabine at 1.5 g (twice daily) and oxaliplatin therapy at 200 mg for three cycles from February 2016; followed by administering capecitabine tablets orally (1.5 g bid) for five cycles as post-operative palliative care. The patient tested positive for hepatic C virus, which was managed by oral antiviral agents. Following recurrence of rectal adenocarcinoma after 4 years and disease progression with a previous chemotherapeutic regimen, regorafenib was administered at 120 mg once daily combined with sintilimab 200 mg, and the patient's progress was monitored. A follow-up computerized tomography imaging in March 2020 showed disease progression, additionally presented nodule formation (TNM: T3NxM1b; stage IVB). According to Response Evaluation Criteria in Solid Tumors criteria (RECIST), the patient showed a complete response (CR) after treatment with regorafenib and sintilimab immunotherapy. CONCLUSION: Data from this clinical case report support future exploration of combination treatment of the oral multi-kinase inhibitor regorafenib with PD-1 targeted monoclonal antibodies in patients with metastatic microsatellite-stable CRC.

T Cells Expanded from PD-1+ Peripheral Blood Lymphocytes Share More Clones with Paired Tumor-Infiltrating Lymphocytes.

Both tumor-infiltrating lymphocytes (TIL) and PD-1+ peripheral blood lymphocytes (PBL) are enriched for tumor-reactive clones recognizing known and unknown tumor antigens. However, the relationship between the T-cell receptor-ß (TCRß) repertoires of the TILs and T cells expanded from paired PD-1+ PBLs, and whether T cells expanded from PD-1+ PBLs can be used to treat patients with cancer as TIL substitutes remain unclear. Here, we established a highly efficient protocol to prepare polyclonal T cells from PD-1+ PBLs. A functional T-cell assay and tetramer staining revealed that cells from PD-1+ PBLs were relatively enriched for tumor-reactive T cells. Furthermore, deep TCRß sequencing data revealed that an average of 11.29% (1.32%-29.06%; P = 0.015; n = 8) tumor-resident clonotypes were found in T cells expanded from paired PD-1+ PBLs, and the mean accumulated frequency of TIL clones found in T cells expanded from PD-1+ PBLs was 35.11% (7.23%-78.02%; P = 0.017; n = 8). Moreover, treatment of four patients, who failed multiline therapy and developed acquired resistance to anti-PD-1, with autologous T cells expanded from PD-1+ PBLs combined with anti-PD-1 antibody elicited objective responses from three of them. These results indicate that T cells expanded from PD-1+ PBLs share more clones with paired TILs and could be used to treat patients with cancer as TIL substitutes. SIGNIFICANCE: This study harnesses the tumor reactivity of PD-1+ PBLs, developing a method to expand T cells from these clones as a potential therapeutic strategy and TIL substitute in patients with cancer.See related commentary by Ladle, p. 1940.

High Complete Response Rate in Patients With Metastatic Renal Cell Carcinoma Receiving Autologous Cytokine-Induced Killer Cell Therapy Plus Anti-Programmed Death-1 Agent: A Single-Center Study.

Background and Objective: The results of the CheckMate 025 trial established the status of nivolumab in the second-line treatment of metastatic renal cell carcinoma (mRCC), with an objective response rate (ORR) of 25% and a complete response (CR) rate of 1%. Thus, the efficacy of anti-programmed death (PD)-1 antibodies in the second-line treatment of mRCC requires improvement. The purpose of this study was to explore the clinical efficacy and safety of anti-PD-1 agents combined with cytokine-induced killer (CIK) cell therapy for refractory mRCC. Patients and Methods: Patients with mRCC refractory to previous targeted therapy were included in this study. All patients received anti-PD-1 plus CIK cell therapy. The ORR and CR rate, progression-free survival (PFS), overall survival (OS), and safety were assessed. Results: CR was observed in seven of the 29 patients, and partial response was observed in five patients. The ORR was 41.4% and the median PFS was 15.0 months. Up to the last follow-up, 15 patients died with an average survival time of 37 months. Among the patients who achieved a CR, one experienced cerebellar metastasis 18.8 months after discontinuation, but achieved CR again after localized gamma knife and 1-month axitinib treatment. This regimen was tolerated well and there was no treatment-related death. Conclusions: Combination therapy with anti-PD-1 and CIK cell therapy is safe and effective in patients with mRCC refractory to previous targeted therapy. The high CR rate and long disease-free survival even after long-term discontinued therapy suggest that this combination treatment may represent a potential curative regimen for this type of malignancy.

Factors Influencing the Efficacy of Anti-PD-1 Therapy in Chinese Patients with Advanced Melanoma.

PURPOSE: Anti-PD-1 antibody improves the survival of patients with advanced melanoma. However, the efficacy and safety of anti-programmed death protein 1 (PD-1) antibody have not been fully elucidated in Chinese melanoma patients, who show high frequency of mucosal and acral melanoma subtypes; besides, the factors influencing the efficacy of anti-PD-1 antibody have not been evaluated broadly. PATIENTS AND METHODS: Patients with advanced melanoma treated with regimens containing anti-PD-1 antibody from June 2016 to January 2019 were evaluated. Baseline characteristics and blood parameters were assessed, and outcome and adverse events were evaluated according to different regimens. The Cox proportional hazards regression model was used for univariate and multivariate analyses. RESULTS: A total of 51 patients with advanced melanoma were included in this study. The overall objective response rate (ORR) was 17.6%, the disease control rate was 58.5%, and the median time to progression was 5.2 months. The ORR of patients with PD-1 blockade-based combination therapy, without liver metastases and higher level of C-reactive protein (CRP) before PD-1 blockade, is higher than that of those not. Univariate analysis based on clinical features showed that ECOG scores, liver metastasis, elevated lactate dehydrogenase (LDH), and CRP levels were the factors affecting time to progression (TTP). Multivariate analysis showed that elevated CRP before PD-1 blockade was an independent predictive factor for ORR of PD-1 blockade therapy (P=0.009), while only Eastern Cooperative Oncology Group (ECOG) score was an independent predictor for TTP (P=0.032). The treatment was well tolerated in these cohort patients, and there was no treatment-related death. CONCLUSION: Anti-PD-1 antibody-containing regimen was safe and effective in Chinese patients with advanced melanoma, and elevated CRP and ECOG score were independent factors predicting the efficacy of anti-PD-1 therapy.

Clinical value of neutrophil-to-lymphocyte ratio as a predictor of prognosis of RetroNectin®-activated cytokine-induced killer cell therapy in advanced non-small-cell lung cancer.

AIM: To assess the impact of neutrophil-to-lymphocyte ratio (NLR) on time to progression (TTP) and overall survival (OS) and explore the value of NLR as an indicator in patients with non-small-cell lung cancer (NSCLC) treated with RetroNectin®-activated cytokine-induced killer (R-CIK) cells. PATIENTS & METHODS: Using data gathered from a single center between January 2010 and June 2015, 201 patients with stage IIIB or IV NSCLC receiving at least four cycles of R-CIK cell therapy were included. Univariate and multivariate Cox regression analyses were performed to evaluate the associations of NLR with TTP and OS. RESULTS: The pretreatment NLR was correlated with TTP and OS. Multivariate analysis showed that NLR was an independent factor for survival. CONCLUSION: NLR was an independent indicator to predict benefit from R-CIK-based combination therapy.

Combination of PD-1 blockade and RetroNectin®-activated cytokine-induced killer in preheavily treated non-small-cell lung cancer: a retrospective study.

AIM: To analyze the efficacy of PD-1 blockade combined with RetroNectin®-activated cytokine-induced killer (R-CIK) cells in preheavily treated advanced non-small-cell lung cancer (NSCLC). METHODS: We retrospectively analyzed patients with advanced NSCLC who received PD-1 blockade combined with R-CIK cells whose treatments failed at least two regimens. RESULTS: The median number of previous treatment regimens was three (range: 2-7). Partial remission was achieved in two patients, stable disease in four patients and one patient experienced progressive disease. The median time-to-progression was 4.8 months. CONCLUSION: PD-1 blockade combined with R-CIK cells is safe and effective in patients with advanced NSCLC who have failed at least two treatment regimens.

Efficacy and safety of trastuzumab as maintenance or palliative therapy in advanced HER2-positive gastric cancer.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC) is a unique subtype of this disease. Few studies focus on the feasibility of trastuzumab as maintenance or palliative therapy for patients with HER2-positive advanced GC. PATIENTS AND METHODS: We retrospectively analyzed the data of 11 patients, evaluated the efficacy and safety of trastuzumab, and attempted to investigate the prognostic factors for trastuzumab treatment. Among the 11 patients, one achieved partial response (PR), six achieved stable disease (SD), and four were evaluated as progressive disease (PD). RESULTS: The overall response rate (ORR) was 9.10%, and the disease control rate (DCR) was 63.64%. The median overall survival (OS) was 6.10 months, and the median progression-free survival (PFS) was 6.10 months. A significant association was found between trastuzumab treatment cycles and efficacy (P=0.027), cycles and PFS (P=0.001), and cycles and OS (P=0.005). Among the five patients who accepted more than five cycles of trastuzumab, the median OS and median PFS achieved 23.83 months and 14.67 months, respectively. Moreover, we have found the correlation between tumor marker changes and efficacy (P=0.002) and HER2 status and PFS (P=0.027). No association was found between HER2 status and OS (P=0.597). CONCLUSION: The most common adverse events were left ventricular ejection fraction (LVEF) reduction, fatigue, and anorexia. LVEF reduction was found in seven of 11 patients, but the absolute decline in the LVEF was within 10% from the baseline. The results of this study suggest that trastuzumab is a feasible option as maintenance or palliative therapy for patients with HER2-positive metastatic GC.

Linc00210 drives Wnt/ß-catenin signaling activation and liver tumor progression through CTNNBIP1-dependent manner.

BACKGROUND: Liver tumor initiating cells (TICs) have self-renewal and differentiation properties, accounting for tumor initiation, metastasis and drug resistance. Long noncoding RNAs are involved in many physiological and pathological processes, including tumorigenesis. DNA copy number alterations (CNA) participate in tumor formation and progression, while the CNA of lncRNAs and their roles are largely unknown. METHODS: LncRNA CNA was determined by microarray analyses, realtime PCR and DNA FISH. Liver TICs were enriched by surface marker CD133 and oncosphere formation. TIC self-renewal was analyzed by oncosphere formation, tumor initiation and propagation. CRISPRi and ASO were used for lncRNA loss of function. RNA pulldown, western blot and double FISH were used to identify the interaction between lncRNA and CTNNBIP1. RESULTS: Using transcriptome microarray analysis, we identified a frequently amplified long noncoding RNA in liver cancer termed linc00210, which was highly expressed in liver cancer and liver TICs. Linc00210 copy number gain is associated with its high expression in liver cancer and liver TICs. Linc00210 promoted self-renewal and tumor initiating capacity of liver TICs through Wnt/ß-catenin signaling. Linc00210 interacted with CTNNBIP1 and blocked its inhibitory role in Wnt/ß-catenin activation. Linc00210 silencing cells showed enhanced interaction of ß-catenin and CTNNBIP1, and impaired interaction of ß-catenin and TCF/LEF components. We also confirmed linc00210 copy number gain using primary hepatocellular carcinoma (HCC) samples, and found the correlation between linc00210 CNA and Wnt/ß-catenin activation. Of interest, linc00210, CTNNBIP1 and Wnt/ß-catenin signaling targeting can efficiently inhibit tumor growth and progression, and liver TIC propagation. CONCLUSION: With copy-number gain in liver TICs, linc00210 is highly expressed along with liver tumorigenesis. Linc00210 drives the self-renewal and propagation of liver TICs through activating Wnt/ß-catenin signaling. Linc00210 interacts with CTNNBIP1 and blocks the combination between CTNNBIP1 and ß-catenin, driving the activation of Wnt/ß-catenin signaling. Linc00210-CTNNBIP1-Wnt/ß-catenin axis can be targeted for liver TIC elimination.

Survival benefit from RectroNectin-activated cytokine-induced killer cells combined with chemotherapy in advanced EGFR wild-type lung adenocarcinoma.

AIM: To investigate the efficacy of chemotherapy and RectroNectin-activated cytokine-induced killer (R-CIK) cell immunotherapy in patients with advanced EGFR wild-type lung adenocarcinoma. METHODS: Using data gathered from a single institution, 125 patients with stage IIIB or IV EGFR wild-type lung adenocarcinoma between January 2009 and June 2015 were identified and enrolled in this retrospective study. RESULTS: The disease control rates and median overall survival was better in R-CIK group compared with control group. Multivariate survival analysis showed that R-CIK cell treatment was an independent prognostic factor for overall survival. CONCLUSION: R-CIK cell immunotherapy may prolong survival of patients with advanced EGFR wild-type lung adenocarcinoma.

Platelet-to-lymphocyte ratio in peripheral blood: A novel independent prognostic factor in patients with melanoma.

OBJECTIVES: This retrospective study aimed to investigate the prognostic value of pre-treatment platelet-to-lymphocyte ratio (PLR), which is an inflammatory indicator, in patients with melanoma. METHODS: Patients in this retrospective analysis were admitted between January 1, 2010 and December 31, 2015 in Henan Cancer Hospital. Receiver operating characteristic (ROC) curve was performed the optimal cut-off value for PLR. The 140 patients were divided into two groups: high PLR group and low PLR group. The relationship between PLR and overall survival (OS) was analyzed. The Kaplan-Meier and Log rank tests were used for univariate survival analysis and Cox proportional hazards regression model for multivariate analysis. RESULTS: The optimal cut-off value of PLR determined by ROC curve was 120.15. Univariate and Cox multivariate survival analysis all showed that PLR and clinical stage were factors affecting OS in melanoma patients (P < 0.05). The overall median OS was 21.0 months (95% confidence interval (CI): 18.1-23.9), for 17.0 months in the high PLR group, and 34.0 months in the low PLR group (hazard ratio: 0.436, 95% CI: 0.291-0.652, P < 0.001), respectively. Clinical subgroup analysis showed that PLR was a risk factor in patients with stage II, III, and IV disease (P < 0.05). CONCLUSION: The elevated PLR was an independent prognostic predictor for OS in patients with melanoma.

Biological Character of RetroNectin Activated Cytokine-Induced Killer Cells.

Adoptive cell therapy (ACT) using autologous cytokine-induced killer (CIK) cells is a promising treatment for metastatic carcinomas. In this study, we investigated the impact of RetroNectin on the proliferation, phenotype alternation, cytokine secretion, and cytotoxic activity of CIK cells from pancreatic cancer patients. Furthermore, we treated 13 patients with metastatic or locally advanced pancreatic cancer using autologous RetroNectin-activated CIK cells (R-CIK cells) alone or in combination with chemotherapy. Compared with only CD3 activated CIK cells (OKT-CIK cells), R-CIK cells showed stronger and faster proliferative ability, with a lower ratio of spontaneous apoptosis. Moreover, this ability continued after IL-2 was withdrawn from the culture system. R-CIK cells could also secrete higher levels of IL-2 and lower levels of IL-4 and IL-5 versus OKT-CIK cells. There was no difference between OKT-CIK and R-CIK cells in cytotoxic ability against lymphoma cell line K562. In patients who received auto-R-CIK cell infusion therapy, the overall objective response rate was 23.1%. Median survival time (mOS) after first R-CIK cell infusion was 10.57 months; the 1-year survival rate was 38.5%. No serious toxicity was associated with R-CIK cell infusion. In conclusion, RetroNectin may enhance antitumor activity of CIK cells: it is safe for use in treating pancreatic cancer.

Autologous cytokine-induced killer cell transfusion increases overall survival in advanced pancreatic cancer.

BACKGROUND: Advanced pancreatic cancer (PC) has very poor prognosis with present treatments, thus necessitating continued efforts to find improved therapeutic approaches. Both preclinical and preliminary clinical data indicate that cytokine-induced killer (CIK) cells are an effective tool against various types of solid tumors. Here, we conducted a study to determine whether CIK cell-based therapy (CBT) can improve the outcomes of advanced PC. METHODS: Eighty-two patients with advanced PC, whose predicted survival time was longer than 3 months, were analyzed retrospectively. Of all the patients, 57 individuals were receiving chemotherapy, while the remaining 25 individuals were treated with CBT. RESULTS: The overall survival analysis was based on 48 deaths in the 57 patients in the chemotherapy group (84.2%) and 18 deaths in the 25 patients in the CBT group (72.0%). In the CBT group, the median overall survival time was 13.5 months, as compared to 6.6 months in the chemotherapy group (hazard ratio for death, 0.39; 95% confidence interval, 0.23 to 0.65; p < 0.001). The survival rate was 88.9% in the CBT group versus 54.2% in the chemotherapy group at 6 months, 61.1% versus 12.5% at 12 months, and 38.9% versus 4.2% at 18 months. The disease control rate was 68.0% in the CBT group and 29.8% in the chemotherapy group (p < 0.001). CONCLUSIONS: These results from this retrospective analysis appeared to imply that CBT might prolong survival in these high-risk PC patients. Prospective study is needed to corroborate this observation.

MDSC-decreasing chemotherapy increases the efficacy of cytokine-induced killer cell immunotherapy in metastatic renal cell carcinoma and pancreatic cancer.

Adoptive immunotherapy using cytokine-induced killer (CIK) cells is a promising cancer treatment, but its efficacy is restricted by various factors, including the accumulation of myeloid-derived suppressor cells (MDSCs). In this study, we determine whether chemotherapeutic drugs that reduce MDSC levels enhance the efficacy of CIK cell therapy in the treatment of solid tumors. Fifty-three patients were included in this study; 17 were diagnosed with metastatic renal cell carcinoma (MRCC), 10 with advanced pancreatic cancer (PC), and 26 with metastatic melanoma (MM). These patients were divided into two groups: CIK cell therapy alone and CIK cell therapy combined with chemotherapy. Combining CIK cell therapy and chemotherapy increased 1-year survival rates and median survival times in MRCC and PC patients, but not in MM patients. The disease control rate did not differ between treatment groups for MRCC or MM patients, but was higher in PC patients receiving combined treatment than CIK cell treatment alone. These data suggest that addition of MDSC-decreasing chemotherapy to CIK cell therapy improves survival in MRCC and PC patients.