Autologous Cytokine-induced Killer Cells Research Articles

Generation and assessment of cytokine-induced killer cells for the treatment of colorectal cancer liver metastases

Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. Cytokine-induced killer (CIK) cells are an adoptive immunotherapy reported to have strong anti-tumour activity across a range of cancers. They are a heterogeneous mix of lymphoid cells generated by culturing human peripheral blood mononuclear cells with cytokines and monoclonal antibodies in vitro. In this study, we investigated the yield and function of CIK cells generated from patients with CRC liver metastases. We first showed that CIK cells generated in serum free medium X-VIVO 15 were comparable to those from RPMI medium with 10% FBS in terms of the number and percentages of the main subsets of cells in the CIK culture, and the intracellular levels of granzyme B and perforin, and the pro-inflammatory cytokines IL-2, IFN-γ and TNF-α. The CIK cells were cytotoxic to CRC cell lines grown in 2D cultures or as spheroids, and against autologous patient-derived tumour organoids. Donor attributes such as age, sex, or prior chemotherapy exposure had no significant impact on CIK cell numbers or function. These results suggest that functional CIK cells can be generated from patients with CRC liver metastatic disease, and support further investigations into the therapeutic application of autologous CIK cells in the management of patients with CRC liver metastases.

The safety and feasibility of adjuvant immunotherapy with autologous cytokine-induced killer cells for patients with hepatocellular carcinoma beyond Milan criteria after liver transplantation

The safety and feasibility of adjuvant immunotherapy with autologous cytokine-induced killer cells for patients with hepatocellular carcinoma beyond Milan criteria after liver transplantation

CTIM-08. LOCAL IMMUNOTHERAPY WITH AUTOLOGOUS CIK CELLS FOR HIGH GRADE GLIOMAS: A PILOT STUDY WITH 20 YEARS FOLLOW-UP AND FAVORABLE FACTORS FOR LONG-TERM SURVIVAL

Abstract BACKGROUND Between November 2002 and March 2004, a pilot study was conducted to evaluate the tolerance and survival following local administration of autologous cytokine-induced killer (CIK) cells through Ommaya reservoirs implanted into the tumor resection cavity in 6 patients with high grade glioma (HGG) at Sun Yat-sen University Cancer Center. METHODS We reviewed the clinicopathological characteristics of these patients and updated their long-term follow-up. Profiles of tumor genome, transcriptome and immune microenvironment were also investigated by genomic target sequencing, RNA sequencing, electrochemiluminescence assay and immunohistochemistry (IHC) staining. RESULTS Four patients died from tumor progression and their overall survival ranged from 10.0 to 33.9 months. Remarkably, 2 patients, including one diagnosed as astrocytoma (IDH1 mutation, WHO 3) and the other diagnosed as diffuse hemispheric glioma H3 G34-mutant (G34-DHG), survived more than 19 years without evidence of recurrence. The distinctive clinical feature of the 2 long-term survivors was tumor gross total resection (GTR) before CIK therapy. Comparing with the short-term survivors, NTRK1 mutation was uniquely present and 353 genes were differentially expressed in the long-term survivors. These differential expression genes were highly associated with immune function. Electrochemiluminescence assay and IHC staining revealed higher expressions of cytokines and lower infiltrations of tumor-associated macrophages in the tumors of the long-term survivors. CONCLUSION These findings suggest that certain HGG patients can acquire long-term survival after local immunotherapy with CIK cells. Tumor GTR before CIK therapy and relatively weaker immunosuppressive tumor microenvironment may be the favorable factors for long-term survival.

Optimizing tumor-associated antigen-stimulated autologous dendritic cell and cytokine-induced killer cell coculture to enhance cytotoxicity for cancer immunotherapy in manufacturing

BackgroundDendritic Cell Cytokine-induced killer cell (DC-CIK) coculture treatment in cancer immunotherapy has been shown to be effective. However, the cost of DC- CIK therapy is prohibitive for many patients, and the lack of standard manufacturing processes and treatment strategies are major limitations. Our study used tumor lysate as a tumor-associated antigen source and DCs and CIK cells in coculture. We developed an efficient method to obtain autologous DCs- and CIK cells from peripheral blood. We used flow cytometry to assess DC activation and the cytometric bead array assay to quantify cytokines secreted by CIK cells.ResultsWe evaluated the antitumor activity of DC- CIK coculture in vitro with the K562 cell line. We demonstrated that a manufacturing process employing frozen immature DCs can yield the lowest loss with the highest economic benefits. DC-CIK coculture can effectively upgrade CIK cells’ immunological specificity to tumors in the presence of tumor-associated antigens.ConclusionIn vitro experiments revealed that when the DC- CIK cell ratio was 1: 20 in the coculture, CIK cells secreted the highest number of cytokines on the 14th day and the antitumor immune effect showed the highest potency. CIK cells’ cytotoxicity to K562 cells was highest when the CIK: K562 cell ratio was 25: 1. We developed an efficient manufacturing process for DC- CIK coculture, while also establishing the optimal DC- CIK cell ratio for immunological activity and the best cytotoxic CIK: K562 cell ratio.

Long-term outcome for patients with advanced non‒small-cell lung cancer treated by autologous cytokine-induced killer (CIK) cell immunotherapy in combination with sintilimab plus chemotherapy: NSCLC-CCICC-002.

9096 Background: Autologous cytokine-induced killer (CIK) cell immunotherapy in combination with Sintilimab demonstrated robust antitumor activity and safety in the phase Ib CCICC-002 study (NCT03987867) of Non‒Small-Cell Lung Cancer. Long-term outcomes in patients are reported herein. Methods: Systemic therapy naïve patients received platinum-based doublet chemotherapy, Sintilimab (PD1 inhibiter), and CIK cells every 3 weeks for 4 cycles, then maintenance treatment with Sintilimab in squamous and with Sintilimab plus pemetrexed in non-squamous NSCLC until disease progression or unacceptable toxicity or two years. Kaplan-Meier estimates of overall survival (OS) and progression-free survival (PFS) were calculated. OS and PFS were based on immune-related response criteria by investigator assessment (data cut-off, January 31, 2023). Results: From May 2019 to Jan 2021, CCICC-002 enrolled 33 patients（19 squamous, 14 non-squamous NCSLC; 1 patient was excluded because the second biopsy revealed EGFR mutation) aged 46-73 years with median follow-up was 31.4 months (range, 7.6-44.4 months). Estimated 3-year OS was 51.8% in all patients; median OS was not reached (95% CI, 26.6 months-not reached) in all patients. In subgroups, median OS was 27.6 months (95% CI, 13.4 months-not reached) in squamous NCSLC and not reached (95% CI, 29.9 months-not reached) in non-squamous NCSLC, respectively. Median OS was not reached (95% CI, 27.6 months-not reached) in PD-L1 positive patients and 28.3 months (95% CI, 15.6 months-not reached) in PD-L1 negative patients, respectively. Estimated 3-year PFS rate was 27.5% and median PFS was 17.9 months (95% CI, 8.2-26.5 months) in all patients. Median PFS was 17.3 months (95% CI, 5.0-24.0 months) in squamous NCSLC and 22.4 months (95% CI, 5.7 months-not reached) in non-squamous NCSLC, respectively. Median response duration was 18.7 months (95% CI, 10.1-27.6 months). 30.3% of patients were ongoing at data cut-off, and the longest response was ongoing at 41.3 months. 1 of the 5 CMR (complete metabolic response by PET-CT) patients experienced disease progression during observation. Treatment-related AEs (TRAEs) occurred in 94.0% of patients and resulted in study discontinuation in 7.8%, and 15.2% experienced grade 3/4 TRAE. Conclusions: This long-term analysis of CCICC-002 represents the longest follow-up for CIK to date and confirms the durable antitumor activity and tolerability of CIK cells therapy in combination with Sintilimab plus chemotherapy in advanced NCSLC. Further studies are warranted to confirm these preliminary results. Clinical trial information: NCT03987867 .

CTIM-13. LOCAL ADOPTIVE CELLULAR IMMUNOTHERAPY WITH CYTOKINE-INDUCED KILLER (CIK) CELLS FOR HIGH GRADE GLIOMAS: A PILOT STUDY WITH LONG-TERM FOLLOW-UP AND POTENTIAL FACTORS FOR SURVIVAL BENEFITS

Abstract BACKGROUND Immunotherapy is emerging as a promising approach for the treatment of high grade gliomas (HGGs). We reported the long-term follow-up of 6 HGG patients treated by local administration of autologous cytokine-induced killer (CIK) cells through Ommaya reservoirs implanted into the tumor cavity following operation. Meanwhile, Gene expression profiles and immune microenvironments of tumors were further compared between the long-term and short -term survivors. METHODS Clinicopathological characteristics and outcomes of patients were reviewed and updated. Gene expression profiles, expressions of cytokines and infiltrations of immune cells in tumors were investigated by RNA sequencing, an electrochemiluminescence assay and immunohistochemistry staining, respectively RESULTS Fever and symptoms of encephaledema occurred in 5 patients after local administration of CIK cells, and could be efficiently relieved by mannitol and dexamethasone. Four patients died from progressive disease during follow-up, and their overall survival ranged from 6 to 26 months. Remarkably, 2 patients have survived more than 200 months without evidence of recurrence. Comparing with the tumors of the short-term survivors, 353 genes which were highly associated with tumor microenvironment immune were differentially expressed (false discovery rate (FDR) < 0.05 and log2 fold change (FC) ≥ 1) in the tumor of the long-term survivor. Higher expressions of cytokines, especially IL-8 and IL-10, were observed in the tumor of the long-term survivor, while the infiltrations of M2 polarized macrophages were significantly higher in the tumors of short-term survivors. CONCLUSION Long-term survival of HGG patients could achieve after local administration of CIK cells into tumor cavity postoperatively. High expressions of cytokines and low infiltrations of M2 polarized macrophages in the tumors potentially benefited the CIK cell therapy.

A Phase IB Trial of Autologous Cytokine‐Induced Killer Cells in Combination with Sintilimab, Monoclonal Antibody Against Programmed Cell Death‐1, plus Chemotherapy in Patients with Advanced Non‐Small‐Cell Lung Cancer

IntroductionCan the Cytokine-induced killer (CIK) cells in combination with immune checkpoint inhibitor further improve the efficacy of chemotherapy in non-small cell lung cancer (NSCLC) patients? What are the adverse reactions of this combination therapy? But these problems are not clear. Therefore, we conducted a phase 1b trial to evaluate the safety and efficacy of autologous CIK cells therapy combined with Sintilimab, antibody against programmed cell death-1, plus chemotherapy in untreated, advanced NSCLC patients. Patients and MethodsPatients with stage IIIB/IIIC/IV NSCLC received Sintilimab, platinum-based doublet chemotherapy, and CIK cells every 3 weeks for 4 cycles, then maintenance treatment with Sintilimab in squamous and with Sintilimab plus pemetrexed in non-squamous NSCLC until disease progression or unacceptable toxicity or 2 years. The primary endpoints were safety and objective response rate (ORR). ResultsThirty-four patients received the treatment. 94.1% of patients experienced treatment-related adverse events (TRAEs). Grade 3 or greater TRAEs occurred in 64.7% of patients. One (2.9%) patient died of grade 5 immune-related pneumonia. The ORR and DCR were 82.4% (95% CI, 65.5%-93.2%) and 100.0% (95% CI, 89.7%-100.0%), respectively. Objective responses were evaluated in 14 of 15 non-squamous patients (93.3%; 95% CI, 68.1%-99.8%) and in 14 of 19 squamous patients (73.7%; 95% CI, 48.8%-90.9%). Median PFS was 19.3 months (95% CI, 8.3 months to not available). ConclusionAutologous CIK cells immunotherapy in combination with Sintilimab plus chemotherapy was well tolerable and showed encouraging efficacy in patients with previously untreated, advanced NSCLC (ClinicalTrials.gov number, NCT03987867).

Autologous Cytokine-Induced Killer Cell Immunotherapy Enhances Chemotherapy Efficacy against Multidrug-Resistant Tuberculosis.

Objective Multidrug-resistant tuberculosis (MDR-TB) causes persistent infection and challenges tuberculosis control worldwide. T cell-mediated immunity plays a critical role in controlling Mycobacterium tuberculosis (Mtb) infection, and therefore, enhancing Mtb-specific T cell immune responses represents a promising therapeutic strategy against TB. Cytokine-induced killer (CIK) immunotherapy is based on autologous infusion of in vitro expanded bulk T cells, which include both pathogen-specific and nonspecific T cells from patient peripheral blood mononuclear cells (PBMC) into TB patients. Preclinical mouse studies have shown that the adoptive T cell therapy inhibited Mtb infection. However, the efficacy of CIK immunotherapy in the treatment of MDR-TB infection has not been evaluated in clinical trials. Methods We performed a retrospective study of MDR-TB patients who received CIK immunotherapy in combination with anti-TB chemotherapy and those who had standard chemotherapy. Results Our results showed that CIK immunotherapy in combination with anti-TB chemotherapy treatment increased the conversion rate of sputum smear and Mtb culture, alleviated symptoms, improved lesion absorption, and increased recovery. The kinetics of serology and immunology index monitoring data showed good safety profiles for the CIK treatment. Conclusion Our study has provided strong evidence that CIK immunotherapy in combination with anti-TB chemotherapy is beneficial for MDR-TB patients. A multicenter clinical trial is warranted to evaluate CIK as a new immune therapy for MDR-TB.

A Novel Antibody-Cell Conjugation Method to Enhance Cellular Therapies for the Treatment of Hematological Malignancies

IntroductionCellular therapies including γδ T cells, NK-92 cells, and cytokine-induced killer (CIK) cells have shown modest anti-tumor activity against multiple hematological and solid malignancies in preclinical and phase I/II clinical trials. We investigate whether the antitumor activity of these cellular therapies can be augmented by using a novel method that rapidly affixes tumor-targeting antibodies directly to cell surface proteins.MethodsMonoclonal antibodies including rituximab and daratumumab were conjugated to the cell surface proteins using a three step approach. First, we conjugate single-stranded DNAs (ssDNAs) to the therapeutic monoclonal antibodies, as previously described (ref below). Next, we conjugate complementary ssDNAs to surface proteins of cells being used for cellular therapy. Finally, the modified antibodies are attached to the modified cells via hybridization of the complementary DNA strands.ResultsWe demonstrate that multiple anti-neoplastic monoclonal antibodies including rituximab and daratumumab can be conjugated to the surface proteins on a variety of cell including γδ T cells, NK-92 cells, CIK cells, and primary human T cells. Then we evaluated the killing activity of these conjugated cells in vitro, in vivo, and ex vivo . In vitro, Rituximab-armed γδ T cells and NK-92 cells demonstrated increased cytokine production (IFN-γ and granzyme B) and enhanced cytotoxic killing against of multiple human B-cell non-Hodgkin lymphoma (NHL) and multiple myeloma cell lines. Similar enhanced anti-tumor activity was seen with rituximab-armed or daratumumab-armed CIK cells, as well as increased CD107a expression (a marker of cytotoxicity activity) by the antibody-armed CIK cells. Rituximab-armed primary T cells also show enhanced cytotoxic killing against Raji cells, although not as pronounced as autologous rituximab-armed CIK cells. We next evaluated the therapeutic potential of antibody-armed cell therapies in vivo in a disseminated xenograft mouse model using SCID-beige mice. Rituximab-armed γδ T cells exhibited potent anti-lymphoma activity against Raji cells, which lead to improved overall survival; whereas unarmed γδ T cells alone or with rituximab co-infusion demonstrated limited anti-lymphoma activity. We also evaluated the therapeutic activity of antibody-armed cell therapies against a primary lymphoma target ex vivo. Rituximab-arm CIK cells demonstrated enhanced cytolytic activity against primary follicular lymphoma freshly collected from a patient via fine needle aspiration biopsy.DiscussionWe have demonstrated a novel approach to create tumor-specific cellular immunotherapies without the need for genetic engineering. The antibody to cell conjugation method is straight forward. The modified antibodies can be made and stored until needed. It takes approximately 1 hour to attaching these modified antibodies to the cell surface and is performed in standard aqueous buffers, such as phosphate-buffered saline (PBS). This method is also flexible being able to conjugate multiple different antibodies to the surface proteins of a variety of different cell types. We also see enhanced cell killing across multiple hematological targets using multiple cell populations including γδ T cells, NK-92 cells, CIK cells, and primary human T cells. Overall, our data demonstrate existing monoclonal antibodies can be used to “antibody program” cell therapies for the treatment of hematological malignancies.RefHsiao et al Langmuir 2009,25(12), 6985-6991 DisclosuresHsiao:Acepodia, Inc: Employment.

A single-arm phase Ib study of autologous cytokine-induced killer (CIK) cell immunotherapy in combination with sintilimab plus chemotherapy in patients with advanced non-small cell lung cancer (NSCLC)-CCICC-002.

2531 Background: Immune checkpoint inhibitors plus chemotherapy had showed benefits for advanced non–small-cell lung cancer (NSCLC) patients without targetable mutations. Autologous cytokine-induced killer (CIK) cells can restore the antitumor immunity to improve patient outcome. Combining CIK cells with anti-PD-1 mAb plus chemotherapy may strengthen the results in patients with advanced NSCLC. Methods: This is a single-center, open-label, phase 1b trial of combination CIK cells with sintilimab (anti-PD-1 mAb) plus chemotherapy in stage IIIB-IV NSCLC patients. Systemic therapy naïve patients received platinum-based doublet chemotherapy, sintilimab, and CIK cells every 3 weeks for 4 cycles，then sintilimab, and CIK cells for maintenance therapy until disease progression or unacceptable toxicity. Results: From May 2019 to Jan 2021, 34 patients (19 squamous， 15 non-squamous NCSLC)aged 46-73 years (median age 64 years) were enrolled. Among 32 evaluable patients, the ORR was 81.3% (73.7% in squamous and 92.3% in non-squamous NSCLC)and DCR was 100%. Among the 25 PR assessed by RECIST, CMR was demonstrated in 5 (23.1%) by PET-CT. Among 3 patients with brain metastases, 2 patients achieve intracranial CR, and 1 was PR. With a median follow-up of 7.5 months, the median DOR was not reached (range 0.5m-NA), and the median PFS and OS were not mature. Grade 3 or more TRAEs included pneumonia (n = 3); thrombocytopenia, leukopenia (n = 2 each); anemia, dysphagia, cardiomyopathy, rash (n = 1 each). Biomarkers and subgroups which correlated with efficacy and AEs are being analyzed included TMB, PDL1 expression, distribution of TILs, cytokines and so on. Conclusions: CIK cells therapy in combination with sintilimab plus chemotherapy were well tolerated and showed encouraging efficacy. Further studies are warranted to confirm these preliminary results. Research Sponsor: Tianjin Medical University Cancer Institute and Hospital. Clinical trial information: NCT03987867. [Table: see text]

Cytokine-induced killer cells/dendritic cells and cytokine-induced killer cells immunotherapy for the treatment of esophageal cancer: A meta-analysis.

Objectives:This meta-analysis was designed to systematically evaluate whether autologous cytokine-induced killer cells (CIK) or dendritic cells and cytokine-induced killer cells (DC-CIK) immunotherapy combined with chemotherapy can improve the therapeutic effect and safety of chemotherapy in esophageal cancer (EC).Materials and methods:Randomized controlled trials (RCTs) were electronically searched databases including CNKI, WanFang, WeiPu, CBMDisc, PubMed, Web of Science, EMbase, the Cochrane Library, and Clinical Trials. The databases were searched for articles published until June 2019. Two researchers independently screened the literature, extracted data, and evaluated the quality of the included literature. Meta-analysis was performed using RevMan5.3.Results:Seventeen studies (1416 participants) were included. The differences between CIK/DC-CIK combination chemotherapy and chemotherapy alone were significant. The results displayed that the number of CD3+, CD4+, CD4+/CD8+, and NK cells was significantly increased after 1 to 2 weeks of treatment with CIK/DC-CIK cells in the treatment group (all P < .05). In addition, the results shown that 1-year overall survival was significantly prolonged (P < .0001) and quality of life was improved (P = .001) in EC chemotherapy combined with immunotherapy groups compared with conventional treatment. Furthermore, cytokine expression levels of interleukin 2 (IL-2), tumor necrosis factor α (TNF-α), and interleukin 12 (IL-12) were significantly increased (P = .0003) as well as the levels of immunoglobulins were elevated (P < .00001). Serum levels of tumor marker molecules, carcinoembryonic antigen (CEA), carbohydrate antigen (CA)-199, and CA-125 were lower in treatment groups than that of control groups (P < .00001). No fatal adverse reactions were noted (P = .04).Conclusions:It is safe and effective for patients to use chemotherapy combined with CIK/DC-CIK immunotherapy. Immunotherapy can simultaneously improve the antitumor immune response. Specifically, DC-CIK cells can increase T lymphocyte subsets, CIK cells, NK cells, and immunoglobulins in peripheral blood to enhance antitumor immunity. Therefore, combination therapy enhances the immune function and improves the therapeutic efficacy of patients with EC.

Study on the antitumor effects of autologous and allogeneic CIK cells in patients with breast cancer*

Abstract Objective This study aimed to compare the anti-tumor effects of cytokine-induced killer (CIK) cells induced by autologous cytokines in patients with breast cancer and those of allogeneic CIK cells from healthy adults. Methods We used conventional methods to induce CIK cells originating from two peripheral blood mononuclear cell types (from patients with breast cancer and healthy adults). Killing activity was detected using an LDH assay, immunophenotypic changes were analyzed by flow cytometry, and the IFN-γ level of culture supernatants was detected by ELISA. Results The results showed that the proliferative capacity of the allogeneic CIK cells was significantly higher than that of the autologous CIK cells. Compared with autologous CIK cells, the allogeneic CIK cells had significantly enhanced anti-tumor activity against SKBR-3 cells (P &lt; 0.01) and IFN-γ secretion (P &lt; 0.05); moreover, they increased the ratio of CD3+ CD56+ cells and CD3+ CD8+ cells (P &lt; 0.05). Conclusion Healthy adult-derived induced CIK cells exhibited a stronger anti-tumor effect than induced CIK cells derived from patients with breast cancer. The results of this study could provide experimental evidence for the clinical application of CIK cells.

24MO Randomized, multicenter, open-label trial of autologous cytokine-induced killer cell immunotherapy plus chemotherapy for squamous non-small cell lung cancer

24MO Randomized, multicenter, open-label trial of autologous cytokine-induced killer cell immunotherapy plus chemotherapy for squamous non-small cell lung cancer

Autologous cytokine-induced killer (CIK) cells enhance the clinical response to PD-1 blocking antibodies in patients with advanced non-small cell lung cancer: A preliminary study.

BackgroundProgrammed death‐1 (PD‐1) blocking antibodies have been shown to improve progression‐free survival (PFS) and overall survival in a subset of patients with non–small cell lung cancer (NSCLC). However, the objective response rate with these agents remains low, and the vast majority of NSCLC patients require alternative combination treatment regimens to prolong their survival. The purpose of this study was to evaluate the clinical efficacy of autologous cytokine‐induced killer (CIK) cell infusions combined with PD‐1 blocking antibodies in patients with NSCLC.MethodsIn this preliminary study, we investigated the safety and immune function effectiveness of PD‐1 blockade antibodies pembrolizumab or nivolumab administered in combination with or without autologous CIK cell infusions in 18 patients with advanced NSCLC. The peripheral blood mononuclear cells were isolated from these patients and the expression level of some cell surface molecules like PD‐1 were detected using flow cytometry to reflect the effectiveness of this combination regimen.ResultsNo treatment‐related deaths occurred in either cohort. In comparison with the pretreatment level, CD3+CD56+CD16+ T cells were significantly increased with the combination therapy, while myeloid‐derived suppressor cells were significantly increased with PD‐1 blocking antibody therapy alone but not with combination therapy. Although the serum interleukin‐4 level was downregulated following treatment with the combination regimen, interferon‐γ levels were unchanged.ConclusionsThe purpose of this clinical study was to report the clinical efficacy and lack of exacerbated autoimmune adverse events with a combination of PD‐1 blockade and CIK cell infusions in patients with advanced NSCLC, further supporting assessments of this combination in future clinical trials.

386P A single-arm phase Ib study of autologous cytokine-induced killer (CIK) cell immunotherapy in combination with sintilimab plus chemotherapy in patients with advanced non-small cell lung cancer (NSCLC)

Immune checkpoint inhibitors plus chemotherapy has demonstrated significant survival benefits for advanced non-small-cell lung cancer (NSCLC) patients without targetable mutations. Autologous cytokine-induced killer (CIK) cell therapy can restore the antitumor immunity to improve the patient outcomes. Therefore, a single-center, open-label, phase Ib trial was conducted to explore the efficacy and safety of autologous CIK cell therapy combined with sintilimab (anti-PD-1) plus chemotherapy as 1L treatment in advanced NSCLC patients (NCT03987867). Systemic therapy naïve patients with stage IIIB-IV NSCLC would receive platinum-based doublet chemotherapy, sintilimab (200mg, d1), and intravenous autologous CIK cells (1010, d14) every 3 weeks until disease progression or unacceptable toxicity. The primary endpoints were safetyand the objective response rate (ORR) assessed per RECIST v1.1.Secondary endpoints were progression-free survival (PFS) and overall survival (OS). From May 2019 to Jun 2020, 16 pts aged 46-72 years (median age 62 years) were enrolled. The squamous/non-squamous ratio was 44%/56%. 14 (87.5%) were men, 15(93.7%) were ECOG PS=0-1, 3 (18.75%) had liver metastases, and 2 (12.5%) had brain metastases. Among 13 evaluable pts, the ORR and DCR were 84.6% and 100%, respectively. Among the 11 PR assessed by RECIST, CR was demonstrated in 3 (23.1%) by PET-CT. At the time of data cutoff, the median DOR was not reached (range 2.43m-NA), and the median PFS and OS were not mature (median follow-up time 5.65m, range 0.63-13.3).Adverse events (AEs) occurred in 15 (93.75%), including 4 Grade≥3 AEs events (25%). The most common AEs were nausea (12, 75%), anemia (11, 68.75%), and leukopenia (10, 62.5%).Immune-related AEs were cardiomyopathy (1, 6.25%) and pneumonia (3, 18.75%),1 pts had immune-related grade 5 pneumonia. Autologous CIK cell therapy in combination with sintilimab plus chemotherapy were well tolerated and showed encouraging efficacy. Further studies are warranted to confirm these preliminary results.

376O Randomized, multicenter trial of autologous cytokine-induced killer cell immunotherapy plus chemotherapy for squamous non-small cell lung cancer: NCT01631357

376O Randomized, multicenter trial of autologous cytokine-induced killer cell immunotherapy plus chemotherapy for squamous non-small cell lung cancer: NCT01631357

Autologous Cytokine-Induced Killer Cell Immunotherapy for Patients with High-Risk Diffuse Large B Cell Lymphoma After the First Complete Remission.

PurposeTo evaluate whether autologous cytokine-induced killer (CIK) cell immunotherapy improves the prognosis of patients with high-risk diffuse large B cell lymphoma (DLBCL) after the first complete remission (CR).Patients and MethodsPeripheral blood mononuclear cells (PBMCs) were extracted from 20 patients with high-risk DLBCL (IPI≥3) after the first CR. Twenty CR patients who were age- and sex-matched during the same period were selected as controls. PBMCs were cultured with IFN-γ, IL-2 and anti-CD3 mAb to generate CIK cells. These obtained cells were then transfused back into the patients; the transfusion was repeated every 3 months up to a total of four courses. Changes in peripheral blood lymphocyte subgroups and survival were assessed.ResultsCompared with the baseline proportions, the proportion of CD3+ T cells, CD3+CD8+ T cells, and NK cells in the peripheral blood were significantly higher after transfusions (p<0.05). The 5-year DFS was improved from 45.0 ± 11.1% to 79.3 ± 9.2% in the CIK group (HR favoring CIK, 0.29; 95% CI, 0.09 to 0.92; p = 0.035), and the 5-year OS was estimated at 90 ± 6.7% for CIK versus 55 ± 11.1% for control (HR favoring CIK, 0.20; 95% CI, 0.04 to 0.93; p = 0.040). No severe side effects were observed related to CIK treatment.ConclusionAutologous CIK cell immunotherapy has emerged as a safe and efficacious option to improve the prognosis of patients with high-risk DLBCL after the first CR.

Randomized, Multicenter, Open-Label Trial of Autologous Cytokine-Induced Killer Cell Immunotherapy Plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer

Objective: This randomized, multicenter trial was designed to evaluate the efficacy of cytokine-induced killer (CIK) cell immunotherapy combination with chemotherapy in patients with advanced squamous non-small-cell lung cancer (NSCLC). Patients and Methods: In this phase II trial, 90 patients with untreated, stage IIIB/IV squamous NSCLC were randomized to autologous CIK cell immunotherapy plus gemcitabine and cisplatin (CIK-CT group, n = 45), or gemcitabine and cisplatin (CT group, n = 45). The primary endpoint was progression-free survival (PFS) evaluated by Kaplan–Meier analyses and treatment hazard ratios (HRs) with the Cox proportional hazards model. Results: After a median follow-up of 29.3 months, the median PFS was 8.7 months (95% CI, 7.1 to 10.3) in the CIK-CT group and 4.0 months (95% CI, 3.1 to 5.0) in the CT group (HR, 0.26; 95% CI, 0.16 to 0.43; P < .001). The median OS was 21.0 months (95% CI, 17.8 to 24.2) in the CIK-CT group and 10.3 months (95% CI, 7.9 to 12.1) in the CT group (HR, 0.22; 95% CI, 0.13 to 0.40; P < .001). The objective response rate was 62.2% (95% CI, 47.9% to 76.5%) in the CIK-CT group and 31.1% (95% CI, 17.4% to 44.8%) in the CT group ( P < .001). The adverse events of grade 3 or higher were 28.9% (13/45) and 42.2% (19/45) in the CIK-CT group and CT group, respectively. Conclusions: These data suggested that CIK cell immunotherapy could improve the efficacy of chemotherapy in patients with previously untreated, advanced squamous NSCLC. A large sample, multi-center randomized, phase III trial is being carried out in our hospital to further validate these findings. Trial Registration: This trial is registered as an international standard randomized trial with ClinicalTrials.gov Identifier: NCT01631357. Funding Statement: Supported by the National Key Technologies R&D Program of China grant Awards No. 2015BAI12B12 (to Xiubao Ren) and 2018YFC1313400 (to Jianchuan Xia), by the National Natural Science Foundation of China grants Awards No. 81572913 and 81872487 (to Liang Liu). Declaration of Interests: The authors reported no potential conflicts of interest. Ethics Approval Statement This study was approved by the State Food and Drug Administration of China (2006L01023), by the National Key Technologies R&D Program of China (2015BAI12B12), and by the Ethical Committee of Cancer Hospital of Tianjin Medical University, according to the guidelines of the Declaration of Helsinki. Informed consent was obtained from all subjects.

The Phase II Clinical Trial for Palliative Immunotherapy Using Autologous Cytokine-Induced Killer Cells in Refractory Metastatic Colorectal Cancer (NCT03220984)

The Phase II Clinical Trial for Palliative Immunotherapy Using Autologous Cytokine-Induced Killer Cells in Refractory Metastatic Colorectal Cancer (NCT03220984)

Adjuvant cytokine-induced killer cells with minimally invasive therapies augmented therapeutic efficacy of unresectable hepatocellular carcinoma.

To investigate the safety and therapeutic efficacy of adjuvant cytokine-induced killer (CIK) cells to minimally invasive therapies in unresectable hepatocellular carcinoma (u-HCC). Hundred patients diagnosed with having u-HCC in our department from January 1, 2001, to July 31, 2018, were recruited. Forty-three patients received microwave ablation (MWA) and transcatheter arterial chemoembolization (TACE) together with autologous CIK cell treatment (TACE + MWA + CIK group), whereas 57 patients received TACE and MWA only (TACE + MWA group). Postprocedural complications and cumulative therapeutic effects were assessed in all patients. The disease control rate, median survival time (MST), and cumulative survival rate were compared between the cohorts using the Kaplan-Meier method and unpaired Student's t-tests. The overall response (complete response [CR] + partial response [PR]) rate was 74.42% (32/43) and 77.19% (44/57) for TACE + MWA + CIK and TACE + MWA groups, respectively (P = 0.243). Those of the TACE + MWA + CIK group had better rates of disease control (CR + PR + stable disease) in contrast to the TACE + MWA group (87.72% vs. 79.07%, respectively) but this failed to achieve statistical significance (P = 0.748). Based on the Kaplan-Meier survival graphs, those of the TACE + MWA + CIK groups possessed markedly increased overall survival (41 months vs. 24 months, P = 0.002) and progression-free survival (17 months vs. 10 months, P = 0.023) rates in compared to the TACE + MWA group. Survival rates were raised also TACE + MWA + CIK group than in TACE + MWA group (P = 0.002), with a MST of 6.13 ± 0.83 months and 11.61 ± 1.59 months in the TACE + MWA + CIK and TACE + MWA groups, respectively. Patients in the TACE + MWA + CIK group were not reported to have any severe complications. CIK cell immunotherapy as an adjuvant to TACE and MWA enhanced long-term prognosis and improved quality of life in patients with u-HCC. This regimen may be recommended as a novel treatment regime in u-HCC patients.