Dendritic Cell Vaccine In Combination Research Articles

Dendritic cell vaccination in combination with erlotinib in a patient with inoperable lung adenocarcinoma: a case report

BackgroundSatisfactory treatment for patients with unresectable advanced lung cancer has not yet been established. We report a case of unresectable advanced lung cancer (stage IIIb: T2aN3M0) treated with a total of 15 doses of dendritic cells pulsed with a Wilms’ tumor 1 and mucin 1 vaccine in combination with erlotinib, a small molecule epidermal growth factor receptor tyrosine kinase inhibitor, for more than 699 days without recurrence or metastasis.Case presentationA 63-year-old Korean woman was diagnosed with lung adenocarcinoma by pathology and computed tomography. The adenocarcinoma showed an epidermal growth factor receptor (EGFR) mutation, no anaplastic lymphoma kinase expression, and less than 1% expression of programmed death ligand 1. She received erlotinib alone for approximately 1 month. She then received erlotinib and the dendritic cells pulsed with Wilms’ tumor 1 and mucin 1 vaccine. The diameter of the erythema at the vaccinated sites was 30 mm at 48 hours after the first vaccination. Moreover, it was maintained at more than 20 mm during the periods of vaccination. These results suggested the induction of antitumor immunity by the vaccine. Remarkably, the tumor size decreased significantly to 12 mm, a 65.7% reduction, after combined therapy with eight doses of the dendritic cells pulsed with Wilms’ tumor 1 and mucin 1 vaccine and erlotinib for 237 days based on fluorodeoxyglucose uptake by positron emission tomography/computed tomography and computed tomography. Interestingly, after 321 days of combination therapy, the clinical findings improved, and no tumor was detected based on computed tomography. Validation of the tumor’s disappearance persisted for at least 587 days after treatment initiation, without any indication of recurrence or metastasis.ConclusionStandard anticancer therapy combined with the dendritic cells pulsed with Wilms’ tumor 1 and mucin 1 vaccine may have therapeutic effects for such patients with unresectable lung adenocarcinoma.

Effect of dendritic cell vaccine on blood redox status in patients with cervical cancer

Purpose of the study. The purpose of the study was to evaluate the dynamics of parameters of malondialdehyde (MDA), reduced glutathione and antioxidant enzyme activity in patients with advanced cervical cancer (CC) receiving anticancer treatment with dendritic cell vaccine (DCV).Patients and methods. Levels of malondialdehyde (MDA), reduced glutathione and antioxidant enzyme activity were studied in 27 patients aged 27–65 years with advanced primary and recurrent CC receiving chemotherapy (CT) with DCV or DCV as monotherapy at a dose of 10 million cells intradermally once a week. The same indices were studied in 20 healthy women from the comparison group.Results. The majority of patients showed the initial increase of MDA: in blood plasma by an average of 66.7 %, in red blood cells – statistically insignificant. After CT, MDA levels were elevated respectively in primary and recurrent patients in erythrocytes by 85.6 % and 96.4 % compared to donors, and by 53.9 % and 33.7 % compared to the initial values; the levels in plasma were elevated by 79.8 % and 57.1 % compared to donors. After 5–7 DCVs in combination with CT, MDA levels in erythrocytes and in blood plasma were similar to the donor values. MDA in erythrocytes of patients receiving DCV without CT decreased by 36 % compared to initial values. Oxidase activity of ceruloplasmin, initially increased by 34.2–57.1 %, normalized after DCV. Superoxide dismutase activity decreased by 16.7–27.3 % after 4–6 DCVs and normalized after 7 DCVs. Catalase activity, initially reduced by more than 40 %, remained 20–38 % lower than the norm at all stages of DCV. In this setting, hydrogen peroxide was probably inactivated by glutathione peroxidase whose activity was increased at all stages of treatment and decreased only when MDA was normalized after 7 DCVs.Conclusion. Administration of 5–7 DCVs in combination with CT or as monotherapy to patients with advanced CC normalizes parameters of free radical oxidation and antioxidant system of the blood.

Efficacy of Adjuvant Immune-cell Therapy Combined With Systemic Therapy for Solid Tumors.

The efficacy of adjuvant systemic therapy after surgical resection remains unsatisfactory; therefore, a new treatment strategy is required. We aimed to examine the efficacy of adjuvant immune-cell therapy using activated T lymphocytes with or without dendritic cell vaccination in combination with standard adjuvant systemic therapies in terms of the survival of patients with solid tumors, such as lung, gastric, pancreatic, colorectal, and breast cancers. A total of 141 patients with solid tumors were enrolled in this study. The correlation of overall survival and disease-free survival with various clinical factors such as age, sex, performance status score, clinical stage, treatment strategies, and vital status was investigated by univariate and multivariate analyses. Multivariate analysis revealed that a performance status score of 0 was a favorable prognostic factor in the full analysis set of solid tumors (HR=0.209, 95%CI=0.065-0.676, p=0.0089) and might be the indication for immune-cell therapy in the adjuvant setting. Adjuvant immune-cell therapy combined with other systemic therapies would potentially provide a survival benefit in patients with solid tumors.

Phase I trial of adjuvant mature autologous dendritic cell/allogeneic tumor lysate vaccines in combination with temozolomide in newly diagnosed glioblastoma.

BackgroundGlioblastoma (GBM) has poor prognosis despite aggressive treatment. Dendritic cell (DC) vaccines are promising, but widespread clinical use has not been achieved, possibly reflecting manufacturing issues of antigen choice and DC potency. We previously optimized vaccine manufacture utilizing allogeneic human GBM tumor cell lysate and potent, mature autologous DCs. Here, we report a phase I study using this optimized DC vaccine in combination with standard therapy.MethodsFollowing surgical resection and radiation with concurrent temozolomide (TMZ), newly diagnosed adult GBM patients received intradermal DC vaccines plus TMZ. Primary endpoints were safety and feasibility. Immune and treatment responses were recorded.ResultsTwenty-one patients were enrolled in this study. One progressed between leukapheresis and vaccine manufacture. Twenty patients received treatment per protocol. Vaccine doses (≥15) were generated following a single leukapheresis for each patient. No dose-limiting vaccine toxicities were encountered. One patient had symptomatic, histologically proven pseudoprogression. Median progression-free survival was 9.7 months. Median overall survival was 19 months. Overall survival was 25% at 2 years and 10% at 4 years. One patient remains progression-free 5 years after enrollment. Specific CD8 T-cell responses for the tumor-associated antigen gp100 were seen post-vaccination. Patients entered the trial with a leukocyte deficit compared to healthy donors which partly normalized over the course of therapy.ConclusionsThis vaccine platform is safe and highly feasible in combination with standard therapy for newly diagnosed patients. Imaging, histological, survival, and immunological data suggest a positive biological response to therapy that warrants further investigation.

FP14.01 A Phase 1b/2 Study of Autologous Dendritic Cell Vaccination in Combination With Atezolizumab in Patients With Small Cell Lung Cancer (SCLC)

IMpower133 trial showed a significant benefit of the combination of the anti PD-L1 antibody atezolizumab with chemotherapy over chemotherapy alone in extensive SCLC, with a 18 and 24-month landmark OS of 34% and 22% vs. 21% and 16.8%, respectively. Despite this improvement, patients achieving long-lasting remission are still uncommon. New therapeutic strategies are needed for this population. Dendritic Cells (DCs) are the most powerful antigen-presenting cells of the immune system, capable of stimulating naïve and memory immune responses.

Safety and efficacy of autologous tumor lysate particle-loaded dendritic cell vaccination in combination with systemic therapies in patients with recurrent and metastatic melanoma.

Immunotherapy has revolutionized the treatment of melanoma, yet survival remains poor for patients with metastatic disease. The autologous tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine has been shown to be safe adjuvant therapy for patients with resected stage III/IV melanoma who complete the primary vaccine series. Here, we describe an open-label trial of patients with metastatic melanoma treated with TLPLDC vaccine in addition to standard of care (SoC) therapies. The TLPLDC vaccine is created by loading autologous tumor lysate into yeast cell wall particles, which are phagocytosed by autologous dendritic cells ex vivo. Patients who recurred while enrolled in a phase IIb trial of adjuvant TLPLDC vaccine (crossover cohort) and patients with measurable metastatic melanoma cohort were offered TLPLDC vaccine along with SoC therapies. Tumor response was measured by RECIST 1.1 criteria. Overall survival (OS) and progression-free survival (PFS) were estimated by intention-to-treat analysis. Fifty-four patients were enrolled (28 in crossover cohort; 26 in metastatic melanoma cohort). The vaccine was well-tolerated with no grade ≥3 adverse events when given with SoC therapies to include checkpoint inhibitors, BRAF/MEK inhibitors, tyrosine kinase inhibitors, intralesional therapy and/or radiation. In the crossover arm, OS was 76.5% and PFS was 57.1% (median follow-up of 13.9 months). In the metastatic melanoma arm, OS was 85.7% and PFS was 52.2% (median follow-up 8.5 months). The TLPLDC vaccine is well-tolerated and safe in combination with SoC therapies. Future trials will determine the efficacy of TLPLDC in combination with SoC therapies in metastatic melanoma.

Prognostic Factors for Advanced/Recurrent Breast Cancer Treated With Immune-cell Therapy.

Advanced/recurrent breast cancer (ARBC) still has a poor prognosis; therefore, new treatment strategies are required. In this retrospective study, we aimed to investigate the efficacy of immune-cell therapy using T lymphocytes activated in vitro with or without dendritic cell vaccination in combination with standard therapies in terms of the survival of patients with ARBC. A total of 127 patients with ARBC were enrolled in this study. The correlation between overall survival and various clinical factors of each ARBC subset was examined by univariate and multivariate analyses. Multivariate analysis demonstrated that performance status (PS) 0, the absence of prior chemotherapy, liver/pleural metastasis, and the presence of combined surgery in ARBC and PS 0 or the absence of liver metastasis in the HR+/HER- subset are indications for immune-cell therapy. A survival benefit could be potentially obtained by a combination of immune-cell therapy with other therapies in ARBC patients.

Multimodality Targeting of Dendritic Cell Vaccination Combined with Immunomodulatory Drug and Immune Checkpoint Blockade Has Synergistically Induced a Marked Tumor Regression By Modulating Tumor Microenvironment in a Murine Myeloma Model

There is emerging evidence that the maximal benefit of dendritic cell (DC)-based cancer immunotherapy may be achieved by combination with other therapies that act to immunomodulation and tumor microenvironment. In this study, we tried to obtain the best efficacy of immunotherapy using DC vaccination in combination with lenalidomide and PD-1 blockade in a murine myeloma model. After establishing myeloma-bearing mice, five treatment groups were designed to be a mimic protocol as like treatment in clinics as following: 1) PBS control, 2) DCs, 3) DCs + lenalidomide, 4) DCs + PD-1 blockade, and 5) DCs + lenalidomide + PD-1 blockade. After treatment, preclinical response and in vitro immunological responses were evaluated. DCs combined with lenalidomide and PD-1 blockade showed the best tumor regression among the study groups. These anti-tumor effects have meaningfully related to the decrease of immuno-regulatory populations, such as myeloid-derived suppressor cells (MDSCs), M2 macrophages, and regulatory T cells (Treg) and the increase of effector immune cell populations, including CD4+ and CD8+ T cells, natural killer (NK) cells, and M1 macrophages, accompanied with the activation of cytotoxic T lymphocytes (CTLs) and NK cells in the splenocytes from the treated mice. Moreover, the level of immunosuppressive cytokines, such as TGF-ß and IL-10, was significantly reduced in tumor microenvironment. DC vaccination in combination with lenalidomide plus PD-1 blockade has synergistically induced a strong antitumor immunity by modulating tumor microenvironment in a murine myeloma model. This protocol will become a promising translational approach to improve the efficacy of immunotherapy in the field of MM. DisclosuresNo relevant conflicts of interest to declare.

Therapeutic efficacy of dendritic cell vaccine combined with programmed death 1 inhibitor for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) remains a serious cause of cancer-related deaths worldwide. Developing new therapeutic strategies is urgently needed to improve the outcomes of HCC patients. Dendritic cell (DC)-based vaccines and programmed death 1 (PD-1) immune checkpoint inhibitors have been regarded as potential immunotherapeutics for HCC. However, the therapeutic efficacy of combining these two treatments for HCC remains to be evaluated. In this study, DCs were derived from mouse bone marrow and pulsed with mouse HCC cell lysates to generate a DC vaccine. A monoclonal antibody that blocks the interaction of mouse PD-1 with its ligands was used as a PD-1 inhibitor. An orthotopic HCC mouse model was established to assess the effect of a DC vaccine in combination with a PD-1 inhibitor on overall survival and tumor volume. Compared with the untreated control, single treatment with a DC vaccine or PD-1 inhibitor prolonged the overall survival and reduced the tumor volume of HCC mice. Further, compared with the single treatment with the DC vaccine or the PD-1 inhibitor, a combination treatment using both agents elicited a higher cytotoxicity of T cells against HCC cells and resulted in a better overall survival, smaller tumor volume, and greater tumor cell apoptosis in HCC mice. Our results suggest that a combination treatment with DC vaccine and PD-1 inhibitor may be a promising therapeutic strategy for HCC.

Prognostic Factors for Endometrial and Cervical Cancers of Uterus Treated With Immune-cell Therapy: A Retrospective Study.

In this retrospective study, we aimed to investigate the efficacy of immune-cell therapy using T lymphocytes activated in vitro with or without dendritic cell vaccination in combination with standard therapies in terms of the survival of patients with advanced or recurrent endometrial and cervical cancers of the uterus. A total of 187 patients with advanced or recurrent uterine cancer were enrolled in this study. The correlation between overall survival and various clinical factors was examined by univariate and multivariate analyses. Univariate analysis revealed that the prognosis was improved in uterine cancer patients who received immune-cell therapy without prior chemotherapy or without distant metastasis. Multivariate analysis demonstrated that the absence of prior chemotherapy for endometrial cancer and liver/lung metastasis of cervical cancer are indications for immune-cell therapy. Survival benefit in uterine cancer patients could be potentially obtained by a combination of immune-cell therapy with other therapies.

Potent anti-myeloma efficacy of dendritic cell therapy in combination with pomalidomide and programmed death-ligand 1 blockade in a preclinical model of multiple myeloma.

Dendritic cell (DC)-based vaccines are recognized as a promising immunotherapeutic strategy against cancer; however, the efficacy of immunotherapy with DCs is controlled via immune checkpoints, such as programmed death-ligand 1 (PD-L1). PD-L1 expressed on DC and tumor cells binds to programmed death-1 (PD-1) receptors on the activated T cells, which leads to the inhibition of cytotoxic T cells. Blocking of PD-L1 on DC may lead to improve the efficacy of DC therapy for cancer. Here we demonstrated that DC vaccination in combination with pomalidomide and programmed death-ligand 1 (PD-L1) blockade inhibited tumor growth of a multiple myeloma (MM) mouse model. DCs + pomalidomide with dexamethasone + PD-L1 blockade significantly inhibited immune immunosuppressive factors and promoted proportions of immune effector cells in the spleen and tumor microenvironment. Additionally, functional activities of cytotoxic T lymphocytes and NK cells in spleen were enhanced by DCs + pomalidomide with dexamethasone + PD-L1 blockade. Taken together, this study identifies a potential new therapeutic approach for the treatment of MM. These results also provide a foundation for the future development of immunotherapeutic modalities to inhibit tumor growth and restore immune function in MM.

Potent anti-myeloma efficacy of dendritic cell therapy in combination with pomalidomide and programmed death-ligand 1 blockade in a preclinical model of multiple myeloma

Dendritic cell (DC)-based vaccines are recognized as a promising immunotherapeutic strategy against cancer, and various combination approaches have been developed to enhance DC function by modulating immune responses and tumor microenvironment. In this study, we investigated the efficacy of DC vaccination in combination with pomalidomide and programmed death ligand-1 (PD-L1) blockade in a murine model of multiple myeloma (MM). MOPC-315 cell lines were injected subcutaneously to establish MM bearing mice.

Dendritic cell vaccination in metastatic uveal melanoma as compassionate treatment: Immunological and clinical responses.

e21024 Background: Other than cutaneous melanoma, metastatic uveal melanoma (UM) is minimally responsive to checkpoint inhibitors. The prognosis remains very poor with mortality rates nearly unchanged over the last decades. The recently growing insight that immunotherapy significantly improves outcomes for cancer patients led to a re-emergence of vaccines including dendritic cell (DC) vaccines. Methods: We vaccinated an UM patient in a compassionate use setting and assessed the immunological and clinical responses. Based on this experience we performed individual compassionate treatments in other UM patients using DC loaded by peptide pulsing and/or mRNA transfection (autologous tumor RNA or RNA coding for tumor antigens). Results: The first patient was vaccinated in 2013 after a liver metastasis was resected and checkpoint blockade with ipilimumab was started. In 2014 the patient showed progression in the liver. We continued DC vaccination in shorter intervals and adapted antigen loading (with mRNA coding for an individual GNAQ driver mutation) accompanied by a further cycle of ipilimumab. Therapy resulted in complete remission of liver metastases, but the patient developed new skin metastases. Again the loading of DC was adapted (peptides of passenger mutations predicted after Next-Generation Sequencing) and infusions with pembrolizumab were started. Pathology from some regressing lesions showed a massive T cell infiltration and in parallel GNAQ mutation-specific T cells could be found in the patient’s blood. Skin metastases regressed and the patient is now free of detectable tumor after 65 months. Immune monitoring in the patient’s blood showed a vaccine-induced functional T cell response against the QNAQ-driver mutation. Three of other four patients are also still alive, one in complete remission under DC vaccination in combination with pembrolizumab, two of them showing measurable disease, and one deceased disease related after 28 months, resulting in a median OS of the five patients of 36.4 months. Immune monitoring in one of those patients showed a CD4+ and CD8+ INF-gamma T cell response against the autologous tumor RNA vaccine. No grade 3 or 4 toxicity occurred. Conclusions: The observed prolonged median OS and the fact that 2/5 patients remain disease-free is definitely encouraging. Vaccination immunotherapy with antigen-laden DC is a potential therapeutic option for patients with metastatic uveal melanoma. Combinations with checkpoint inhibitors proved promising, and should be further evaluated in clinical trials.

Enhancement of Antitumor Immunity Using Dendritic Cells Combined with Lenalidomide and Programmed Death Ligand-1 Blockade in Multiple Myeloma Mouse Model

Background: The therapeutic efficacy of dendritic cell (DC)-based immunotherapy may be potentiated in combination with other anticancer therapies that enhance DC function by modulating immune responses and the tumor microenvironment. In this study, we investigated the efficacy of DC vaccination in combination with lenalidomide and programmed death (PD)-1 blockade in a model of murine myeloma.Materials &Methods: MOPC-315 cell lines were injected subcutaneously to establish myeloma-bearing mice and the following five test groups were established: PBS control, DCs, DCs + lenalidomide, DCs + PD-1 blockade, and DCs + lenalidomide + PD-1 blockade. On day 0, mice were injected subcutaneously in the right flank with 5 × 105 MOPC-315 cells in a volume of 0.1 mL. After tumor growth, lenalidomide (0.5 mg/kg/day) was administrated orally once a day for 25 days with a 3-day break after the first 11-day dosing period. Each dose of DCs (1 × 106/mouse) was injected subcutaneously into the left flank of BALB/c mice in a volume of 0.1 mL PBS on days 11, 15, 25, and 29; anti-PD-1 (250 µg/mouse) was injected intraperitoneally in a 0.1 mL volume on the same days as DC vaccination.Results: This study showed that DC vaccination combined to the lenalidomide and PD-1 blockade regiment further inhibited MM tumor growth, consequently prolonging the survival of tumor-bearing mice. These effects were associated with a significant increase in IFN-γ-secreting splenocytes against MOPC-315 and YAC-1 cells, as well as the significantly increased the number of effector CD4+ T cells, CD8+ T cells, effector memory T cells, effector NK cells, and M1 macrophages while effectively discouraging suppressor cells, such as myeloid-derived suppressor cells (MDSCs), M2 macrophages, and regulatory T cells (Tregs) in the systemic immune compartment. These findings evidence the induction of systemic immune response potentially being able to eradicate disseminated diseases. In this study, DCs combined with lenalidomide and PD-1 blockade also heightened the anti-myeloma cell mediate immunity by inducing the Th1 polarization, as evidenced by the high-level production of IFN-γ in the spleen, and by suppressing Th2 immune responses, as evidenced by the low-level production of IL-10 and TGF-β in the spleen and tumor site. Tregs, MDSCs, and M2 macrophages are major elements molding the potent immunosuppressive environment in tumor tissues. The inhibition of Treg, MDSC, and M2 macrophage accumulation in the spleen should further contribute to effective anti-myeloma cell mediate immunity in the systemic immune compartment by reciprocally activating DCs or cytotoxic T lymphocytes.Conclusion: This study suggests that lenalidomide plus PD-1 blockade treatment synergistically enhances the efficacy of DC vaccination in a murine myeloma model by inhibiting the generation of immunosuppressive cells and the Th2 immune response and enhancing effector cells and the Th1 immune responses. We hereby propose a framework for a more efficacious DC-based vaccination strategy against MM with the combination of immunomodulatory drug lenalidomide and anti-PD-1 antibody. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Lenalidomide and Programmed Death-1 Blockade Synergistically Enhances the Effects of Dendritic Cell Vaccination in a Model of Murine Myeloma.

The therapeutic efficacy of dendritic cell (DC)-based immunotherapy may be potentiated in combination with other anticancer therapies that enhance DC function by modulating immune responses and the tumor microenvironment. In this study, we investigated the efficacy of DC vaccination in combination with lenalidomide and programmed death (PD)-1 blockade in a model of murine myeloma. MOPC-315 cell lines were injected subcutaneously to establish myeloma-bearing mice and the following five test groups were established: PBS control, DCs, DCs + lenalidomide, DCs + PD-1 blockade, and DCs + lenalidomide + PD-1 blockade. The combination of DCs plus lenalidomide and PD-1 blockade more potently inhibited tumor growth compared to the other groups. This effect was associated with a reduction in immune suppressor cells (such as myeloid-derived suppressor cells, M2 macrophages, and regulatory T cells) and an increase in immune effector cells [such as CD4+ and CD8+ T cells, natural killer (NK) cells, and M1 macrophages] in the spleen. Functional activities of cytotoxic T lymphocytes and NK cells were also enhanced by the triple combination. Levels of immunosuppressive cytokines, such as TGF-β and IL-10, were significantly reduced in the tumor microenvironment. These findings suggest that the combination of DCs plus lenalidomide and PD-1 blockade synergistically establishes a robust anti-myeloma immunity through a two-way mechanism, which inhibits immunosuppressive cells while activating effector cells with superior polarization of the Th1/Th2 balance in favor of the tumor immune response. This result should provide an experimental ground for incorporating check point inhibitors to existing immunotherapeutic modalities against multiple myeloma.

A phase-1/2 study of adenovirus-p53 transduced dendritic cell vaccine in combination with indoximod in metastatic solid tumors and invasive breast cancer.

BackgroundIndoleamine 2, 3-dioxygenase is an enzyme that causes immunosuppression in tumors. Indoximod inhibits the indoleamine 2, 3-dioxygenase pathway and enhances immunologic responses to dendritic cell (DC) vaccines preclinically. Adenovirus p53 (Ad.p53) is used to generate DC vaccines against p53. A phase-1/2 trial of indoximod with Ad.p53-DC vaccine was conducted.Materials and MethodsThe phase-1 study combined 7 indoximod dose levels with < 6 Ad.p53-DC vaccinations every 2 weeks. Primary endpoints were maximum-tolerated dose in phase 1 and objective response in phase 2. Flow cytometry measured immune responses.ResultsThirty-nine patients were treated. In combination with Ad.p53-DC vaccine, the maximum-tolerated dose of indoximod was 1600 mg twice daily. Attributable toxicities were grade 1–2. Best response was stable disease in 4 patients. Immunologic responses were detected in 7 out of 23 evaluable patients. Median progression-free survival was 13.3 weeks (95% confidence interval, 12.97–21.85) and median overall survival was 20.71 weeks (95% confidence interval, 25.75–46.15). Nine out of 22 patients (40%) benefitted from chemotherapy after vaccination. Median overall survival in chemotherapy responders was 69.4 weeks (30.1–122.1).ConclusionsIndoximod 1600 mg twice daily with Ad.p53-DC was well tolerated. There may have been a chemosensitization effect. Future trials should explore combining this treatment with chemotherapy.

Dendritic cell vaccination in combination with docetaxel for patients with metastatic castration-resistant prostate cancer: A randomized phase II study

Background aimsWe investigated whether the addition of an autologous dendritic cell–based cancer vaccine (DCvac) induces an immune response in patients with metastatic castration-resistant prostate cancer treated with docetaxel. MethodsForty-three patients were randomized 1:1 to receive up to 10 cycles of docetaxel alone, 75 mg/m2 every 3 weeks or in combination with DCvac. Monocytes were harvested following a leukapheresis procedure, matured ex vivo and subsequently transfected with messenger RNA encoding multiple tumor-associated antigens (TAAs). DCvac was administered intradermally twice through treatment cycles 1–4 and once through treatment cycles 5–10. Immune cell composition and antigen-specific responses were analyzed using flow cytometry, ELISpot and delayed type hypersensitivity (DTH) tests. Toxicity was graded according to Common Terminology Criteria for Adverse Events version 3.0. Progression-free survival (PFS) and disease-specific survival (DSS) was calculated using the Kaplan-Meier method. ResultsProstate-specific antigen responses were similar in patients treated with docetaxel alone and combination therapy (58% versus 38%; P = 0.21). PFS and DSS were comparable: 5.5 versus 5.7 months (P = 0.62, log rank) and 21.9 versus 25.1 months (P = 0.60, log rank). Nine (50%) and 14 (78%) patients treated with docetaxel and DCvac had a TAA-specific or vaccine-specific immune response in the ELISpot and DTH analysis, respectively. Vaccine induced toxicity was limited to local reactions. Decline in myeloid-derived suppressor cells at the third treatment cycle was found to be an independent predictor of DSS. ConclusionsThe addition of DCvac was safe. Immune responses were detected in approximately half of the patients investigated.

1085P - Dendritic cell vaccination in combination with docetaxel for patients with prostate cancer – a randomized phase II study

1085P - Dendritic cell vaccination in combination with docetaxel for patients with prostate cancer – a randomized phase II study

Abstract 2235: Clinical results of a Phase I/II trial of adjuvant therapeutic vaccination in high risk resected prostate cancer patients using autologous dendritic cells loaded with mRNA from primary prostate cancer tissue, hTERT and survivin

Abstract Prostate cancer patients diagnosed with high Gleason score (≥ 8) and large tumors (≥T2c) are considered high-risk patients and &amp;gt;50% will develop an early biochemical relapse. Presently, there is no curative therapy available for patients with biochemical relapse. Based on these findings we initiated in January 2011 a Phase I/II dendritic cell (DC) vaccine study. Patients included have pathological stage pT2 - pT3b, Gleason score 7b-10, pN0, pN+ or pNx and postoperative PSA &amp;lt; 0.2 μg/L. Following surgery autologous tumor cell lines were established from each patient using an in-house culturing method. mRNA from the tumor cell line was produced and used for DC vaccination in combination with mRNA hTERT and mRNA Survivin. DCs were differentiated from enriched monocytes, cultured for 2 days with IL4 and GM-CSF and matured with Jonuleit-maturation cocktail for 24 hours. The matured DCs were transfected separately with the 3 different mRNAs and then frozen and stored until use. The vaccination regimen includes one vaccine per week for four weeks, followed by monthly “vaccine boost” during the first year, then every 3 months the second and third year. Recently, a novel 3 days DC protocol using a TLR7/8-agonist maturation cocktail has been implemented at our department. Based on encouraging clinical results with this type of DCs in compassionate use patients with different types of tumors, we decided to change our DCs protocol to the new generation DCs. Of the 20 patients included in this trial 15 patients have been given the standard fast DCs and 5 have been vaccinated with the new type of DCs. 8 Patients given standard DC has completed 3 years of vaccination and 4 has completed 2 years of vaccination. 3 of 15 patient given standard DC has experienced PSA relapse during vaccination. None of the patients given the new type of DC has so far experienced raise in PSA levels. To our knowledge this is the first adjuvant DC vaccine study in high risk prostate cancer and we conclude that the study is feasible, safe and utmost promising. Extensive immune monitoring is ongoing taking advantage of the established autologous tumor cell lines from all patients. Citation Format: Anne Merete Aa. Tryggestad, Karol Axcrona, Iris Bigalke, Else M. Inderberg-Suso, Gjertrud Skorstad, Ulrika Axcrona, Steinar Aamdal, Gustav Gaudernack, Dolores Schendel, Wolfgang Lilleby, Svein Dueland, Gunnar Kvalheim. Clinical results of a Phase I/II trial of adjuvant therapeutic vaccination in high risk resected prostate cancer patients using autologous dendritic cells loaded with mRNA from primary prostate cancer tissue, hTERT and survivin. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2235.

MRNA-transfected dendritic cell vaccine in combination with metronomic cyclophosphamide as treatment for patients with advanced malignant melanoma

ABSTRACTIntroduction: Vaccination with dendritic cells (DCs) has generally not fulfilled its promise in cancer immunotherapy due to ineffective translation of immune responses into clinical responses. A proposed reason for this is intrinsic immune regulatory mechanisms, such as regulatory T cells (Tregs). A metronomic regimen of cyclophosphamide (mCy) has been shown to selectively deplete Tregs. To test this in a clinical setting, we conducted a phase I trial to evaluate the feasibility and safety of vaccination with DCs transfected with mRNA in combination with mCy in patients with metastatic malignant melanoma (MM). In addition, clinical and immunological effect of the treatment was evaluated.Experimental design: Twenty-two patients were enrolled and treated with six cycles of cyclophosphamide 50 mg orally bi-daily for a week every second week (day 1–7). During the six cycles patients received at least 5 × 106 autologous DCs administered by intradermal (i.d.) injection in the week without chemotherapy. Patients were evaluated 12 and 27 weeks and every 3rd mo thereafter with CT scans according to RECIST 1.0. Blood samples for immune monitoring were collected at baseline, at the time of 4th and 6th vaccines. Immune monitoring consisted of IFNγ ELISpot assay, proliferation assay, and flow cytometry for enumeration of immune cell subsets.Results: Toxicity was manageable. Eighteen patients were evaluable after six cycles. Of these, nine patients had progressive disease as best response and nine patients achieved stable disease. In three patients minor tumor regression was observed. By IFNγ ELISpot and proliferation assay immune responses were seen in 6/17 and 4/17 patients, respectively; however, no correlation with clinical response was found. The percentage of Tregs was unchanged during treatment.Conclusion: Treatment with autologous DCs transfected with mRNA in combination with mCy was feasible and safe. Importantly, mCy did not alter the percentage of Tregs in our patient cohort. There was an indication of clinical benefit; however, more knowledge is needed in order for DCs to be exploited as a therapeutic option.