Autologous Dendritic Cell Vaccine Research Articles

Association of Autologous Tumor Lysate-Loaded Dendritic Cell Vaccination With Extension of Survival Among Patients With Newly Diagnosed and Recurrent Glioblastoma

Glioblastoma is the most lethal primary brain cancer. Clinical outcomes for glioblastoma remain poor, and new treatments are needed. To investigate whether adding autologous tumor lysate-loaded dendritic cell vaccine (DCVax-L) to standard of care (SOC) extends survival among patients with glioblastoma. This phase 3, prospective, externally controlled nonrandomized trial compared overall survival (OS) in patients with newly diagnosed glioblastoma (nGBM) and recurrent glioblastoma (rGBM) treated with DCVax-L plus SOC vs contemporaneous matched external control patients treated with SOC. This international, multicenter trial was conducted at 94 sites in 4 countries from August 2007 to November 2015. Data analysis was conducted from October 2020 to September 2021. The active treatment was DCVax-L plus SOC temozolomide. The nGBM external control patients received SOC temozolomide and placebo; the rGBM external controls received approved rGBM therapies. The primary and secondary end points compared overall survival (OS) in nGBM and rGBM, respectively, with contemporaneous matched external control populations from the control groups of other formal randomized clinical trials. A total of 331 patients were enrolled in the trial, with 232 randomized to the DCVax-L group and 99 to the placebo group. Median OS (mOS) for the 232 patients with nGBM receiving DCVax-L was 19.3 (95% CI, 17.5-21.3) months from randomization (22.4 months from surgery) vs 16.5 (95% CI, 16.0-17.5) months from randomization in control patients (HR = 0.80; 98% CI, 0.00-0.94; P = .002). Survival at 48 months from randomization was 15.7% vs 9.9%, and at 60 months, it was 13.0% vs 5.7%. For 64 patients with rGBM receiving DCVax-L, mOS was 13.2 (95% CI, 9.7-16.8) months from relapse vs 7.8 (95% CI, 7.2-8.2) months among control patients (HR, 0.58; 98% CI, 0.00-0.76; P < .001). Survival at 24 and 30 months after recurrence was 20.7% vs 9.6% and 11.1% vs 5.1%, respectively. Survival was improved in patients with nGBM with methylated MGMT receiving DCVax-L compared with external control patients (HR, 0.74; 98% CI, 0.55-1.00; P = .03). In this study, adding DCVax-L to SOC resulted in clinically meaningful and statistically significant extension of survival for patients with both nGBM and rGBM compared with contemporaneous, matched external controls who received SOC alone. ClinicalTrials.gov Identifier: NCT00045968.

CTIM-27. AUTOLOGOUS TUMOR LYSATE-LOADED DENDRITIC CELL VACCINATION IMPROVES SURVIVAL IN PATIENTS WITH NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA: SURVIVAL RESULTS FROM A PHASE 3 TRIAL

Abstract BACKGROUND Standard of care (SOC) and patient survival in glioblastoma have changed little in the past 17 years. We evaluated in a phase 3 trial whether adding an autologous tumor lysate-loaded dendritic cell vaccine (murcidencel) to SOC extends survival. Patients and METHODS Newly diagnosed glioblastoma patients were randomized 2:1 to either murcidencel or placebo. Under a crossover design, all patients could receive murcidencel following tumor recurrence. All parties remained blinded regarding treatments before recurrence. Patients thus received murcidencel at new diagnosis (nGBM) or at recurrence (rGBM) following crossover from placebo. The primary and secondary endpoints compare overall survival (OS) with contemporaneous, matched external controls. Four sets of analyses were conducted to ensure rigorous matching of the controls, reduce biases, and confirm the robustness of the results. RESULTS 331 patients were enrolled. With the crossover, 89% received murcidencel. Median OS (mOS) for nGBM patients (n = 232) was 19.3 months from randomization (22.4 months from surgery) with murcidencel vs. 16.5 months from randomization in the controls (HR = 0.80, p = 0.002). Survival at 48 months from randomization was 15.7% vs. 9.9%, and at 60 months was 13% vs. 5.7%. For rGBM (n = 64), mOS was 13.2 months from relapse vs. 7.8 months in the controls (HR = 0.58, p &amp;lt; 0.001). Survival at 24 months post-recurrence was 20.7% vs. 9.6%, and at 30 months post-recurrence was 11.1% vs 5.1%. In nGBM patients with methylated MGMT (n = 90), mOS was 30.2 months from randomization (33 months from surgery) with murcidencel vs. 21.3 months from randomization in the controls (HR = 0.74, p = 0.027). The treatment was well tolerated, with only 5 serious adverse events deemed at least possibly related to the vaccine. CONCLUSION Clinically meaningful and statistically significant survival extension was seen in both nGBM and rGBM patients treated with murcidencel and SOC compared with contemporaneous, matched external controls who received SOC alone.

A Phase I-II multicenter trial with Avelumab plus autologous dendritic cell vaccine in pre-treated mismatch repair-proficient (MSS) metastatic colorectal cancer patients; GEMCAD 1602 study

BackgroundImmune check-point blockade (ICB) has shown clinical benefit in mismatch repair-deficient/microsatellite instability high metastatic colorectal cancer (mCRC) but not in mismatch repair-proficient/microsatellite stable patients. Cancer vaccines with autologous dendritic cells (ADC) could be a complementary therapeutic approach to ICB as this combination has the potential to achieve synergistic effects.MethodsThis was a Phase I/II multicentric study with translational sub-studies, to evaluate the safety, pharmacodynamics and anti-tumor effects of Avelumab plus ADC vaccine in heavily pre-treated MSS mCRC patients. Primary objective was to determine the maximum tolerated dose and the efficacy of the combination. The primary end-point was 40% progression-free survival at 6 months with a 2 Simon Stage. ResultsA total of 28 patients were screened and 19 pts were included. Combined therapy was safe and well tolerated. An interim analysis (Simon design first-stage) recommended early termination because only 2/19 (11%) patients were disease free at 6 months. Median PFS was 3.1 months [2.1–5.3 months] and overall survival was 12.2 months [3.2–23.2 months]. Stimulation of immune system was observed in vitro but not clinically. The evaluation of basal RNA-seq noted significant changes between pre and post-therapy liver biopsies related to lipid metabolism and transport, inflammation and oxidative stress pathways.ConclusionsThe combination of Avelumab plus ADC vaccine is safe and well tolerated but exhibited modest clinical activity. Our study describes, for the first-time, a de novo post-therapy metabolic rewiring, that could represent novel immunotherapy-induced tumor vulnerabilities.

Роль факторов иммуносупрессии в прогнозе эффективности клеточной иммунотерапии у пациентов с солидными опухолями

Production of different factors with wide immunosuppressive properties by tumor cells is one of the mechanisms that support tumor growth. We think that immunosuppressive action of tumor cells should be taken into account for cellular antitumor therapy optimization. Aim of the study – to evaluate the effectiveness of cellular immunotherapy factors (ISF) for response prediction in patients receiving tag7/PGRP-S gene modified tumor cells (GMV) or autologous dendritic cells vaccine (DCV) for melanoma (Mel), kidney cancer (RCC) and soft tissue sarcoma (STS). Material and methods. We have treated 204 patients with cellular therapy since 2001 till 2016 (88 – GMV, 1 16 – DCV). ISF (MICA, TGF-β, IL-10 и VEGF) were measured in tumor tissue cultures of 88 patients (71 – Mel, 6 – RCC, 11 – STS). Median age of patients was 51 year. Patient were divided as having insufficient response (IR) or sufficient response (SR) for the analysis purpose. Results. ISF concentration in cultures of patients with IR was higher than in patients with SR (р &lt; 0.05). SR could be predicted correctly in 74.4% using ISF. The most important factor was TGF-β1. In the Cox model TGF-β1 and MICA levels were significant predictors of overall survival for Mel patients (р &lt; 0.05). VEGF was the most important factor for time to progression prognosis. Spirman correlations showed moderate significant correlation between ISF (р &lt; 0.05). Conclusions. ISF concentration in cell cultures obtained from the patients with Mel, RCC or STS is important independent predictive factor for time to progression and overall survival. Our data supports rigid selection criteria based on biological properties of tumor cells for patients receiving cellular therapy for solid tumors

IMG-07. Contralateral transient contrast enhancement in a patient with IDH1wt MGMT promoter-methylated GBM responding to TMZ and individualized multimodal immunotherapy

Abstract Immunotherapy-induced MRI changes remain challenging when treating GBM patients with immunotherapy as part of a combined treatment. The iRANO criteria provide a decision-tree in order to avoid over- and under-treatment reactions when contrast-enhancing lesions become visible and should be interpreted. We report a 34-year female, 34 weeks pregnant, who presented with epilepsy, and was diagnosed with IDH1wt MGMT promoter-methylated GBM after biopsy. On MRI, the left occipital lesion was mostly cystic-necrotic with peripheral contrast enhancement, and crossed over the corpus callosum to the right. The volume was calculated as 64 cm³ (abc/2 formula). She was treated with radiochemotherapy and 12 TMZm cycles. Within each TMZ cycle 5 days of immunogenic cell death (ICD) therapy (5 injections with Newcastle Disease Virus and 5 sessions of modulated electrohyperthermia (Oncotherm 50 min 40-60 Watt) was added at days 8 to 12. After all chemo-/ICD-therapy we continued with active specific immunotherapy: two autologous mature monocyte-derived dendritic cell vaccines loaded with ICD therapy-induced serum-derived antigenic extracellular microvesicles and apoptotic bodies (IO-Vac®). One month after the second IO-Vac®, 17 months after diagnosis, a temporal right FLAIR-visible region showed expansion, and three months later also diffuse contrast enhancement, which was confirmed in a control scan one month later. The original tumor was meanwhile reduced to 16 cm³. However, in the last available scan, two months after the former, the contrast enhancement was disappeared, and the pathologic area on FLAIR was diminished. The original tumor size was reduced to 2 cm³, two year after first diagnosis. She showed allergic skin reactions to TMZ, which was covered with systemic histamine intake. There were no side effects related to multimodal immunotherapy. Transient MRI changes can be observed even in distance from the original tumor and can be interpreted as immune-mediated effects when the original tumor is responding.

Lung Cancer Therapeutics Landscape, A Current Overview

Lung cancer is the leading cause of death across the world, both among men and women. According to the CDC, Center for Disease Control and Prevention, every year, about 200,000 people are diagnosed and about 150,000 people die because of lung cancer. Lung cancer begins in the lungs, a pair of respiratory organs in the thoracic cavity. Majority of the lung cancers are carcinogenic in nature, which means the uncontrolled tumor cell growth causes malignant tumor cells, eventually spread out from the lungs to the nearby lymph nodes and possibly to other organs, for example, the brain. Two major types of lung cancers are small cell and non-small cell lung cancers. Non-small cell lung cancer constitutes 80 to 90% of all lung cancers and can further be subdivided into adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. These different types of lung cancers develop differently, grow differently, and are treated differently. Cigarette smoking has been attributed to the number one cause of lung cancer across the world and links to almost 80 to 90% of all lung cancers. Historically, lung cancers have been treated, using conventional therapies which include resection surgery, radiotherapy, and chemotherapies. Recent advancement in science lead to targeted therapies for lung cancer, which includes ALK inhibitors, EGFR inhibitors, VEGF inhibitors, and immunotherapies. This review delves into the recent advancement in the lung cancer therapeutic landscape and discusses recent treatment strategies and options available to the patients. This review also discusses new therapies in the pipeline for lung cancers including allogeneic vaccines. Peptide or protein vaccines, autologous dendritic cell vaccines, DNA vaccines, vector-based vaccines, CAR-T therapies, and Heme-sequestering proteins, which are used to target cancer cells.

Phase I Clinical Trial of an Autologous Dendritic Cell Vaccine Against HER2 Shows Safety and Preliminary Clinical Efficacy.

BackgroundDespite recent advances, there is an urgent need for agents targeting HER2-expressing cancers other than breast cancer. We report a phase I study (NCT01730118) of a dendritic cell (DC) vaccine targeting HER2 in patients with metastatic cancer or bladder cancer at high risk of relapse.Patients and MethodsPart 1 of the study enrolled patients with HER2-expressing metastatic cancer that had progressed after at least standard treatment and patients who underwent definitive treatment for invasive bladder cancer with no evidence of disease at the time of enrollment. Part 2 enrolled patients with HER2-expressing metastatic cancer who had progressed after anti-HER2 therapy. The DC vaccines were prepared from autologous monocytes and transduced with an adenoviral vector expressing the extracellular and transmembrane domains of HER2 (AdHER2). A total of five doses were planned, and adverse events were recorded in patients who received at least one dose. Objective response was evaluated by unidimensional immune-related response criteria every 8 weeks in patients who received at least two doses. Humoral and cellular immunogenicity were assessed in patients who received more than three doses.ResultsA total of 33 patients were enrolled at four dose levels (5 × 106, 10 × 106, 20 × 106, and 40 × 106 DCs). Median follow-up duration was 36 weeks (4–124); 10 patients completed five doses. The main reason for going off-study was disease progression. The main adverse events attributable to the vaccine were injection-site reactions. No cardiac toxicity was noted. Seven of 21 evaluable patients (33.3%) demonstrated clinical benefit (1 complete response, 1 partial response, and 5 stable disease). After ≥3 doses, an antibody response was detected in 3 of 13 patients (23.1%), including patients with complete and partial responses. Lymphocytes from 10 of 11 patients (90.9%) showed induction of anti-HER2 responses measured by the production of at least one of interferon-gamma, granzyme B, or tumor necrosis factor-alpha, and there were multifunctional responses in 8 of 11 patients (72.7%).ConclusionsThe AdHER2 DC vaccine showed evidence of immunogenicity and preliminary clinical benefit in patients with HER2-expressing cancers, along with an excellent safety profile. It shows promise for further clinical applications, especially in combination regimens.

A Phase I Study of Autologous Dendritic Cell Vaccine Pulsed with Allogeneic Stem-like Cell Line Lysate in Patients with Newly Diagnosed or Recurrent Glioblastoma

Abstract Purpose: Glioblastoma (GBM) is a heterogeneous malignancy with multiple subpopulations of cancer cells present within any tumor. We present the results of a phase I clinical trial using an autologous dendritic cell (DC) vaccine pulsed with lysate derived from a GBM stem-like cell line. Patients and Methods: Patients with newly diagnosed and recurrent GBM were enrolled as separate cohorts. Eligibility criteria included a qualifying surgical resection or minimal tumor size, ≤ 4-mg dexamethasone daily dose, and Karnofsky score ≥70. Vaccine treatment consisted of two phases: an induction phase with vaccine given weekly for 4 weeks, and a maintenance phase with vaccines administered every 8 weeks until depletion of supply or disease progression. Patients with newly diagnosed GBM also received standard-of-care radiation and temozolomide. The primary objective for this open-label, single-institution trial was to assess the safety and tolerability of the autologous DC vaccine. Results: For the 11 patients with newly diagnosed GBM, median progression-free survival (PFS) was 8.75 months, and median overall survival was 20.36 months. For the 25 patients with recurrent GBM, median PFS was 3.23 months, 6-month PFS was 24%, and median survival was 11.97 months. A subset of patients developed a cytotoxic T-cell response as determined by an IFNγ ELISpot assay. Conclusions: In this trial, treatment of newly diagnosed and recurrent GBM with autologous DC vaccine pulsed with lysate derived from an allogeneic stem-like cell line was safe and well tolerated. Clinical outcomes add to the body of evidence suggesting that immunotherapy plays a role in the treatment of GBM.

A Personalized Neoantigen Vaccine in Combination with Platinum-Based Chemotherapy Induces a T-Cell Response Coinciding with a Complete Response in Endometrial Carcinoma.

Simple SummaryWe investigated the feasibility and immunogenicity of an autologous Dendritic Cell (DC) vaccine pulsed with peptide neoantigens in combination with a standard of care regimen. The vaccine program took place in a serous endometrial mismatch repair (MMR) deficiency setting. We demonstrate for the first time the feasibility of producing a peptide DC vaccine in endometrial carcinoma. The safety and immunogenicity of this personalized vaccine was demonstrated by the detection of polyfunctional and durable T-cell responses.Endometrial cancer (EC) is a common gynecological malignancy and the fourth most common malignancy in European and North American women. Amongst EC, the advanced serous, p53-mutated, and pMMR subtypes have the highest risk of relapse despite optimal standard of care therapy. At present, there is no standard of care maintenance treatment to prevent relapse among these high-risk patients. Vaccines are a form of immunotherapy that can potentially increase the immunogenicity of pMMR, serous, and p53-mutated tumors to render them responsive to check point inhibitor-based immunotherapy. We demonstrate, for the first time, the feasibility of generating a personalized dendritic cell vaccine pulsed with peptide neoantigens in a patient with pMMR, p53-mutated, and serous endometrial adenocarcinoma (SEC). The personalized vaccine was administered in combination with systemic chemotherapy to treat an inoperable metastatic recurrence. This treatment association demonstrated the safety and immunogenicity of the personalized dendritic cell vaccine. Interestingly, a complete oncological response was obtained with respect to both radiological assessment and the tumor marker CA-125.

An Autologous Tumor Lysate Dendritic Cell Vaccine Is Most Effective in Recurrent, Advanced-Stage Melanoma in a Randomized Controlled Trial

O'Shea, Anne MD; Chick, Robert C. MD; Adams, Alexandra MD, MPH; McCarthy, Patrick MD; Bohan, Phillip Kemp MD; Vreeland, Timothy J. MD, FACS; Clifton, Guy T. MD, FACS; Peoples, George E. Jr. MD, FACS Author Information

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.

A Bayesian network meta-analysis of comparison of cancer therapeutic vaccines for melanoma.

Several approaches to active immunotherapy for melanoma, including peptide‐based vaccines (PVs), autologous tumour cell vaccines (TCVs), allogeneic TCVs and autologous dendritic cell vaccines (DCVs), have been investigated in clinical trials. However, comprehensive evidence comparing these interventions remains unavailable. The objective of this study was to expand previous work to compare and rank the immunotherapeutic strategies for melanoma in terms of overall survival and toxic effects with a Bayesian network meta‐analysis. Methodologically, we performed a network meta‐analysis of head‐to‐head randomized controlled trials comparing and ranking cancer vaccine approaches for patients with melanoma. PubMed, MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, the WHO International Clinical Trials Registry Platform and ClinicalTrials.gov were searched up to 31 July 2020. We estimated summary hazard ratios for death and risk ratios for toxicity. The effects of the underlying prognostic variable on survival benefits were examined by meta‐regression. We performed subgroup analysis for the outcomes based on metastatic categories. Overall, we identified 4776 citations, of which 15 head‐to‐head randomized controlled trials (3162 participants) were included in the analysis. In terms of efficacy, allogeneic tumour cell vaccines plus immunotherapy adjuvants, peptide‐based vaccines plus immunotherapy adjuvants and standard therapy were more effective than peptide vaccines. The proportion of women was inversely associated with mortality risk. For safety, all treatments were inferior to allogeneic tumour cell vaccines except for allogeneic tumour cell vaccines plus chemotherapy. Peptide vaccines plus immunotherapy adjuvants led to an increased risk of adverse events compared to allogeneic tumour cell vaccines plus immunotherapy adjuvants. These results suggest that allogeneic TCV and autologous DCV are better than standard therapy. PV plus immune modulators are the most effective strategy among all comparable strategies but is associated with increased toxicity. Any combination regimens for cancer therapeutic vaccines need to be balanced between risk and benefit profiles.

The Immunotherapy Landscape in Adrenocortical Cancer.

Simple SummaryAdrenocortical carcinoma is a rare and life-threatening cancer originating from the adrenal glands. Although aggressive surgical interventions may cure this cancer when detected at early stages, treatments for advanced or metastatic disease are limited and often unable to shrink or control the growth of this tumor. Research into new treatments is needed for adrenal cortical carcinoma and other rare cancers. For cancers and other medical conditions, new therapies can be tested through clinical trials, in which patients are treated with new medications or innovative medication combinations. Among these novel and innovative treatments are immunotherapies. These therapies are playing an increasingly important role in the treatment of multiple different cancers. This article focuses on the various immunotherapies that have been, currently are, or will be tested in clinical trials for the treatment of adrenocortical carcinoma.Adrenocortical carcinoma (ACC) is a rare cancer of the adrenal gland that is frequently associated with excess production of adrenal hormones. Although surgical resection may be curative in early-stage disease, few effective therapeutic options exist in the inoperable advanced or metastatic setting. Immunotherapies, inclusive of a broad array of immune-activating and immune-modulating antineoplastic agents, have demonstrated clinical benefit in a wide range of solid and hematologic malignancies. Due to the broad activity across multiple cancer types, there is significant interest in testing these agents in rare tumors, including ACC. Multiple clinical trials evaluating immunotherapies for the treatment of ACC have been conducted, and many more are ongoing or planned. Immunotherapies that have been evaluated in clinical trials for ACC include the immune checkpoint inhibitors pembrolizumab, nivolumab, and avelumab. Other immunotherapies that have been evaluated include the monoclonal antibodies figitumumab and cixutumumab directed against the ACC-expressed insulin-like growth factor 1 (IGF-1) receptor, the recombinant cytotoxin interleukin-13-pseudomonas exotoxin A, and autologous tumor lysate dendritic cell vaccine. These agents have shown modest clinical activity, although nonzero in the case of the immune checkpoint inhibitors. Clinical trials are ongoing to evaluate whether this clinical activity may be augmented through combinations with other immune-acting agents or targeted therapies.

Phase 1 trial of autologous dendritic cell vaccination with imiquimod immunomodulation in children and adults with refractory sarcoma.

11542 Background: Sarcomas are rare, heterogeneous, and aggressive neoplasms that often affect otherwise healthy individuals. Patients with advanced or metastatic sarcomas have dismal outcomes. Immunotherapy presents promising new modalities to help treat sarcomas. One such therapy, autologous dendritic cell (DC) vaccines, using antigen-loaded DCs, intensify the adaptive immune response by enhancing T-cell activity and inducing tumor cell death through apoptosis and cytolysis. We present the results of a phase 1 study of DC vaccine for refractory sarcomas. Methods: A phase 1 dose-escalation study of autologous DC vaccination was conducted in children and adults with recurrent/refractory sarcomas who underwent surgical resection of a primary or metastatic tumor between 2014-2019. A 5+3 dose-escalation schema was chosen to determine safety and recommended phase 2 dose. Patient monocytes were collected by pheresis and incubated with GM-CSF plus IL-4 to generate immature DCs which were then loaded with autologous tumor lysates from the patient’s surgical resection. Three dose levels, 3, 6, and 12 million DCs per treatment were tested. The DC product was administered intradermally in imiquimod-treated skin to complete in situ maturation. Treatment consisted of four weekly injections of the DC product, followed by four monthly “boosters” of tumor lysate. The primary and secondary endpoints included safety/feasibility and preliminary clinical efficacy, respectively. Results: Nineteen patients were enrolled with a median age 50 years (13-75 years) and 47% female. Seven patients were treated on dose level 1 and six each on dose level 2 and 3. Thirteen patients received all planned injections while the remaining six patients progressed during treatment. There was no treatment related dose limiting toxicity. Grade 1-2 fever, headache, arthralgia, injection site reaction attributable to treatment were noted in four patients. There were no adverse events &gt; grade 2. Disease progression before or after completion of study treatment was noted in 15 patients with a median PFS of 9.5 months (95%CI 5.6-28.7). The two-year PFS and OS was 36.8% and 68.1%, respectively. There were seven deaths due to disease, one patient was discharged to hospice and two patients have been lost to follow up. Five patients are currently receiving alternative therapy. Four patients remain in follow up without evidence of disease progression including three patients (pleomorphic myxofibrosarcoma, pleomorphic myosarcoma, and leiomyosarcoma) who are disease free over two years from initiating study therapy and one pediatric patient (Ewing sarcoma) disease free for over one year. Conclusions: Autologous DC vaccine with imiquimod immunomodulation for patients with relapsed/refractory sarcomas is feasible and well-tolerated. Refinement to augment initial and sustained antitumor activity is needed. Clinical trial information: NCT01803152.

Dendritic cell vaccine (DCVAC) combined with chemotherapy (CMT) in patients with newly diagnosed epithelial ovarian carcinoma (EOC) after primary debulking surgery (PDS): Biomarker exploratory analysis of a phase 2, open-label, randomized, multicenter trial.

5521 Background: Most patients with EOC relapse despite PDS and CMT. Autologous DCVAC can present tumor antigens to elicit a durable immune response. We hypothesized that adding DCVAC to CMT stimulates antitumor immunity and improves clinical outcomes. Methods: Key eligibility criteria were FIGO stage III EOC (serous, endometrioid, or mucinous), post-PDS with &lt; 1 cm maximal residuum, no prior systemic therapy, and ECOG 0-2. In part 1, patients were randomized up to 6 weeks after PDS, 1:1:1, into arm A (A; DCVAC concomitant with CMT), arm B (B; DCVAC sequential after CMT), and arm C (C; CMT). Patients were stratified by tumor residuum (0 or &lt; 1 cm). CMT consisted of 6 cycles of carboplatin (AUC 5-7) and paclitaxel (175 mg/m2). Patients in A and B received up to 10 doses of DCVAC (1×107 DCs/dose). The primary endpoint was radiologically assessed progression-free survival (PFS). The key secondary endpoint was overall survival (OS). Results presented refer to a protocol-defined modified intention-to-treat population (mITT) including patients who received ≥1 CMT dose in C or ≥1 DCVAC dose in A and B. Results: Between November 2013 and March 2016, 99 patients were randomized. At the final analysis, the mITT included 31 patients in A, 29 patients in B, and 30 patients in C. Key baseline characteristics and DCVAC exposure were comparable across treatment arms. Median PFS was 20.3 months in A, not reached in B, and 21.4 months in C, with corresponding HRs (95% CI) compared to C of 0.98 (0.48-2.00) in A and 0.39 (0.16-0.96) in B. The PFS benefit in B was statistically significant (p = 0.034) This was supported by a non-significant trend in OS in A and B. Median OS was not reached in any arm at the time of median follow-up of 66 months (34% of events). Patients with low CD8+ T-cell counts (CD8Lo) in tumor samples in A and B had significantly improved clinical outcomes compared to patients in C with CD8Lo: median PFS gain of 6 months (19 vs 13 months) and a more robust OS gain (median not reached vs 31 months), with minimal difference between A and B. This effect could not be attributed to statistical differences in high CD8+ T-cell counts (CD8Hi) density patients. These findings indicated the best clinical outcome in DCVAC patients with immunologically “cold” tumors in both DCVAC arms. DCVAC showed a good safety profile with only 8 DCVAC-related adverse events (Grade 1-2). Conclusions: DCVAC improved PFS and OS outcomes in patients with newly diagnosed EOC, predominantly in patients with immunologically “cold” tumors, thus representing a promising treatment option in this patient population. Clinical trial information: NCT02107937.

Impact of dendritic cell vaccines added to neoadjuvant CT on pathological complete responses in early breast cancer patients according to PD-L1 expression.

585 Background: Breast cancer (BC) in early stages exhibit a naïve and competent immune system that translates into a more prominent TIL infiltration and higher PD-L1 expression as compared to the advanced BC scenario were immunoescape and exhaustion are more prevalent. Expression of PD-L1 has been related to a better pCR when immune checkpoint inhibitors (IPI) have been added to neaodjuvant chemotherapy (NACT) in triple negative BC (TNBC). Our prior results shown dendritic cells vaccines (DCV) increased pCR in both TNBC and luminal B subtypes, with an absolute gain of 20% (p = 0.03) and a safe tolerance. Methods: Eighty-three HER2 negative BC patients with untreated stage II-III were included: 39 patients from the NCT01431196 trial that combine NACT with autologous DCV and 44 patients from a historic control group treated with the same NACT alone. NACT consists of dose dense Epirubicin plus Cyclophosphamide for 4 cycles sequenced to Docetaxel for 4 cycles. PD-L1 expression was measured in the membrane of tumoral cells with monoclonal rabbit anti PD-L1 28.8 pharmaDX (DAKO, Agilent Technologies) in FFPE samples at diagnosis. Primary endpoint was pathologic complete response (pCR) stratified by PD-L1 expression (positive or negative), while secondary endpoints were event-free survival (EFS) and overall survival (OS), also stratified by PD-L1 expression. Results: Both cohorts were well balanced in most of the features. Thirty-three percent of the tumors in the experimental group were PD-L1 positive, whereas 50% of them in the CG expressed PD-L1 (p = 0.06). Pathological CR was observed in 50% of the PD-L1 positive population, in contrast to a 2.8% in the PD-L1 negative in the NACT cohort (p &lt; 0.01) as compared to the patients assigned to the DCV group (33.4% in PD-L1 positive vs 23.1% in PD-L1 negative population; p = 0.16). Among PD-L1 positive population, more pCR were seen in the CG than in the DCV group (50% vs 33.4%; p = 0.06). Within the PD-L1 negative population, more pCR were observed in the DCV group than in the CG (23.1% vs 2.8%; p &lt; 0.05). With a median follow-up of 7 years, no significant differences were observed between the different subgroups neither in EFS (HR = 1.7; 0.42-6.8; p = 0.19) nor in OS (HR = 2.5; 0.56-11, p = 0.43). At 7 years, 20% and 14.4% of the patients relapsed according to the PD-L1 positive versus negative status respectively, and 10.78% versus 13.33% were dead. Conclusions: The benefit of DCV seems to be outstanding in the PD-L1 negative tumors that have a basal immune appropriate milieu. PD-L1 expression implies a more suppressed niche in which DCV are not able to stimulate antigen presentation and cell cytotoxic activity. PD-L1 positive population reach higher responses with both NACT±DCV than PD-L1 negative group, although the benefit seem to be higher in the NACT alone cohort. Further studies combining DVC+IPI together with NACT are needed. Clinical trial information: NCT01431196.

Personalized neoantigen pulsed dendritic cell vaccine for advanced lung cancer

Neoantigens are considered to be ultimate target of tumor immunotherapy due to their high tumor specificity and immunogenicity. Dendritic cell (DCs) vaccines based on neoantigens have exciting effects in treatment of some malignant tumors and are a promising therapeutic modality. Lung cancer is a lethal disease with the highest morbidity and mortality rate in the world. Despite the rapid development of targeted therapy and immune checkpoint inhibitors for lung cancer in recent years, their efficacy is still unsatisfactory overall. Therefore, there is an urgent unmet clinical need for lung cancer treatment. Here, we attempted to treat lung cancer using a personalized neoantigen peptide-pulsed autologous DC vaccine and conducted a single-arm, 2 medical centers, pilot study initiated by the investigator (ChiCTR-ONC-16009100, NCT02956551). The patients enrolled were patients with heavily treated metastatic lung cancer. Candidate neoantigens were derived from whole-exome sequencing and RNA sequencing of fresh biopsy tissues as well as bioinformatics analysis. A total of 12 patients were enrolled in this study. A total of 85 vaccine treatments were administered with a median value of 5 doses/person (range: 3–14 doses/person). In total, 12–30 peptide-based neoantigens were selected for each patient. All treatment-related adverse events were grade 1–2 and there were no delays in dosing due to toxic effects. The objective effectiveness rate was 25%; the disease control rate was 75%; the median progression-free survival was 5.5 months and the median overall survival was 7.9 months. This study provides new evidence for neoantigen vaccine therapy and new therapeutic opportunities for lung cancer treatment.

Preliminary Evaluation of an Autologous Dendritic Cell Vaccine Using Nanoparticle Technology for the Treatment of Canine Malignant Melanoma

Canine malignant melanoma is an aggressive neoplasm that carries a poor prognosis due to its minimal responsiveness to traditional therapy protocols, particularly if the oral cavity, mucocutaneous junctions, or subungual sites are involved. This proof-of-concept study evaluated a prototype autologous dendritic cell vaccine using poly-lactic-co-glycolic (PLGA) nanoparticles containing antigens from patient-derived whole tumor lysate and the adjuvant monophosphoryl lipid A in five canines with stages III-IV malignant melanoma. Nanoparticle constructs biochemical characterization; encapsulation efficiency and kinetic release studies were determined. Our results showed that tumor antigens were successfully incorporated in the PLGA/monophosphoryl lipid A nanoparticle constructs. Additional in vitro experiments showed that the PLGA/monophosphoryl lipid A nanoparticle constructs effectively activated autologous dendritic cells, and generated a greater than twofold increase in the release of the pro-immune cytokine IFN-γ. No significant adverse effects were observed in any of the patients following intradermal vaccination, and flow cytometry of whole blood revealed increased CD4:CD8 T lymphocyte ratios by the completion of the study. These results suggest that a dendritic cell vaccine utilizing PLGA/monophosphoryl lipid A nanoparticle technology could potentially initiate an adaptive immune response and is safe to administer to canine patients. Further in vivo studies with a larger cohort of patients are warranted.

DIPG-38. ADDITION OF MULTIMODAL IMMUNOTHERAPY TO COMBINATION TREATMENT STRATEGIES FOR CHILDREN WITH DIPG: FINAL RESULTS OF A COHORT OF CHILDREN

The prognosis of children with Diffuse Intrinsic Pontine Glioma (DIPG) remains dismal in spite of radio- and chemotherapy or therapies based on molecular biology diagnostics. Immunotherapy is a powerful and promising approach for improving the overall survival (OS). A retrospective analysis for feasibility, immune responsiveness and OS was performed on 41 children treated in compassionate use with Newcastle Disease Virus, hyperthermia and autologous dendritic cell vaccines as part of an individualized combined treatment approach for DIPG patients at diagnosis (n=28), or at time of progression (n=13). All except one patient had reduced values of at least one immune test before starting immunotherapy. In all patients at least one PanTum Detect test was outside the normal range. Ten patients had PDL1 mRNA expression in circulating tumor cells at diagnosis. Multimodal immunotherapy was feasible as scheduled, until progression, in all patients without major toxicity. When immunotherapy was part of primary treatment, median PFS and OS were 8.4m and 14.4m respectively with a 2-year OS of 10.7%. When immunotherapy was given at the time of progression, median PFS and OS calculated from diagnosis were 6.5m and 9.1m respectively. Th1 shift and rise in PanTum Detect test scores were linked with longer OS. Multimodal immunotherapy is feasible without major toxicity, and its value as part of a combination treatment for primary diagnosed DIPG should be elaborated in clinical trials.