Autologous Tumor Cell Vaccine Research Articles

New Development of Vaccine Technology in Tumor Therapy

Abstract. Cancer vaccines are a crucial component of tumors immunotherapy, offering the advantage of minimizing adverse reactions to induce tumor regression. They also enable the establishment of lasting anti-tumor memory. Recent years have seen significant breakthroughs in cancer vaccines, including the customization of personalized vaccines and the transition from passive immunization to active treatment. Currently, most cancer vaccine future goals focus on improving cost and efficiency such as combining immunology and bioinformatics to predict more accurate vaccine epitopes. This paper focuses on three innovative technologies in therapeutic cancer vaccines: cell vaccine, peptide cancer vaccine and nucleic acid cancer vaccine. This paper summarizes new selection of antigen-presenting cells for autologous tumor cell vaccine and allogeneic tumor cell vaccine, new research on adjuvants of peptide cancer vaccines and new nucleic acid cancer vaccine delivery platform. In addition, the combination of therapeutic vaccines is briefly discussed. These new technologies offer cancer patients new treatment options and hope.

Metal-Phenolic Nanocloaks on Cancer Cells Potentiate STING Pathway Activation for Synergistic Cancer Immunotherapy.

Due to the presence of natural neoantigens, autologous tumor cells hold great promise as personalized therapeutic vaccines. Yet autologous tumor cell vaccines require multi-step production that frequently leads to the loss of immunoreactive antigens, causing insufficient immune activation and significantly hampering their clinical applications. Herein, we introduce a novel whole-cell cancer vaccine by cloaking cancer cells with lipopolysaccharide-decorated manganese(II)-phenolic networks (MnTA nanocloaks) to evoke tumor-specific immune response for highly efficacious synergistic cancer immunotherapy. The natural polyphenols coordinate with Mn2+ and immediately adhere to the surface of individual cancer cells, thereby forming a nanocloak and encapsulating tumor neoantigens. Subsequent decoration with lipopolysaccharide induces internalization by dendritic cells, where Mn2+ ions are released in the cytosol, further facilitating the activation of the stimulator of the interferon genes (STING) pathway. Highly effective tumor suppression was observed by combining the nanocloaked cancer cell treatment with anti-programmed cell death ligand 1 (anti-PD-L1) antibodies-mediated immune checkpoint blockade therapy. Our work demonstrates a universal yet simple strategy to engineer a cell-based nanobiohybrid system for enhanced cancer immunotherapy.

Metal‐Phenolic Nanocloaks on Cancer Cells Potentiate STING Pathway Activation for Synergistic Cancer Immunotherapy

AbstractDue to the presence of natural neoantigens, autologous tumor cells hold great promise as personalized therapeutic vaccines. Yet autologous tumor cell vaccines require multi‐step production that frequently leads to the loss of immunoreactive antigens, causing insufficient immune activation and significantly hampering their clinical applications. Herein, we introduce a novel whole‐cell cancer vaccine by cloaking cancer cells with lipopolysaccharide‐decorated manganese(II)‐phenolic networks (MnTA nanocloaks) to evoke tumor‐specific immune response for highly efficacious synergistic cancer immunotherapy. The natural polyphenols coordinate with Mn2+ and immediately adhere to the surface of individual cancer cells, thereby forming a nanocloak and encapsulating tumor neoantigens. Subsequent decoration with lipopolysaccharide induces internalization by dendritic cells, where Mn2+ ions are released in the cytosol, further facilitating the activation of the stimulator of the interferon genes (STING) pathway. Highly effective tumor suppression was observed by combining the nanocloaked cancer cell treatment with anti‐programmed cell death ligand 1 (anti‐PD‐L1) antibodies‐mediated immune checkpoint blockade therapy. Our work demonstrates a universal yet simple strategy to engineer a cell‐based nanobiohybrid system for enhanced cancer immunotherapy.

RWTC-MBTA: autologous vaccine prevents metastases via antitumor immune responses

BackgroundAutologous tumor cell-based vaccines (ATVs) aim to prevent and treat tumor metastasis by activating patient-specific tumor antigens to induce immune memory. However, their clinical efficacy is limited. Mannan-BAM (MB), a pathogen-associated molecular pattern (PAMP), can coordinate an innate immune response that recognizes and eliminates mannan-BAM-labeled tumor cells. TLR agonists and anti-CD40 antibodies (TA) can enhance the immune response by activating antigen-presenting cells (APCs) to present tumor antigens to the adaptive immune system. In this study, we investigated the efficacy and mechanism of action of rWTC-MBTA, an autologous whole tumor cell vaccine consisting of irradiated tumor cells (rWTC) pulsed with mannan-BAM, TLR agonists, and anti-CD40 antibody (MBTA), in preventing tumor metastasis in multiple animal models.MethodsThe efficacy of the rWTC-MBTA vaccine was evaluated in mice using breast (4T1) and melanoma (B16-F10) tumor models via subcutaneous and intravenous injection of tumor cells to induce metastasis. The vaccine’s effect was also assessed in a postoperative breast tumor model (4T1) and tested in autologous and allogeneic syngeneic breast tumor models (4T1 and EMT6). Mechanistic investigations included immunohistochemistry, immunophenotyping analysis, ELISA, tumor-specific cytotoxicity testing, and T-cell depletion experiments. Biochemistry testing and histopathology of major tissues in vaccinated mice were also evaluated for potential systemic toxicity of the vaccine.ResultsThe rWTC-MBTA vaccine effectively prevented metastasis and inhibited tumor growth in breast tumor and melanoma metastatic animal models. It also prevented tumor metastasis and prolonged survival in the postoperative breast tumor animal model. Cross-vaccination experiments revealed that the rWTC-MBTA vaccine prevented autologous tumor growth, but not allogeneic tumor growth. Mechanistic data demonstrated that the vaccine increased the percentage of antigen-presenting cells, induced effector and central memory cells, and enhanced CD4+ and CD8+ T-cell responses. T-cells obtained from mice that were vaccinated displayed tumor-specific cytotoxicity, as shown by enhanced tumor cell killing in co-culture experiments, accompanied by increased levels of Granzyme B, TNF-α, IFN-γ, and CD107a in T-cells. T-cell depletion experiments showed that the vaccine’s antitumor efficacy depended on T-cells, especially CD4+ T-cells. Biochemistry testing and histopathology of major tissues in vaccinated mice revealed negligible systemic toxicity of the vaccine.ConclusionThe rWTC-MBTA vaccine demonstrated efficacy in multiple animal models through T-cell mediated cytotoxicity and has potential as a therapeutic option for preventing and treating tumor metastasis with minimal systemic toxicity.

Abstract 6800: Unique autologous cancer vaccine comprised of irradiated whole tumor cells and MBTA (rWTC-MBTA) triggers antitumor immune response to prevent metastasis

Abstract Despite the advances made in cancer treatment over the past decades, one statistic has remained unchanged: metastatic cancer accounts for 90 percent of annual cancer deaths in the United States. Our group previously demonstrated that an autologous whole tumor cell vaccine (rWTC-MBTA: irradiated autologous whole tumor cells pulsed with Mannan-BAM, TLR ligands, and anti-CD40 antibody) had a potent anti-tumor immune response and prolonged survival in a mouse colon carcinoma model. To investigate whether rWTC-MBTA would work in “cold” tumor models, we evaluated the vaccine’s effect on preventing and treating tumor metastasis in 4T1 breast tumors. Our data showed that vaccinated mice could significantly prevent lung metastasis in both intravenous injection and mammary pad subcutaneous implantation animal models. Further, we used another metastasis model that more closely mimics clinical practice by resecting the primary tumor after metastasis development. The data showed that vaccinated mice could prevent tumor recurrence, increase T-cell infiltration in the metastatic tumor, and prolong the survival curve. The mechanistic investigation by immunophenotyping revealed that rWTC-MBTA vaccination induced both effector memory (CD44+CD62L−) and center memory (CD44+CD62L+) T cells as well as increased overall CD4+ and CD8+ T-cell count while depletion experiments demonstrated that CD8+ T cells were required for vaccine efficacy. Isolated splenocytes co-cultured with 4T1 cells showed rWTC-MBTA significantly increased T-cell mediated cytotoxicity through TNF-a and IFN-γ in CD107a+CD4+ T cells and Granzyme B and IFN-γ in CD107a+CD8+ T cells. In all experiments, vaccination exerted negligible systemic toxicity. Collectively, our study demonstrates that the rWTC-MBTA vaccine is a safe and promising therapeutic option to prevent and treat tumor metastasis by triggering an antitumor immune response. Citation Format: Juan Ye, Herui Wang, Mitchell Sun, Ondrej Uher, Mark R. Gilbert, Karel Pacak, Zhengping Zhuang, Rogelio Medina, Samik Chakraborty, Jan Zenka. Unique autologous cancer vaccine comprised of irradiated whole tumor cells and MBTA (rWTC-MBTA) triggers antitumor immune response to prevent metastasis. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6800.

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.

Whole tumor cell vaccines engineered to secrete GM‐CSF (GVAX)

AbstractGeneration of immunity against cancer through vaccination has long been an elusive goal for tumor immunologists. Putative candidates for vaccination targets include oncofetal antigens, viral antigens, neoantigens, and differentiation antigens. The first attempts at cancer vaccination used injections of whole autologous tumor cells. However, these unmodified tumor cells did not engender a robust immune response. Subsequent efforts were focused at enhancing the immunogenicity of whole autologous tumor cell vaccines through genetic modification, often through virally mediated transduction of genes encoding immunostimulatory molecules. Of many immunostimulatory cytokines evaluated in the context of gene‐modified tumor cell vaccines, granulocyte–macrophage colony‐stimulating factor (GM‐CSF) emerged as the most potent in generating protective antitumor immunity. Vaccination using irradiated, GM‐CSF producing tumor cells (GVAX) consistently induced antitumor immunity across several experimental tumor models. The term GVAX can connote GM‐CSF secreting cell vaccines prepared with different vectors as well as vector targets including autologous tumor cells, allogeneic tumor cell lines, and bystander third party tumor cells lines. GVAX has been evaluated against solid tumors, hematologic malignancies, and in the context of hematopoietic stem cell transplantation. GVAX has been extensively studied in clinical trials, both alone and in conjunction with lymphodepleting chemotherapy, immune checkpoint inhibitors, and other vaccines.

Maintenance vigil immunotherapy in newly diagnosed advanced ovarian cancer: Efficacy assessment of homologous recombination proficient (HRP) patients in the phase IIb VITAL trial.

5502 Background: In the VITAL (NCT02346747) trial, maintenance therapy with Vigil, an autologous tumor cell vaccine transfected with a DNA plasmid encoding GMCSF and bi-shRNA-furin for TGFβ expression control, following frontline platinum-based chemotherapy led to a recurrence-free survival (RFS) benefit in patients with advanced high-grade ovarian cancer (HR=0.69, 90% CI 0.44–1.07, p=0.078) and significantly in BRCA-wt patients (HR=0.51, 90% CI 0.30-0.88, p=0.020) ( Rocconi et al. Lancet Oncol. 2020). Here we report post-hoc HR deficiency (HRD) subgroup analysis and identification of an additional molecular subgroup sensitive to Vigil therapy involving STRING analysis. Methods: This double-blind, placebo-controlled, Phase 2b study randomized 92 patients with newly diagnosed stage III/IV ovarian cancer with a complete clinical response (CR) to frontline surgery and chemotherapy. Patients received 1 x 10e7 cells/ml of Vigil or placebo intradermally once a month for up to 12 doses or disease progression. RFS was the primary endpoint assessed by blinded independent central review. HRD status was determined according to the Myriad Genetics myChoice CDx assay (HRD score < 42 for proficient). Using tumor annotated DNA polymorphism data, a protein-protein interaction network was constructed using the STRING database. Properties of this network including topological distance and the identification of hub genes were used to predict a target molecular population sensitive to Vigil. Results: In the per-protocol population (PP, n=91), 62 BRCA-wt patients were tested for HRD status. Forty-five patients were HR proficient (HRP) and 17 patients were HR deficient (HRD). No HRP patients in the Vigil group reported treatment related Grade 3 or higher adverse events. From the time of study randomization median RFS was improved with Vigil (n=25) in HRP patients compared to placebo (n=20) (Table 1). Similarly, overall survival (OS) benefit was observed in the Vigil group compared to placebo (Table 1). Improved RFS was demonstrated for a subset of patients with STRING predicted molecular profile. Conclusions: Vigil immunotherapy as frontline maintenance in Stage III/IV ovarian cancer is well tolerated and showed clinical benefit in both BRCA-wt and HRP molecular profile patients. Results suggest a unique molecular network that enhances sensitivity to Vigil therapy. Clinical trial information: NCT02346747. [Table: see text]

Randomized double-blind placebo-controlled trial of primary maintenance vigil immunotherapy (VITAL study) in stage III/IV ovarian cancer: Efficacy assessment in BRCA1/2-wt patients

Objective: Despite advances, overall prognosis for advanced epithelial ovarian cancer (EOC) remains poor. Considering elevated TGFβ expression correlates with poor prognosis in ovarian cancer, this study aims to determine whether a maintenance vigil could provide improvement in relapse-free survival. Vigil is an autologous tumor cell vaccine constructed from autologous harvested tumor tissue transfected with a DNA plasmid encoding GMCSF and bi-shRNA-furin, thereby creating TGFβ expression control.

Abstract 4574: A novel method for inactivating tumor cells for use in a personalized cancer vaccine

Abstract With the recent interest in personalized medicine for cancer patients and immune therapy, the field of cancer vaccines has been resurrected. Previous autologous, whole cell tumor vaccine trials have not produced convincing results due, in part, to poor patient selection and inactivation methods that are harsh on the cells. Such methods can inadvertently alter protein structure and antigenic profile in ways that make vaccine candidates ineffective in stimulating immune response to autochthonous tumor cells. We decided to investigate a novel method for inactivating tumor cells that uses UVA/UVB light and the benign chemical riboflavin (Riboflavin and UV Light Inactivation, RF+UV). This process is fast and results in complete inactivation of the tumor cells, but preserves tumor cell integrity and antigenicity due to its rapid, yet gentle inactivation process. Our results demonstrate that the inactivation is complete, that proteins are preserved on the surface of the tumor cells, and that the inactivated tumor cells are immunogenic in that they induce dendritic cell maturation, increased IFNγ production, and the generation of tumor cell-specific IgG immune responses. Moreover, when formulated with an adjuvant (“Innocell vaccine”) and tested in two different murine primary tumor models and one metastatic tumor model, the vaccine led to decreased tumor growth, prolonged survival and decreased metastatic disease. In addition, immune cells obtained from tumor tissue following vaccination showed a decrease in exhausted and regulatory cells, suggesting that activation of intratumoral T cells may be playing a role leading to the reduce tumor growth. Lastly, tumor tissue was obtained from 3 client-owned dogs with spontaneous tumors and used to generate an autologous Innocell vaccines. The vaccine was well-tolerated and induced an inflammatory response in 2 of the 3 dogs. This data suggests that the RF+UV process of inactivating tumor cells for use as antigen-presenting agents in cancer vaccine therapy may provide a more rapid, safer and gentler way to generate autologous whole tumor cell vaccines for use in cancer patients. Citation Format: Amanda Michele Guth, Raymond Goodrich, Haemin Park, Matthew Gladstone, Crystal Shanley, Lindsay Hartson, Jon Weston. A novel method for inactivating tumor cells for use in a personalized cancer vaccine [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4574.

Engineering autologous tumor cell vaccine to locally mobilize antitumor immunity in tumor surgical bed.

Autologous tumor cell-based vaccines (ATVs) are emerging as a transformable approach for personalized immunotherapy, but their therapeutic efficacy remains unsatisfying in patients with cancer. Here, we design a photodynamic therapy (PDT)-motivated ATV (P-ATV) in Fmoc-KCRGDK-phenylboronic acid (FK-PBA) hydrogel, which mobilizes local immune activation to inhibit relapse of postoperative tumors. The FK-PBA targeting overexpressed sialic acid on tumor cells can enable on-demand gelation in residue tumor areas and maintain continuous vaccination in surgical bed. Unlike neoantigen-based vaccine or adoptive cell therapy that takes several months to prepare, P-ATV can be easily manufactured within a few days and efficiently boost neoepitope-specific CD8+ T cells to activate personalized immunotherapy. This simple and powerful approach of engineered ATVs provides an alternative strategy for personalized immunotherapy and is readily transformable to various kinds of cell-based antigens to inhibit the relapse of postoperative tumors.

Safety and efficacy of autologous tumour cell vaccines as a cancer therapeutic to treat solid tumours and haematological malignancies: a meta-analysis protocol for two systematic reviews

IntroductionAutologous cancer cell vaccines are promising personalised immunotherapeutic options for solid and haematological malignancies that uses the patient’s own cells to arm an immune response. Evidence suggests that among patients...

Randomized double-blind placebo-controlled trial of primary maintenance vigil immunotherapy (VITAL study) in stage III/IV ovarian cancer: Efficacy assessment in BRCA1/2-wt patients.

6017 Background: Vigil is an autologous tumor cell vaccine constructed from autologous harvested tumor tissue transfected with a DNA plasmid encoding GMCSF and bi-shRNA-furin thereby creating TGFβ expression control. Methods: A randomized double-blind placebo-controlled trial of Vigil vs. placebo was performed in advanced stage frontline OC patients. Relapse-free survival (RFS) and safety were endpoints. Patients who achieved complete clinical response were randomized [1:1 to placebo (control group, CG) or Vigil (Vigil group, VG)] after completion of frontline surgery and chemotherapy. All patients received 1 x 10e7 cells/ml of Vigil or placebo intradermally once a month for up to 12 doses. Results: Ninety-two patients were randomized with 91 patients in the per-protocol population (PP), (VG n=46; CG n=45). 62 patients were tested for BRCA1/2 status. VG showed no added overall toxicity compared to CG and no grade 4/5 toxicities were observed. Grade 2/3 toxic events were observed in 18% of CG patients (most common bone pain, fatigue) compared to 8% of VG patients (most common nausea, musculoskeletal pain). From time of randomization median RFS for all 91 patients was favorable in the VG (HR 0.69, one-sided p 0.088).Stratified by BRCA status, an advantage in RFS was seen in the BRCA1/2-wt patients in VG (19.4 mo) compared to CG (8 mo) (HR 0.51, 90% CI 0.26 – 1.01, one-sided p 0.050) from time of randomization and HR of 0.49 (90% CI 0.25 – 0.97, one-sided p 0.038) from time of surgery. Median time from surgery to randomization was 208.5 days (6.9 mo) in VG vs. 200 days (6.6 mo) in CG. 37.5% BRCA1/2-wt Vigil treated patients relapsed compared to 71% of placebo at time of data snap for analysis (HR 0.51, one-sided p 0.05), (median follow-up of 34.3 mo for all n=91 subjects). Germline and somatic BRCA1/2 molecular testing via central third party is underway on all 91 patients under continued blinded conditions to validate activity in BRCA1/2-wt. Conclusions: Vigil immunotherapy as frontline maintenance in Stage III/IV ovarian cancer is well tolerated and showed RFS clinical benefit, particularly in BRCA1/2-wt disease. Clinical trial information: NCT02346747. [Table: see text]

A novel cancer immunotherapy utilizing autologous tumour tissue.

With the recent interest in personalized medicine for cancer patients and immune therapy, the field of cancer vaccines has been resurrected. Previous autologous, whole cell tumour vaccine trials have not produced convincing results due, in part to poor patient selection and inactivation methos that are harsh on the cells. These methods can alter protein structure and antigenic profiles making vaccine candidates ineffective in stimulating immune response to autochthonous tumour cells. We investigated a novel method for inactivating tumour cells that uses UVA/UVB light and riboflavin (vitamin B2) (RF+UV). RF+UV inactivates the tumour cells' ability to replicate, yet preserves tumour cell integrity and antigenicity. Our results demonstrate that proteins are preserved on the surface of RF+UV-inactivated tumour cells and that they are immunogenic via induction of dendritic cell maturation, increase in IFNγ production and generation of tumour cell-specific IgG. Moreover, when formulated with an adjuvant ('Innocell vaccine') and tested in different murine tumour primary and metastatic disease models, decreased tumour growth, decreased metastatic disease and prolonged survival were observed. In addition, immune cells obtained from tumour tissue following vaccination had decreased exhausted and regulatory T cells, suggesting that activation of intra-tumoural T cells may be playing a role leading to reduced tumour growth. These data suggest that the RF+UV inactivation of tumour cells may provide an efficacious method for generating autologous whole tumour cell vaccines for use in cancer patients.

Cytokine network analysis of immune responses before and after autologous dendritic cell and tumor cell vaccine immunotherapies in a randomized trial

BackgroundIn a randomized phase II trial conducted in patients with metastatic melanoma, patient-specific autologous dendritic cell vaccines (DCV) were associated with longer survival than autologous tumor cell vaccines (TCV). Both vaccines presented antigens from cell-renewing autologous tumor cells. The current analysis was performed to better understand the immune responses induced by these vaccines, and their association with survival.Methods110 proteomic markers were measured at a week-0 baseline, 1 week before the first of 3 weekly vaccine injections, and at week-4, 1 week after the third injection. Data was presented as a deviation from normal controls. A two-component principal component (PC) statistical analysis and discriminant analysis were performed on this data set for all patients and for each treatment cohort.ResultsAt baseline PC-1 contained 64.4% of the variance and included the majority of cytokines associated with Th1 and Th2 responses, which positively correlated with beta-2-microglobulin (B2M), programmed death protein-1 (PD-1) and transforming growth factor beta (TGFβ1). Results were similar at baseline for both treatment cohorts. After three injections, DCV-treated patients showed correlative grouping among Th1/Th17 cytokines on PC-1, with an inverse correlation with B2M, FAS, and IL-18, and correlations among immunoglobulins in PC-2. TCV-treated patients showed a positive correlation on PC-1 among most of the cytokines and tumor markers B2M and FAS receptor. There were also correlative changes of IL12p40 with both Th1 and Th2 cytokines and TGFβ1. Discriminant analysis provided additional evidence that DCV was associated with innate, Th1/Th17, and Th2 responses while TCV was only associated with innate and Th2 responses.ConclusionsThese analyses confirm that DCV induced a different immune response than that induced by TCV, and these immune responses were associated with improved survival.Trial registration Clinical trials.gov NCT004936930 retrospectively registered 28 July 2009

Abstract 1357: Serum levels of programmed cell death molecule-1 (PD-1) as a biomarker in metastatic melanoma patients randomized for treatment with autologous dendritic cell or tumor cell vaccines

Abstract The purpose of this study was to analyze PD-1 serum levels, in patients with metastatic melanoma who were enrolled in a randomized phase 2 trial, to determine: [1] if baseline PD-1 serum levels were prognostic for overall survival (OS), [2] if baseline PD-1 levels were predictive for survival benefit in the specific treatment arms, [3] if PD-1 levels changed between week-0 and week-4 by treatment, and [4] if changes in PD-1 levels were predictive of survival benefit overall and by treatment. Patients with metastatic melanoma were enrolled in a randomized phase 2 clinical trial comparing treatment with autologous dendritic cell vaccines (DCV) presenting autologous tumor antigens (ATA) derived from irradiated cancer cells from short-term autologous cell lines, compared to tumor cell vaccines (TCV) consisting of irradiated tumor cells [Dillman et al. J ImmunoTher Cancer 2018]. Vaccines were injected s.c. weekly for three weeks, then at weeks 8, 12, 16, 20, and 24. OS was longer for patients treated with DCV (median 43 vs 20 months; 70% reduction in risk of death). Cryopreserved serum samples from week-0 and week-4 for 39/42 patients were analyzed using a quantitative, multiplex enzyme-linked immunosorbent assay (Raybiotech, Inc., Norcross, GA). The patients for whom PD-1 levels were missing were two TCV-treated subjects who had rapidly progressive disease and had no week-4 samples, and one DCV-treated subject who survived more than 5-years, but rescinded permission to test his blood. Baseline serum PD-1 levels ranged from 0 to 511 ng/ml. After three weekly vaccinations, median serum levels of PD-1 did not change between week-0 and week-4 (1.51 and 1.58 ng/ml), nor did mean serum levels change (52.5 and 52.6 ng/ml). For all 39 patients, baseline PD1 levels were not prognostic for OS. DCV was associated with longer OS than TCV both in patients whose baseline PD1 was <1.2 ng/ml and > 1.2 ng/ml. Among DCV-treated subjects, baseline levels <50 ng/ml were associated with OS > 3.5 years in 9/13 compared to 0/4 for those with levels > 50 ng/ml (p=0.029), but there was no difference in the TCV arm (5/19 vs 1/3, p=1.00). Overall, PD1 levels decreased after 3 DCV injections, but increased after 3 TCV injections. DCV-treated subjects who had a decrease in PD-1 were more likely to survive 4 years (6/9 vs 1/8, p=0.05) but this difference was not seen in patients treated with TCV (0/6 vs 6/16, p=0.289). CONCLUSONS: In these metastatic melanoma patients, baseline serum PD1 levels were not prognostic for survival, but were predictive of survival benefit in patients treated with DCV, as was a decrease in PD1 level after 3 weekly DCV vaccinations. PD1 levels should be prospectively evaluated in larger studies to see if they may be useful as a companion diagnostic and/or surrogate marker for efficacy. Citation Format: Robert O. Dillman, Gabriel I. Nistor, Aleksandra J. Poole, Andrew N. Cornforth. Serum levels of programmed cell death molecule-1 (PD-1) as a biomarker in metastatic melanoma patients randomized for treatment with autologous dendritic cell or tumor cell vaccines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1357.

Survival by stage and tumor measurability in metastatic melanoma patients treated with autologous dendritic cell tumor cell vaccines.

2637 Background: Survival of cancer patients is greatly affected by stage and tumor burden. The purpose of this study was to determine survival for melanoma patients who were treated with patient specific vaccines in the context of prospective clinical trials, by cohorts defined by stage and tumor measurability. Methods: Metastatic melanoma patients were treated with autologous dendritic cells loaded with antigens from irradiated cells from short-term autologous tumor cell lines (DCV). All patients had a metastatic melanoma lesion surgically resected, from which a tumor cell line was established. Irradiated tumor cells (ITC) were incubated with autologous dendritic cells (DC) to produce the DCV, which were injected s.c. in 500 micrograms GM-CSF weekly x 3 weeks, then monthly for 5 months. Data was pooled for DCV-treated patients enrolled in either of two phase II trials: one single-arm (NCT00948480), one randomized (NCT00436930). Patients were assigned to one of three cohorts based on their most advanced stage of disease prior to treatment, and whether they had measurable disease at the time of treatment. Survival was determined per Kaplan and Meier. Results: The final therapeutic products consisted of autologous DC with non-phagocytosed ITC making up 0% to 20% of cells in the final product. There were 45 men and 27 women. Median age was 52 years (range 17 to 83). Tumor sources were 37-lymph node, 20-viscera, and 15-soft tissue. No patients were lost to follow up; all surviving patients were followed 5 years. Toxicity was minimal. Median overall survival (OS) for all 72 patients was 49.4 mos; 5-year OS 46%. There was no correlation between survival and the number of DC or ITC in the first three injections. Patients with recurrent stage 3 disease that had not recurred (n=18) had a 72% 5-year OS; patients with non-measurable stage 4 (n=30) had a 53% 5-year OS. Patients with measurable stage 4 (n=18) had received an average of four prior therapies. They had a median OS of 18.5 months, and 2-year OS of 46%. Conclusions: This patient-specific DCV was associated with encouraging survival in all three clinical subsets. Because of its mechanism of action and absence of toxicity, it should be evaluated further. Clinical trial information: NCT00948480, NCT00436930.

Correction to: Autologous tumor cell vaccination combined with systemic CpG-B and IFN-α promotes immune activation and induces clinical responses in patients with metastatic renal cell carcinoma: a phase II trial.

In the original publication of the article the following abstract and keywordswere inadvertently omitted.

The adjuvant treatment of kidney cancer: a multidisciplinary outlook.

Approximately 70% of cases of kidney cancer are localized or locally advanced at diagnosis. Among patients who undergo surgery for these cancers, 30-35% will eventually develop potentially fatal metachronous distant metastases. Effective adjuvant treatments are urgently needed to reduce the risk of recurrence of kidney cancer and of dying of metastatic disease. To date, almost all of the tested adjuvant agents have failed to demonstrate any benefit. Only two trials of an autologous renal tumour cell vaccine and of the vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor sunitinib have shown positive results, but these have been criticized for methodological reasons and conflicting data, respectively. The results of two additional trials of targeted agents as adjuvant therapies have not yet been published. Novel immune checkpoint inhibitors are promising approaches to adjuvant therapy in kidney cancer, and a number of trials are now underway. An important component of the management of patients with kidney cancer, particularly those who undergo radical resection for localized renal cell carcinoma, is the preservation of kidney function to reduce morbidity and mortality. The optimal management of these patients therefore requires a multidisciplinary approach involving nephrologists, oncologists, urologists and pathologists.

Autologous tumor cell vaccination combined with systemic CpG-B and IFN-\u03b1 promotes immune activation and induces clinical responses in patients with metastatic renal cell carcinoma: a phase II trial

In this study the toxicity and efficacy of an irradiated autologous tumor cell vaccine (ATV) co-injected with a class-B CpG oligodeoxynucleotide (CpG-B) and GM-CSF, followed by systemic CpG-B and IFN-α administration, were examined in patients with metastatic renal cell carcinoma (mRCC). A single-arm Phase II trial was conducted, in which patients with mRCC were intradermally injected with a minimum of three whole-cell vaccines containing 0.7–1.3 × 107 irradiated autologous tumor cells (ATC), admixed with 1 mg CpG-B and 100 µg GM-CSF, followed by bi-weekly s.c. injections with 8 mg CpG-B and s.c. injections with 6 MU IFN-α three times per week. Fifteen patients were treated according to the protocol. Treatment was well tolerated. Objective clinical responses occurred in three patients, including one long-term complete response. Disease stabilization occurred in another three patients. Positive delayed type hypersensitivity (DTH) responses to ATC were absent before treatment but present in 13 out of 15 patients during treatment. Immune monitoring revealed activation of plasmacytoid dendritic cells, non-classical monocytes and up-regulation of both PD-1 and CTLA4 on effector T cells upon treatment. Moreover, a pre-existing ex vivo IFN-γ response to ATC was associated with clinical response. ATV combined with systemic CpG-B and IFN-α is tolerable, safe, immunogenic and able to elicit anti-tumor responses in patients with mRCC. Immune activation and treatment-induced up-regulation of PD-1 and CTLA4 on circulating T cells further suggest an added benefit of combining this approach with immune checkpoint blockade [added]