Anticancer Vaccines Research Articles

Immunization of Mice with Gold Nanoparticles Conjugated to Thermostable Cancer Antigens Prevents the Development of Xenografted Tumors.

Gold nanoparticles as part of vaccines greatly increase antigen stability, antigen accumulation in the lymph nodes, and antigen uptake by antigen-presenting cells. The use of such particles as part of anticancer vaccines based on heat shock proteins to increase vaccine effectiveness is timely. We prepared and characterized nanoconjugates based on 15-nm gold nanoparticles and thermostable tumor antigens isolated from MH22a murine hepatoma cells. The whole-cell lysate of MH22a cells contained the main heat shock proteins. BALB/c mice were injected with the conjugates and then received transplants of MH22a cells. The highest titer was produced in mice immunized with the complex of gold nanoparticles + antigen with complete Freund's adjuvant. The immunized mice showed no signs of tumor growth for 24 days. They also showed a decreased production of the INF-γ, IL-6, and IL-1 proinflammatory cytokines compared to the mice immunized through other schemes. This study is the first to show that it is possible in principle to use gold nanoparticles in combination with thermostable tumor antigens for antitumor vaccination. Antitumor vaccines based on thermostable tumor antigens can be largely improved by including gold nanoparticles as additional adjuvants.

IMMU-31. PROTEASOME REARRANGED PEPTIDES ARE A NOVEL SOURCE OF ANTIGENS FOR THE PEPTIDE VACCINE IMMUNOTHERAPY OF GLIOBLASTOMAS

Abstract pepVIII, an anticancer vaccine targeting EGFRvIII, has been tested in several trials for glioblastoma including ACT IV. a randomized Phase III trial for newly diagnosed patients. While results from ACT IV were equivocal, available data suggests the elimination of EGFRvIII was not robust. Despite its essential role in antigen presentation, enhancing proteasomal processing is an unexploited strategy for improving vaccines. We examined 20 peptides in silico and experimentally, which showed that a tyrosine substitution (Y6-pepVIII) maximizes proteasome cleavage and survival in a subcutaneous tumor model. In an intracranial glioma model, Y6-pepVIII showed a 62 and 31% improvement in median survival compared to control animals and pepVIII-vaccinated mice. Y6-pepVIII vaccination altered tumor-infiltrating lymphocyte subsets and expression of PD-1 on intratumoral T cells. Combination with anti–PD-1 therapy cured 45% of the Y6-pepVIII–vaccinated mice but was ineffective for pepVIII-treated mice. LC-MS/MS analysis of proteasome-digested pepVIII and Y6-pepVIII revealed that most fragments were similar but more abundant inY6-pepVIII digests and 77% resulted from proteasome-catalyzed peptide splicing (PCPS). We identified 10 peptides that bound human and murine MHC class I. Nine were PCPS products and only one peptide was colinear with EGFRvIII, indicating that PCPS fragments may be a component of MHC class I recognition. Despite not being colinear with EGFRvIII, two of three PCPS products tested were capable of increasing survival when administered independently as vaccines. We hypothesize that the immune response to a vaccine represents the collective contribution from multiple PCPS and linear products. Our work suggests a strategy to increase proteasomal processing of a vaccine that results in an augmented immune response and enhanced survival in mice.

The findings of glucosyltransferase enzymes derived from oral streptococci

Glucosyltransferase enzymes (Gtfs) distribute among some streptococcal species in oral cavity and are known as key enzymes contributing to the development of oral biofilm such as dental plaque. In 18 streptococcal species, 45 glucosyltransferase genes (gtf) are detected from genome database. Gtfs catalyze the synthesis of the glucans, which are polymers of glucose, from sucrose and they are main component of oral biofilm. Especially, the Gtfs from Streptococcus mutans are recognized as one of dental caries pathogens since they contribute to the formation of dental plaque and the establishment of S. mutans in the tooth surface. Therefore, Gtfs has been studied particularly by many researchers in the dentistry field to develop the anti- caries vaccine. However, it is not still accomplished. In these days, the phylogenetic and crystal structure analyses of Gtfs were performed and the study of Gtfs will enter new situation from the technique in the past old viewpoint. The findings from those analyses will affect the development of the anti-caries vaccine very much after this. In this review, we summarize the findings of oral streptococcal Gtfs and consider the perspectives of the dental caries prevention which targeted Gtf.

Tumor Antigen Loaded Nanovaccine Induced NIR-Activated Inflammation for Enhanced Antigen Presentation During Immunotherapy of Tumors.

Although anticancer vaccines have achieved certain effects in early clinical practice, T cell immunity as the most common responsive pattern of anticancer vaccines is still limited by unsatisfied tumor recognition and inhibition efficiency. As the critical step of T cell immunity, uptake and presentation of specific antigen by antigen-presenting cells (APC) can be activated by inflammation for enhancing the response of T cells to the antigen source. Here, a hybrid nanovaccine named PTh/MnO2 @M activated with a near-infrared ray (NIR) is prepared by coating an autologous tumor cell membrane on the surface of a polythiophene/MnO2 composite core. The photoelectrical material polythiophene can produce local microinflammation under NIR radiation and activate specific T cell antitumor immunity by promoting APC maturation and autologous tumor antigens presentation. Moreover, the synthesized nanovaccine PTh/MnO2 @M is shown to induce a significant antitumor immune response, effectively inhibit the progression of melanoma in mice, and significantly prolong the survival time of mice in vivo. This strategy aims to enhance T-cell immune responses by promoting antigen presentation, leading to effective and specific cancer therapy.

Safety of mRNA-COVID-19 Vaccines in Patients With Thoracic Cancers

BackgroundPivotal trials of COVID-19 vaccines did not include cancer patients with questions remaining in this population. Particularly in patients with thoracic malignancies receiving anticancer treatments, the safety of these vaccines has so far been little investigated.MethodsThis is a prospective trial of patients with thoracic cancer receiving anticancer treatments and COVID-19 vaccines at the Division of Thoracic Oncology of European Institute of Oncology between February and September 2021.Results207 patients affected by thoracic cancers (199 lung cancers and 8 mesotheliomas) had received Covid-19 vaccines (206 mRNA vaccines and 1 virus-vectored vaccine). The majority of patients had at least one comorbidity (76.3%). They were concomitantly treating with targeted therapy (TT) (45.9%), immunotherapy (IO) (22.7%), and chemotherapy (CT) (14%). A total of 64 AEs (15.6%) were observed after administration of Sars-Cov-2 vaccine. The majority of AEs were grade 1 [G1] (6.3%) and G2 (8.8%), only two events were G3 (0.5%). The median follow-up was 9 months (range 1-22 months), during this follow-up 21 patients (10.1%) had a positive nasal swab, most of the patients were asymptomatic (67%) and the symptomatic ones (33%) had mild symptoms and fewer complications and hospitalizations.ConclusionsCOVID-19 m-RNA vaccines appear to be safe in the cohort of patients with thoracic malignances in active treatment, including those receiving immunotherapy. Considering the high morbidity and mortality associated with COVID-19 in patients with lung cancer receiving active treatments, our study supports the current vaccine prioritization, third and/or fourth dose, of all cancer patients with active treatment.Micro-abstractThis is a prospective trial of 207 patients with thoracic cancer receiving anticancer treatments and COVID-19 vaccines.After long follow-up, there were no safety signals of concern and only 0.5% of patients experienced grade 3 vaccine-related adverse events.Our study supports the current vaccine prioritization, third and/or fourth dose of all lung cancer patients with active treatment.

The impact of antigenic molecular mimicry on anti-cancer T-cell immune response.

Individuals are exposed to intracellular pathogens (i.e. viruses and intracellular bacteria) and intestinal microbiota, collectively microorganisms (MOs), which enter the body during the host's lifetime. Altogether, MOs are a natural source of non-self antigens (MoAs) expressed by host's cells in the context of the HLA class I molecules, inducing a wide pool of specific memory CD8+ T cell clones. Such MoAs have been shown in selected cases to share sequence and structural homology with cellular self-antigens (molecular mimicry), possibly inducing autoimmune reactions leading to autoimmune diseases (ADs). We have recently shown that a molecular mimicry may be found also to self-antigens presented by cancer cells (i.e. tumor-associated antigens, TAAs). Consequently, memory CD8+ T cell clones specific for the MoAs may turn out to be a natural "anti-cancer vaccination" if a nascent tumor lesion should express TAAs similar or identical to MoAs. We postulate that selecting MoAs with high homology to TAAs would greatly improve the efficacy of cancer vaccines in both preventive and therapeutic settings. Indeed, non-self MoAs are potently immunogenic because not affected by central immune tolerance. Unravelling the impact of the antigenic molecular mimicry between MoAs and TAAs might pave the way for novel anti-cancer immunotherapies with unprecedented efficacy.

Primary Resistance to Immunotherapy-Based Regimens in First Line Hepatocellular Carcinoma: Perspectives on Jumping the Hurdle.

Simple SummaryImmune checkpoint inhibitors (ICIs) had been explored extensively in patients affected by unresectable hepatocellular carcinoma. These agents were expected to be the keystones of the disease’s first-line treatment because they were theoretically able to revert the immune suppressive tumor microenvironment of the cancerous liver, and because of their manageable safety profile. However, when used as monotherapies, they showed important activity and efficacy limitations. In this mini-review, we summarize the characteristics of the different ICIs-based regimens which constitute the present gold standard of first-line treatment, then, moving from their shortcomings, we discuss the rationale supporting the strategies currently under investigation: systemic triplets and new paradigms of immune-therapeutic agents such as CAR-T and vaccines.Immune checkpoint inhibitors (ICIs) are a key component of different stages of hepatocellular carcinoma (HCC) treatment, particularly in the first line of treatment. A lesson on the primary resistance which hampers their efficacy and activity was learned from the failure of the trials which tested them as first-line mono-therapies. Despite the combination of anti-PD(L)1 agents with anti-VEGF, anti CTLA4, or TKIs demonstrating relevant improvements in efficacy, the “doublets strategy” still shows room for improvement, due to a limited overall survival benefit and a high rate of progressive disease as best response. In this review, we discuss the results from the currently tested doublet strategies (i.e., atezolizumab+bevacizumab, durvalumab+tremelimumab with a mention to the newly presented ICIs/TKIs combinations), which highlight the need for therapeutic improvement. Furthermore, we examine the rationale and provide an overview of the ongoing trials testing the treatment intensification strategy with triplet drugs: anti-PD1+anti-CTLA4+anti-VEGF/TKIs and anti-PD1+anti-VEGF+alternative immunity targets. Lastly, we report on the alternative strategy to integrate ICIs into the new paradigm of immune therapeutics constituted by CAR-T and anti-cancer vaccines. This review provides up-to-date knowledge of ongoing clinical trials of the aforementioned strategies and critical insight into their mechanistic premises.

Les nouveautés en immunothérapie : nouvelles cibles, rationnel et données précoces dans les cancers broncho-pulmonaires non à petites cellules

Therapeutic strategies with anti-PD-(L)1 antibodies are now well established in patients with nonsmall-cell lung cancer (NSCLC) without oncogenic addiction. The benefit of immunotherapy, sometimes leading to healing, remains restricted to “hot” tumors characterized by an inflammatory tumor micro-environment. Consequently, there is a need to develop new therapeutics improving the cytotoxic T cell activity. Antibodies targeting co-stimulatory or co-inhibitory receptors are evaluated in combination with anti-PD-(L)1 antibodies. Other approaches include anti-cancer vaccines or oncolytic virus. Overall, the goal is to effectively redirected the immune system against the tumor. This could be achieved and optimized by the identification of predictive biomarkers specific to the tumor and the patient for new individual therapeutic proposals.1877-1203/© 2022 SPLF. Published by Elsevier Masson SAS. All rights reserved.

A novel telomerase-derived peptide GV1001-mediated inhibition of angiogenesis: Regulation of VEGF/VEGFR-2 signaling pathways

GV1001, a human telomerase reverse transcriptase catalytic subunit-derived 16-mer peptide, has been developed as a novel anticancer vaccine against various cancers including pancreatic cancer. In the current study, we demonstrate the regulatory roles and mechanisms of GV1001 in endothelial cell responses in vitro and microvessel sprouting ex vivo. GV1001 markedly inhibits vascular endothelial growth factor-A (VEGF-A)-stimulated endothelial cell permeability, proliferation, migration, invasion, tube formation as well as microvessel outgrowth from rat aortic rings. These anti-angiogenic effects of GV1001 were associated with the inhibition of VEGF-A/VEGFR-2 signaling pathways, redistribution of vascular endothelial-cadherin to cell–cell contacts, and down-regulation of VEGFR-2 and matrix metalloproteinase-2. Furthermore, GV1001 suppresses the proliferation and invasion of non-small cell lung cancer cells, and the release of VEGF from the cells, suggesting the regulatory role of GV1001 in tumor-derived angiogenesis as well as cancer cell growth and progression. Collectively, our study reports the pharmacological potential of GV1001 in the regulation of angiogenesis, and warrants further evaluation and development of GV1001 as a promising therapeutic agent for a variety of angiogenesis-related diseases including cancer.

Muramyl dipeptide-based analogs as potential anticancer compounds: Strategies to improve selectivity, biocompatibility, and efficiency.

According to the WHO, cancer is the second leading cause of death in the world. This is an important global problem and a major challenge for researchers who have been trying to find an effective anticancer therapy. A large number of newly discovered compounds do not exert selective cytotoxic activity against tumorigenic cells and have too many side effects. Therefore, research on muramyl dipeptide (MDP) analogs has attracted interest due to the urgency for finding more efficient and safe treatments for oncological patients. MDP is a ligand of the cytosolic nucleotide-binding oligomerization domain 2 receptor (NOD2). This molecule is basic structural unit that is responsible for the immune activity of peptidoglycans and exhibits many features that are important for modern medicine. NOD2 is a component of the innate immune system and represents a promising target for enhancing the innate immune response as well as the immune response against cancer cells. For this reason, MDP and its analogs have been widely used for many years not only in the treatment of immunodeficiency diseases but also as adjuvants to support improved vaccine delivery, including for cancer treatment. Unfortunately, in most cases, both the MDP molecule and its synthesized analogs prove to be too pyrogenic and cause serious side effects during their use, which consequently exclude them from direct clinical application. Therefore, intensive research is underway to find analogs of the MDP molecule that will have better biocompatibility and greater effectiveness as anticancer agents and for adjuvant therapy. In this paper, we review the MDP analogs discovered in the last 10 years that show promise for antitumor therapy. The first part of the paper compiles the achievements in the field of anticancer vaccine adjuvant research, which is followed by a description of MDP analogs that exhibit promising anticancer and antiproliferative activity and their structural changes compared to the original MDP molecule.

Antitumor effects of Chinese herbal medicine compounds and their nano-formulations on regulating the immune system microenvironment.

Traditional Chinese medicine (TCM), including herbal medicine, acupuncture and meditation, has a wide range of applications in China. In recent years, herbal compounding and active ingredients have been used to control tumor growth, reduce suffering, improve quality of life, and prolong the life span of cancer patients. To reduce side effects, herbal medicine can be used in conjunction with radiotherapy and chemotherapy or can be used as an adjuvant to strengthen the immune effect of anticancer vaccines. In particular, in the immunosuppressed tumor microenvironment, herbal medicine can have antitumor effects by stimulating the immune response. This paper reviews the advances in research on antitumor immunomodulation in Chinese herbal medicine, including the regulation of the innate immune system, which includes macrophages, MDSCs, and natural killer cells, and the adaptive immune system, which includes CD4+ T cells, CD8+ T cells, and regulatory T cells (Tregs), to influence tumor-associated inflammation. In addition, a combination of active ingredients of herbal medicine and modern nanotechnology alter the tumor immune microenvironment. In recent years, immunological antitumor therapy in TCM has been applied on a reasonably large scale both nationally and internationally, and there is potential for further clinical expansion. Investigation of immune modulation mechanisms in Chinese herbal medicine will provide novel perspectives of how herbal medicine controls tumor growth and metastasis, which will contribute to the evolution of tumor research.MethodologyExperimental research between the years of 2012-2022, meta-analysis and reviews for the period 2002-2022 found on the Databases including PubMed, Embase, and the Cochrane database were used. The inclusion criteria were experimental research literature addressing the anti-tumor immunological effects of active ingredients and nanoparticles in Chinese herbal medicine. Exclusion criteria were articles that addressed Chinese herbal medicine and nano-formulations without discussing anti-tumor immunological effects in innate, adaptive immune cells, MDSCs, and nuclear factors.

Targeting Mutant p53 for Cancer Treatment: Moving Closer to Clinical Use?

Simple SummaryCancer is largely caused by genetic alterations such as mutations in a group of genes known as cancer driver genes. Many of the key advances in cancer treatment in recent years have involved blocking these driver genes using a new generation of anti-cancer drugs. Although p53 is the most frequently mutated gene in human cancers, historically, it has proved difficult to develop drugs against it. However, recently, several new drugs have become available for neutralizing the cancer-promoting effects of mutant p53. The aim of this article is to discuss the most promising of these drugs, especially those that are being investigated in clinical trials.Mutant p53 is one of the most attractive targets for new anti-cancer drugs. Although traditionally regarded as difficult to drug, several new strategies have recently become available for targeting the mutant protein. One of the most promising of these involves the use of low molecular weight compounds that promote refolding and reactivation of mutant p53 to its wild-type form. Several such reactivating drugs are currently undergoing evaluation in clinical trials, including eprenetapopt (APR-246), COTI-2, arsenic trioxide and PC14586. Of these, the most clinically advanced for targeting mutant p53 is eprenetapopt which has completed phase I, II and III clinical trials, the latter in patients with mutant TP53 myelodysplastic syndrome. Although no data on clinical efficacy are currently available for eprenetapopt, preliminary results suggest that the drug is relatively well tolerated. Other strategies for targeting mutant p53 that have progressed to clinical trials involve the use of drugs promoting degradation of the mutant protein and exploiting the mutant protein for the development of anti-cancer vaccines. With all of these ongoing trials, we should soon know if targeting mutant p53 can be used for cancer treatment. If any of these trials show clinical efficacy, it may be a transformative development for the treatment of patients with cancer since mutant p53 is so prevalent in this disease.

Streptococcus mutans glutamate binding protein (GlnH) as antigen target for a mucosal anti-caries vaccine.

In recent years, several studies have demonstrated that bacterial ABC transporters present relevant antigen targets for the development of vaccines against bacteria such as Streptococcus pneumoniae and Enterococcus faecalis. In Streptococcus mutans, the glutamate transporter operon (glnH), encoding an ABC transporter, is associated with acid tolerance and represents an important virulence-associated factor for the development of dental caries. In this study, we generated a recombinant form of the S. mutans GlnH protein (rGlnH) in Bacillus subtilis. Mice immunized with this protein antigen elicited strong antigen-specific antibody responses after sublingual administration of a vaccine formulation containing a mucosal adjuvant, a non-toxic derivative of the heat-labile toxin (LTK63) originally produced by enterotoxigenic Escherichia coli (ETEC) strains. Serum anti-rGlnH antibodies reduced adhesion of S. mutans to the oral cavity of naïve mice. Moreover, mice actively immunized with rGlnH were partially protected from oral colonization after exposure to the S. mutans NG8 strain. Our results indicate that S. mutans rGlnH is a potential target antigen capable of inducing specific and protective antibody responses after immunization. Overall, these observations raise the prospect of the development of mucosal anti-caries vaccines.

Enzymatic processing and MHC loading in cancer immunotherapyAdvanced immunopeptidomics based discovery engine for the development of personalized cancer immunotherapy

The remarkable clinical efficacy of the immune checkpoint blockade therapies has motivated researchers to discover immunogenic epitopes and exploit them for personalized vaccines. Mutated human leukocyte antigen binding peptides (HLAp) are currently the leading targets. Most studies attempt to identify neoantigens based on predicted affinity to HLA molecules. We have shown that the direct identification of tissue-derived neoantigens by mass spectrometry is becoming feasible and we have recently designed a novel high-throughput, reproducible and sensitive method for sequential immuno-affinity purification of HLA-I and -II peptides that is suitable for both cell lines and tissues. The massive amount of HLAp data we acquire while hunting down the neo-antigens is highly valuable. We have compiled a large immunopeptidomics database across dozens of cell types and HLA allotypes. First, we have shown that by taking advantage of co-occurring HLA-I alleles across dozens of immunopeptidomics datasets we can rapidly and accurately identify HLA-I binding motifs. Consequently, training HLA-I ligand predictors on refined motifs significantly improves the identification of neoantigens. Recently, we have acquired the largest reported high-quality HLA-II peptidomics dataset. We introduced completely novel algorithmic tools to analyze such data and developed for the first time HLA-II epitope prediction tool trained on peptidomics data that results in major improvements in prediction accuracy. Second, our database captures the global nature of the in vivo peptidome averaged over many HLA alleles, and therefore, reflects the propensity of peptides to be presented on HLA complexes, which is complementary to the existing neoantigen prediction features. We have shown as a proof of concept that our immunopeptidomics MS-based features improved neoantigen prioritization by up to 50%. Overall, immunopeptidomics facilitates direct identification of neoantigens and it can also improve the prediction of clinically relevant neoantigens, and we develop a novel clinical pipeline for target selection for personalized anti-cancer vaccines.

Antigens Expressed by Breast Cancer Cells Undergoing EMT Stimulate Cytotoxic CD8+ T Cell Immunity.

Simple SummaryThe transition of cells with epithelial characteristics to those with mesenchymal characteristics (termed EMT) facilitates breast cancer invasive capacity. The EMT program can also contribute to immunosuppressive and immunoevasive properties, altering susceptibility to immune cell recognition and killing. The goal of our study was to manipulate EMT to reveal potential neoantigens that might affect the ability of tumor cells to circumvent immune escape and/or be utilized as an anticancer vaccine to kill cancer cells exhibiting the cellular plasticity that permits therapy resistance and metastatic progression. We identified potential neoantigens resulting from EMT-associated altered gene expression and alternative splicing events and observed increased immunogenicity and susceptibility to killing of the more epithelial-like cancer cells. Although the tested peptides did not protect from tumor growth, a limited number of predicted neoantigens derived from intron retention events were tested. In the future, refined prediction programs may facilitate exciting antigen discoveries.Antigenic differences formed by alterations in gene expression and alternative splicing are predicted in breast cancer cells undergoing epithelial to mesenchymal transition (EMT) and the reverse plasticity known as MET. How these antigenic differences impact immune interactions and the degree to which they can be exploited to enhance immune responses against mesenchymal cells is not fully understood. We utilized a master microRNA regulator of EMT to alter mesenchymal-like EO771 mammary carcinoma cells to a more epithelial phenotype. A computational approach was used to identify neoantigens derived from the resultant differentially expressed somatic variants (SNV) and alternative splicing events (neojunctions). Using whole cell vaccines and peptide-based vaccines, we find superior cytotoxicity against the more-epithelial cells and explore the potential of neojunction-derived antigens to elicit T cell responses through experiments designed to validate the computationally predicted neoantigens. Overall, results identify EMT-associated splicing factors common to both mouse and human breast cancer cells as well as immunogenic SNV- and neojunction-derived neoantigens in mammary carcinoma cells.

Immunological Examination of Echinococcus granulosus as a Candidate for Cancer Treatment and Vaccine Development: A Review Study

Echinococcus granulosus, is a cestode parasite that causes cystic echinococcosis. The vaccination procedure with tumor-associated antigens, coming from evolutionary distant organisms such as parasites, can be beneficial to override tolerance problems encountered with human tumor-associated antigens-based cancer therapeutic approaches. In this article, different databases of PubMed, Google Scholar, IranDoc and SID were examined from 2001 to 2021 and related articles were investigated. The review of related studies concerning human beings' treatment revealed the possibility of inhibition of cancer development via HCF antigens and mucin peptides extracted from this cestode. Besides, HCF treatment in animal models mostly showed that anti-cancer immune responses were activated. Of note, an influential issue in the design process of an anti-cancer vaccine is triggering efficacious anti-tumor responses by using idyllic antigens for immunization against cancer. In this realm, many antigens have been studied for this purpose and showed different ranges of effectiveness. Based on the cross-reactivity among parasitic and tumor antigens, detection of parasitic antigens that are highly homologous with cancer antigens is an ideal objective for immunization against cancer cells. As the toxicity of HCF was reported in some studies, further research are required to shed light on finding an innovative anti-cancer vaccine derived from parasites. This review article is useful for health managers and researchers working on the anti-cancer vaccine development.

1019P Pattern of clinical activity of anticancer vaccine OSE2101 in HLA-A2+ non-small cell lung cancer (NSCLC) patients after failure to immune checkpoint inhibitors (IO) in phase III Atalante-1 randomized trial

OSE2101 (Tedopi) is an anticancer vaccine increasing overall survival (OS) with HR of 0.59 (p=0.017) versus Standard of Care Chemotherapy (SoC CT) in the population of interest (PoI) of HLA-A2+ NSCLC patients with IO secondary resistance after sequential CT-IO (ESMO 2021 #47LBA). The objective of this analysis was to explore the pattern of activity of OSE2101. 118 NSCLC EGFR and ALK negative patients were randomized (2:1) in OSE2101 or SoC (docetaxel or pemetrexed) in the PoI. OS of OSE2101 versus SoC was described according to best response (partial response (PR), Stable Disease (SD) and Progressive Disease (PD)) and to the administration of post progression anticancer treatment. OS was described in Late Progressors (LP) defined as no RECIST 1.1 nor clinical PD within the first 6 months after randomization. Median (95%CI) OS in months by best response and by post progression anticancer treatment are described in the table. 16 (20%) patients fulfilled the criteria for Late Progressors with OSE2101. Late Progressors included 4 (25%) patients with PR and 12 (75%) patients with prolonged SD. mOS was 14.7 months with 1-year OS rate of 68%. mPFS was 8.8 months with 23% of patients progression-free at 1-year.Table: 1019PmOS (months)OSE2101 n=80SoC n=38By Best ResponsePRn=6 11.2 (5.4, NE)n=7 13.8 (2.6, NE)HR=0.75 (0.18, 3.23)SDn=36 13.1 (8.8, 16.8)n=19 9.4 (6.5, 12.2)HR=0.61 (0.33, 1.14)PDn=32 8.0 (5.4, 11.1)n=7 5.0 (1.0, 7.2)HR=0.45 (0.19, 1.04)By Post Progression anticancer treatmentWith anticancer treatmentn=55 13.5 (9.6,16.6)n=16 10.6 (7.2, 16.1)HR=0.71 (0.38, 1.30)Without anticancer treatmentn=25 6.3 (3.6, 7.6)n=22 4.5 (2.3, 8.3)HR=0.76 (0.41, 1.41) Open table in a new tab In advanced HLA-A2+ NSCLC patients with IO secondary resistance after sequential CT-IO, OS was longer with OSE2101 versus SoC regardless the use of post progression anticancer treatment. By Best Response to study treatement, OS was longer with OSE2101 in patients with Stable Disease or Progressive Disease compared to SoC. Late progressors with OSE2101 were mainly driven by long Stable Disease. These data suggest that the cancer vaccine OSE2101 may act as an anti-tumor brake in controlling the tumor growth regardless of best response.

1024P Net treatment benefit of OSE2101 in HLA-A2+ non-small cell lung cancer (NSCLC) patients after failure to immune checkpoint inhibitors (IO) in phase III Atalante-1 randomized trial

OSE2101 (Tedopi) is an anticancer vaccine that increased overall survival (OS) (HR 0.59, p=0.017) versus Standard of Care Chemotherapy in the population of interest (PoI N=118) of patients with IO secondary resistance after sequential CT-IO (ESMO 2021 #47LBA). The Net Treatment Benefit (NTB) is an original method combining efficacy and safety endpoints to test the overall improvement in health outcome between 2 treatments (Buyse M. Stat Med 2010). NTB was assessed in the overall population (N=219) from whom OS improvement of OSE2101 (HR 0.86, p=0.35) was lower than in PoI.

538P Adding plasmid encoding p62/SQSTM1 to gemcitabine chemotherapy increases PFS for patients with platinum-resistant ovarian cancer (updated data)

Here we report the results of the second interim analysis of a randomized prospective multi-center clinical study aimed to evaluate safety and efficacy of p62/SQTM1-encoding plasmid applied as an adjuvant to chemotherapy in patients with advanced platinum-resistant ovarian cancer. P62 encoding plasmid acts as an classic anti-cancer DNA vaccine and it also lowers chronic inflammation thus rendering tumor cells more susceptible to immune response and chemotherapy.

Neoantigen-based cancer vaccination using chimeric RNA-loaded dendritic cell-derived extracellular vesicles.

Cancer vaccines critically rely on the availability of targetable immunogenic cancer‐specific neoepitopes. However, mutation‐based immunogenic neoantigens are rare or even non‐existent in subgroups of cancer types. To address this issue, we exploited a cancer‐specific aberrant transcription‐induced chimeric RNA, designated A‐Pas chiRNA, as a possible source of clinically relevant and targetable neoantigens. A‐Pas chiRNA encodes a recently discovered cancer‐specific chimeric protein that comprises full‐length astrotactin‐2 (ASTN2) C‐terminally fused in‐frame to the antisense sequence of the 18th intron of pregnancy‐associated plasma protein‐A (PAPPA). We used extracellular vesicles (EVs) from A‐Pas chiRNA‐transfected dendritic cells (DCs) to produce the cell‐free anticancer vaccine DEXA‐P. Treatment of immunocompetent cancer‐bearing mice with DEXA‐P inhibited tumour growth and prolonged animal survival. In summary, we demonstrate for the first time that cancer‐specific transcription‐induced chimeric RNAs can be exploited to produce a cell‐free cancer vaccine that induces potent CD8+ T cell‐mediated anticancer immunity. Our novel approach may be particularly useful for developing cancer vaccines to treat malignancies with low mutational burden or without mutation‐based antigens. Moreover, this cell‐free anticancer vaccine approach may offer several practical advantages over cell‐based vaccines, such as ease of scalability and genetic modifiability as well as enhanced shelf life.