Therapeutic Immunization Research Articles

Induction of Progenitor Exhausted Tissue-Resident Memory CD8+ T Cells Upon Salmonella Typhi Porins Adjuvant Immunization Correlates With Melanoma Control and Anti-PD-1 Immunotherapy Cooperation.

Immunotherapy has improved the clinical response in melanoma patients, although a relevant percentage of patients still cannot be salvaged. The search for the immune populations that provide the best tumor control and that can be coaxed by immunotherapy strategies is a hot topic in cancer research nowadays. Tumor-infiltrating TCF-1+ progenitor exhausted CD8+ T cells seem to grant the best melanoma prognosis and also efficiently respond to anti-PD-1 immunotherapy, giving rise to a TIM-3+ terminally exhausted population with heightened effector activity. We tested Porins from Salmonella Typhi as a pathogen associated molecular pattern adjuvant of natural or model antigen in prophylactic and therapeutic immunization approaches against murine melanoma. Porins induced protection against melanomas, even upon re-challenging of tumor-free mice. Porins efficiently expanded IFN-γ-producing CD8+ T cells and induced central and effector memory in lymph nodes and tissue-resident (Trm) T cells in the skin and tumors. Porins induced TCF-1+ PD-1+ CD8+ Trm T cells in the tumor stroma and the presence of this population correlated with melanoma growth protection in mice. Porins immunization also cooperated with anti-PD-1 immunotherapy to hamper melanoma growth. Importantly, the potentially protective Trm populations induced by Porins in the murine model were also observed in melanoma patients in which their presence also correlated with disease control. Our data support the use of cancer vaccination to sculpt the tumor stroma with efficient and lasting Trm T cells with effector activities, highlighting the use of Porins as an adjuvant. Furthermore, our data place CD8+ Trm T cells with a progenitor exhausted phenotype as an important population for melanoma control, either independently or in cooperation with anti-PD-1 immunotherapy.

COVID-19 in Pregnancy in Scotland (COPS): protocol for an observational study using linked Scottish national data

IntroductionThe effects of SARS-CoV-2 in pregnancy are not fully delineated. We will describe the incidence of COVID-19 in pregnancy at population level in Scotland, in a prospective cohort study using...

Progress in L2-Based Prophylactic Vaccine Development for Protection against Diverse Human Papillomavirus Genotypes and Associated Diseases.

The human papillomaviruses (HPVs) are a family of small DNA tumor viruses including over 200 genotypes classified by phylogeny into several genera. Different genera of HPVs cause ano-genital and oropharyngeal cancers, skin cancers, as well as benign diseases including skin and genital warts. Licensed vaccines composed of L1 virus-like particles (VLPs) confer protection generally restricted to the ≤9 HPV types targeted. Here, we examine approaches aimed at broadening the protection against diverse HPV types by targeting conserved epitopes of the minor capsid protein, L2. Compared to L1 VLP, L2 is less immunogenic. However, with appropriate presentation to the immune system, L2 can elicit durable, broadly cross-neutralizing antibody responses and protection against skin and genital challenge with diverse HPV types. Such approaches to enhance the strength and breadth of the humoral response include the display of L2 peptides on VLPs or viral capsids, bacteria, thioredoxin and other platforms for multimerization. Neither L2 nor L1 vaccinations elicit a therapeutic response. However, fusion of L2 with early viral antigens has the potential to elicit both prophylactic and therapeutic immunity. This review of cross-protective HPV vaccines based on L2 is timely as several candidates have recently entered early-phase clinical trials.

Abstract 6680: Inclusion of inhibitory neoantigens can abolish efficacy of otherwise protective therapeutic anti-tumor vaccines

Abstract Identification of neoantigens that can elicit strong anti-tumor responses has become critical to vaccine design for cancer immunotherapy. Conventional methods for in silico neoantigen identification have yielded poor predictive value, highlighting the need for methods that identify bona fide neoantigen targets. The Genocea ATLAS™ platform uses autologous antigen presenting cells and T cells to identify pre-existing CD4+ and/or CD8+ T cell responses to patient-specific mutations and therefore selects confirmed neoantigens that can be used for vaccines and cell therapies. Screened neoantigens are characterized as stimulatory or inhibitory based on up- or downregulation of inflammatory cytokine secretion compared to baseline controls. In the mouse B16F10 melanoma model, therapeutic immunization with stimulatory neoantigen peptides arrested tumor growth whereas in contrast, inhibitory antigen immunization (henceforth referred to as inhibigens) resulted in accelerated tumor progression. The presence of an inhibigen in an otherwise protective vaccine formulation completely abolished protection. Global IFNγ responses to neoantigens were abrogated in these mice as measured by ELISpot suggesting that inhibigen pro-tumor responses can be immunodominant. Analysis of tumor-infiltrating lymphocytes (TILs) from mice immunized with ATLAS-identified neoantigen ± inhibigen peptide vaccines revealed significant alterations in the tumor microenvironment. Inclusion of inhibigens resulted in low T cell infiltration into tumors and increased expression of TIL inhibitory surface markers (e.g. PD-1, LAG-3). Immunological mechanisms of the inhibitory phenomenon are currently being explored. These data promote rational methods for neoantigen identification and highlight the potential advantages of excluding deleterious inhibigens from cancer vaccines and immunotherapies. GEN-009, a personalized cancer vaccine filtered for inclusion of only ATLAS-identified neoantigens (excluding inhibigens) is currently being evaluated in a Phase 1/2a clinical trial (NCT03633110). Citation Format: Victoria L. DeVault, Hanna Starobinets, Sanmit Adhikari, Simran Singh, Stephanie Rinaldi, Brendan Classon, Jessica B. Flechtner, Hubert Lam. Inclusion of inhibitory neoantigens can abolish efficacy of otherwise protective therapeutic anti-tumor vaccines [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 6680.

Abstract 2221: Combining irreversible electroporation with TLR7 and CD40 agonists confers systemic anti-tumor immunity in a murine pancreatic cancer model

Abstract Introduction: Pancreatic Cancer (PC) has a highly immunosuppressive microenvironment with a low mutational burden and has so far been resistant to immunotherapy. Irreversible electroporation (IRE) is a non-thermal method of inducing tumor cell death, without damage to adjacent blood vessels, that is being used clinically for selected patients with locally advanced PC. Despite local control rates greater than 90%, most IRE patients develop distant recurrence, emphasizing the need for better methods to treat micrometastatic disease. Using an immunocompetent mouse model of PC, we have previously shown that IRE induces complete regression in 25-33% of subcutaneous tumors, and complete responders are protected from a tumor rechallenge. However, IRE alone did not produce significant therapeutic immunity (abscopal effects) against concomitant distant tumors. We hypothesized that combination of IRE with innate immune stimulators would also enhance the adaptive immune response. Methods: We used a cell line generated from a genetically engineered (KPC) mouse establish bilateral flank tumors. The “primary” tumor was treated with IRE alone or in combination with local delivery of a toll-like receptor 7 (TLR7) agonist (1V270) and CD40 agonistic antibody (CD40Ab). 15 parameter procartaplex (Thermo) was used for cytokine analysis and RNA-Seq was performed using an Illumina MiSeq 1000 platform with total RNA from excised tumor all on day 7 post procedure. Results: We observed complete regression in 8/10 tumors treated with the combination (Combo) of IRE, 1V270 and CD40Ab compared to 3/10 in IRE alone. However, the combo was much more effective than IRE alone at inducing regression of the untreated secondary flank tumor, including complete regression of 7/10 untreated tumors. CD40Ab alone had minimal effect on local or secondary tumor growth. Analysis of systemic cytokines using multiplex analysis showed 112 fold increase in IFNy levels in plasma with the Combo compared to untreated mice (P<0.001) and a 39 fold increase compared to IRE alone (P<0.001). Other factors of Th1 response such as IP-10 and IL12-P70 were also significantly (P<0.001) higher in the Combo group compared to IRE alone along with TNFa (elevated 3.2 fold vs IRE). RNA-Seq of the whole tumor followed by gene set enrichment analysis showed significant elevation in Type II interferon, (P<0.0001), IL2 (P<0.0001), and apoptosis (P=0.0001) pathways in the Combo group. Both IRE alone and the Combo group complete responders were protected from tumor growth after immediate rechallenge (14 days) and delayed rechallenge (180 days). However, flow cytometric analysis of the splenocytes revealed that the combo group had more CD44+CD62L+CD8+ central memory T-cells (16%) in contrast to IRE alone (11%). Conclusion: These data suggest that local delivery of CD40Ab and TLR7 agonists augment the systemic immune effects of IRE and have the potential to improve the overall survival of patients undergoing IRE for locally advanced PC by reducing distant recurrence. Citation Format: Jayanth Surya Narayanan Shankara Narayanan, Diego Vicente, Partha Ray, Thomas Whisenant, Rebekah White. Combining irreversible electroporation with TLR7 and CD40 agonists confers systemic anti-tumor immunity in a murine pancreatic cancer model [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 2221.

Co-delivery of Peptide Neoantigens and Stimulator of Interferon Genes Agonists Enhances Response to Cancer Vaccines.

Cancer vaccines targeting patient-specific neoantigens have emerged as a promising strategy for improving responses to immune checkpoint blockade. However, neoantigenic peptides are poorly immunogenic and inept at stimulating CD8+ T cell responses, motivating a need for new vaccine technologies that enhance their immunogenicity. The stimulator of interferon genes (STING) pathway is an endogenous mechanism by which the innate immune system generates an immunological context for priming and mobilizing neoantigen-specific T cells. Owing to this critical role in tumor immune surveillance, a synthetic cancer nanovaccine platform (nanoSTING-vax) was developed that mimics immunogenic cancer cells in its capacity to efficiently promote co-delivery of peptide antigens and the STING agonist, cGAMP. The co-loading of cGAMP and peptides into pH-responsive, endosomolytic polymersomes promoted the coordinated delivery of both cGAMP and peptide antigens to the cytosol, thereby eliciting inflammatory cytokine production, co-stimulatory marker expression, and antigen cross-presentation. Consequently, nanoSTING-vax significantly enhanced CD8+ T cell responses to a range of peptide antigens. Therapeutic immunization with nanoSTING-vax, in combination with immune checkpoint blockade, inhibited tumor growth in multiple murine tumor models, even leading to complete tumor rejection and generation of durable antitumor immune memory. Collectively, this work establishes nanoSTING-vax as a versatile platform for enhancing immune responses to neoantigen-targeted cancer vaccines.

Converting Immune Cold into Hot by Biosynthetic Functional Vesicles to Boost Systematic Antitumor Immunity.

SummaryImmune cold tumor characterized by low immunogenicity, insufficient and exhausted tumor-infiltrating lymphocytes, and immunosuppressive microenvironment is the main bottleneck responsible for low patient response rate of immune checkpoint blockade. Here, we developed biosynthetic functional vesicles (BFVs) to convert immune cold into hot through overcoming hypoxia, inducing immunogenic cell death, and immune checkpoint inhibition. The BFVs present PD1 and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on the surface, whereas load catalase into their inner core. The TRAIL can specifically induce immunogenic death of cancer cells to initiate immune response, which is further synergistically strengthened by blocking PD1/PDL1 checkpoint signal through ectogenic PD1 proteins on BFVs. The catalase can produce O2 to overcome tumor hypoxia, in turn to increase infiltration of effector T cells while deplete immunosuppressive cells in tumor. The BFVs elicit robust and systematic antitumor immunity, as demonstrated by significant regression of tumor growth, prevention of abscopal tumors, and excellent inhibition of lung metastasis.

Antibodies to SARS-CoV-2 and their potential for therapeutic passive immunization.

We review aspects of the antibody response to SARS-CoV-2, the causative agent of the COVID-19 pandemic. The topics we cover are relevant to immunotherapy with plasma from recovered patients, monoclonal antibodies against the viral S-protein, and soluble forms of the receptor for the virus, angiotensin converting enzyme 2. The development of vaccines against SARS-CoV-2, an essential public health tool, will also be informed by an understanding of the antibody response in infected patients. Although virus-neutralizing antibodies are likely to protect, antibodies could potentially trigger immunopathogenic events in SARS-CoV-2-infected patients or enhance infection. An awareness of these possibilities may benefit clinicians and the developers of antibody-based therapies and vaccines.

Personalized neoantigen/cancer testis antigen nanovaccine (PVAC) mobilize specific therapeutic immunity for high-risk resected gastric cancer.

4535 Background: 35% of stage IIIB/C Gastric cancer patients will recurrent after D2 gastrectomy within one year. Mutation-derived epitopes (neoantigens) has been demonstrated to induce tumor cell specific immune responses controlling the tumor growth. Nanovaccine can increase antigen presentation efficiency and elicit potent antitumor T cell responses with robust therapeutic efficacy. We hypothesized that vaccination with neoantigens/cancer testis (CT) antigens could expand pre-existing and induce antigen-specific T-cells populations, favouring of tumor control enhancement. Here, we report the first-in-human application of this concept in gastric cancer. Methods: Patient-specific mutation-containing neoantigens were selected on the basis of tumour-specific mutations whole-exome sequencing (WES) and RNA sequencing. Cancer testis antigens were obtained according to immunohistochemical staining and HLA-binding affinity prediction. PVAC is an amphiphiles nanovaccine loaded with multiple personalized neoantigens/cancer testis antigens designed to induce antigen specific T cells and associated antitumor responses. PVAC will be administrated to stage IIIB/IIIC gastric carcinoma after six cycles of adjuvant chemotherapy (S-1/Oxaliplatin or S-1/docetaxel). Each patient received PVAC by subcutaneous injection on Days 1, 4, 8, 15, 22, 43, 64, 85, 169, administrated with the adjuvant montanide ISA 51 VG. Safety, immunogenicity and clinical efficacy will be evaluated. Results: 25 stage IIIB or IIIC gastric cancer patients were enrolled in this study. Mean age was 54.3 years old (range: 34-70), and ECOG performance scores were 0 or 1. Repeated dosing has been well tolerated with mild local discomfort and no DLTs. Three patients were observed grade 2 local skin reactions in the injection sites. No SAEs related to PVAC have been observed. Among median follow up time of 12.6 months (range: 8.5-25.0 months), only two patients had local recurrence at 24.0 months and 10.5 months after surgery, respectivelt. The rest 23 patients remain disease free on study. Neoantigen specific T cell responses have been detected by IFN-γ Elispot from PBMCs. Conclusions: PVAC is a multiple neoantigen/CT antigens nanovaccine that personalizes tumor specific antigens and the individual patient’s capacity to respond. Addition of PVAC may prolong progression-free survival (PFS) after the standard of care chemotherapy. Clinical trial information: ChiCTR1800017319 .

Antitumor immunity targeting fibroblast activation protein-α in a mouse Lewis lung carcinoma model.

The tumor stromal microenvironment is an integral part of the occurrence and development of tumor. Cancer-associated fibroblasts (CAFs) are a key component of most tumor stromal microenvironments. The present study aimed to investigate the use of CAFs-targeted immunotherapy to fibroblast activation protein-α (FAP-α) expressed in CAFs. Recombinant adenoviral vectors containing the mouse FAP-α cDNA (rAd-FAP-α) were constructed. C57BL/6 mice were immunized with rAd-FAP-α infected dendritic cells (DCs) against FAP-α, which is overexpress in CAFs. The results demonstrated that mice vaccinated with rAd-FAP-α DCs gave rise to potent FAP-α-specific cytotoxic T lymphocytes capable of lysing Lewis lung cancer (LLC) CAFs. Furthermore, mice vaccinated with rAd-FAP-α-transduced DCs induced an effective therapeutic or protective antitumor immunity to LLC in a subcutaneous model, and prolonged overall survival time compared with mice vaccinated with the control recombinant adenovirus-transduced DCs (rAd-c DCs) or DCs alone. The results of the present study suggested that FAP-α, which is preferentially expressed in CAFs, may be considered as a potential target for killing or destroying CAFs within the tumor stromal microenvironment, and may be exploited to develop immunogenic tumor vaccines.

Abstract B86: Treatment of glioma cells with IGF-1R antisense and irradiation induces the production of antigens that stimulate IFNγ production by tumor-specific CD4 T cells

Abstract We describe here a novel process for the production by glioma cells of cell-free, tumor-specific antigens that supplant the need for intact tumor cells in the induction of immunity against autologous tumor antigen. Radiation is thought to trigger the release of potentially immunostimulatory tumor antigens. However, a variety of tumor cells, including human glioblastoma multiforme (GBM) and mouse GL261 glioma cells, express high levels of insulin-like growth factor-1 receptor (IGF-1R), which has been associated with radioresistance. To determine if the combination of targeting IGF-1R with an antisense oligodeoxynucleotide (AS) and radiation causes the release of glioma antigens, we encapsulated GL261 cells in biodiffusion chambers with different doses of IGF-1R AS, subjected the chambers to 5Gy radiation, and cultured the chambers for approximately 18 hours. Bone marrow-derived dendritic cells (BMDCs) from naive mice were pulsed with the cell-free chamber contents and cultured with CD4 T cells from mice protected against the growth of GL261 cells implanted in the cerebral cortex by immunization with a GL261 cell-based vaccine. The numbers of T cells producing IFNγ in an ELISPOT assay were used as an index of antigen recognition. The contents of chambers that were incubated with viable GL261 or were irradiated but cultured without IGF-1R AS stimulated only weak T-cell responses. Substantial T-cell reactivity was only seen with BMDCs pulsed with the cell-free contents of irradiated chambers containing GL261 cells and IGF-1R AS. Overnight treatment of GL261 cells with IGF-1R AS prior to encapsulation and irradiation also promoted antigen release but was most effective only when a small amount of IGF-1R AS was also added to the chambers. Fully formulated chambers contained tumor tissues that had been cultured overnight with the IGF1-R antisense, encapsulated with additional antisense and irradiated. Chambers were incubated in PBS or implanted in the flanks of naive C57BL/6 mice overnight, then contents were retrieved and used to pulse naive BMDCs. CD4 T cells recovered from GL261-immune C57BL/6 mice were used to detect tumor antigenic determinants presented by the BMDCs with the readout being the number of cells producing IFNγ. We conclude that the treatment of IGF-1R-positive glioma cells with IGF-1R AS and sublethal irradiation stimulates the cells to release antigens capable of stimulating the IFNγ-producing CD4 Th1 cells that have been associated with therapeutic immunity against glioma cells in the GL261 model. When performed in a biodiffusion chamber, this process leads to the accumulation of immunostimulatory antigens in the absence of tumor cell products known to have inhibitory properties for Th1 cells. Immunization via the implantation of irradiated biodiffusion chambers containing autologous tumor cells recovered at surgery and IGF-1R AS is currently under investigation in a clinical trial for patients with GBM (IND 14379; ClinicalTrials.gov, NCT01550523). Citation Format: Samantha Garcia, Rhonda Kean, Aurore Lebrun, Emily Bongiorno, David W. Andrews, D. Craig Hooper. Treatment of glioma cells with IGF-1R antisense and irradiation induces the production of antigens that stimulate IFNγ production by tumor-specific CD4 T cells [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B86.

Transarterial Chemoembolization in Hepatocellular Carcinoma: A Clinical Efficacy Study of Ganoderma Lucidum Extract Polysaccharide Peptide β-Glucan

Background: Hepatocellular carcinoma (HCC) is a primary liver malignancy with high prevalence rate, associated primarily with the Hepatitis B Virus. HCC is the third leading cause of death worldwide. The prevalence in Indonesia is estimated at 100 per100,000 inhabitants. Treatment is generally ineffective as patients are already at advanced stages when diagnosed. Trans-arterial Chemoembolization (TACE) is a promising treatment, and β-Glucan combined therapy is expected to treat HCC more efficiently. This study evaluated the treatment response of TACE in HCC combined with β-Glucan orally. Methods: A randomized clinical trial was conducted on 63 patients with HCC. The subjects of the study were randomly assigned into two groups: 32 administered TACE plus β-Glucan, and 31 with TACE plus placebo. Results: In the β-Glucan group, there were four patients (12.50%) with complete response, 16 (50%) partial response, 3 (9.38%) no response, and 9 (28.12%) in deteriorated response. In the placebo group, there were 0 complete response, 11(35.48%) partial, 2(6.45%) no response, and 18 (58.07%) deteriorated response. The survival rate of the β-Glucan group was longer (median 39 weeks) than the placebo group (median 26 weeks). CD4, CD8 and IL-2 post-TACE increased significantly (p<0.05). The placebo group had 4.143 times, significantly higher hazard risk (p<0.05).Conclusion: HCC therapy with a combination of TACE and β-Glucan is beneficial to increase the therapeutic response, immunity and survival rate.

Abstract A14: Irreversible electroporation is an “in situ vaccine” and induces antitumor immune responses in pancreatic cancer

Abstract The pancreatic cancer (PC) microenvironment is notoriously immunosuppressive and responds poorly to conventional checkpoint blockade immunotherapy, necessitating a need to overcome this challenge. Irreversible electroporation (IRE) is a nonthermal method of inducing cell death that is currently being used clinically for selected patients with locally advanced PC. Using a robust syngeneic mouse model of PC using cells established from a tumor arising in an LSL-KrasG12D/+; LSL-Trp53R172H/+; PDX1Cre/+; LSL-ROSA26 Luc/+ mouse (KPC), we have demonstrated that IRE alone can serve as an “in situ vaccine” and induce systemic immune responses that prevent secondary tumor growth (prophylactic immunity). We have furthermore demonstrated that these effects are augmented by combination with innate immune activators and PD-1 checkpoint blockade. We observed a significant decrease in immunosuppressive myeloid-derived suppressor cells (MDSCs) (CD11b+, CD11c-, GR1+) at one week in the IRE and drug alone groups with an additive effect in the combination groups. We also saw a profound shift in the ratio of immunostimulatory M1 (MHC II+, CD206 lo): immunosuppressive M2 (MHC II -, CD206 hi) macrophages in the combination groups and a modest increase in CD8+ T cells with IRE alone that was almost doubled in the combination groups with a concomitant decrease in T regulatory cells. Using exome and RNA sequencing of the KPC tumors expressed, nonsynonymous mutations in these tumors were identified and 101 long peptides (20 mer) were generated harboring these mutations at positions 9 and 15. When the CD8+ T-cells post-IRE were incubated along with these mutant peptides and bone marrow-derived dendritic cells, we were able to observe that these T cells were reactive (Interferon gamma secretion) to these neoantigenic peptide pools. Further, we were able to identify specific mutant peptides against which T-cell response was stimulated post IRE that were similar or even better than vaccinating the mice with irradiated KPC cells, suggesting that IRE induced tumor neoantigen-specific prophylactic immune response. Specifically, local delivery of toll-like receptor 7 (TLR7) agonist (1V270) and agonistic CD40 antibody resulted in complete regression of treated primary tumors in 7/10 mice in the experimental group. Increased presence of CD8+ dendritic cells (CD45+ CD11C+) in the draining lymph node suggested that the agonistic CD40 antibody could have triggered increased dendritic cell maturation and cross-presentation. Moreover, it resulted in the complete elimination of the untreated secondary tumors in the group, which IRE as a monotherapy failed to achieve, showing that with appropriate combination strategies, successful therapeutic systemic antitumor immunity can also be achieved with IRE to be used for the management of metastatic PC in the near future. Citation Format: Jayanth S. Shankara Narayanan, Aaron Miller, Tomoko Hayashi, Partha Ray, Stephen Schoenberger, Dennis Carson, Rebekah White. Irreversible electroporation is an “in situ vaccine” and induces antitumor immune responses in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A14.

A Phase 1 Trial Assessing the Safety and Tolerability of a Therapeutic DNA Vaccination Against HPV16 and HPV18 E6/E7 Oncogenes After Chemoradiation for Cervical Cancer

This study assessed the safety and tolerability of therapeutic immunization against the human papillomavirus (HPV) viral oncoproteins E6 and E7 in patients with cervical cancer after chemoradiation. MEDI0457 (INO-3112) is a DNA-based vaccine targeting E6 and E7 of HPV-16/18 that is coinjected with an IL-12 plasmid followed by electroporation with the CELLECTRA 5P device. At 2 to 4 weeks after chemoradiation, patients with newly diagnosed stage IB1-IVA (cohort 1) or persistent/recurrent (cohort 2) cervical cancers were treated with 4 immunizations of MEDI0457 every 4 weeks. The primary endpoints were incidence of adverse events and injection site reactions. Immune responses against HPV antigens were measured by ELISpot for interferon-γ (IFNγ), enzyme-linked immunosorbent assay for antibody responses and multiplexed immunofluorescence for immune cells in cervical biopsy specimens. Ten patients (cohort 1, n = 7; cohort 2, n = 3) with HPV16 (n = 7) or HPV18 (n = 3) cervical cancers received MEDI0457 after chemoradiation. Treatment-related adverse events were all grade 1, primarily related to the injection site. Eight of 10 patients had detectable cellular or humoral immune responses against HPV antigens after chemoradiation and vaccination: 6 of 10 patients generated anti-HPV antibody responses and 6 of 10 patients generated IFNγ-producing T cell responses. At the completion of chemoradiation and vaccination, cervical biopsy specimens had detectable CD8+ T cells and decreased PD-1+CD8+, PD-L1+CD8+, and PD-L1+CD68+ subpopulations. All patients cleared detectable HPV DNA in cervical biopsies by completion of chemoradiation and vaccination. Adjuvant MEDI0457 is safe and well tolerated after chemoradiation for locally advanced or recurrent cervical cancers, supporting further investigation into combining tumor-specific vaccines with radiation therapy.

Vector vaccine Flu/ESAT-6 application in the regimen of complex therapy of drug-sensitive and drug-resistant experimental tuberculosis estimation of the efficiency

The steady growth of drug-resistant tuberculosis, charac-terized by low therapeutic efficacy, requires the develop-ment of innovative approaches to the treatment of this infection. One of such approaches is vaccine therapy that has immunostimulating activity and is capable to correct dysfunction of the immune system in this infection. In this study, the authors aimed to estimate the efficacy of the mucosal vector vaccine Flu/ESAT-6 included into the complex therapy of experimental pulmonary tuberculosis. C57BL/6 mice were intravenously infected with drug-sus-ceptible (DS) (M. tuberculosis H37Rv) or drug- resistant (DR) (M. tuberculosis Beijing genotype) MBT strains. DS-in-fection was treated with two anti-TB drugs (HR), and DR-infection with four (AETppBq). Flu/ESAT-6 vaccine based on the attenuated influenza A virus strain expres-sing the mycobacterial protein ESAT-6 was administered intranasally at a dose of 6 lg/mouse. Efficacy of vari-ous therapeutic regimens was assessed with biometric, bacteriological, and histological methods. Two optimal therapeutic regimens of Flu/ESAT-6 administration were chosen: twice (with a 3 week interval) at the beginning of chemotherapy in case of DS infection; and thrice (with a 4 week interval) 2 weeks after the beginning of chemo-therapy in case of DR infection. Flu/ESAT-6 addition to the anti-tuberculosis treatment led to a significant increase in the efficacy of therapy for both forms of infection which manifested in (i) the pulmonary bacterial load decrease at the end of a 2-months therapy of DS tuberculosis by 1.83 lg CFU; and after 4-months therapy of DR tuberculosis by 0.93 lg CFU; (ii) decrease in the prevalence of specific and the severity of exudative inflammation, and reduction of alternative components in case of DR tuberculosis; (iii) stimulation of the lymphoid component of the cellular im-mune response in lungs, demonstrated by reorganization of granulomas’ cellular composition to lymphoid type, and in the formation of peribronchial lymphohistiocytic infiltrates. Thus, therapeutic immunization with Flu/ESAT-6 vaccine significantly increases the efficacy of experimen-tal tuberculosis therapy and can shorten the duration of anti-tuberculosis therapy which is especially important in case of DR tuberculosis characterized by a slow involution of specific inflammation.

Pulmonary sarcomatoid carcinoma: progress, treatment and expectations.

Pulmonary sarcomatoid carcinoma (PSC) is a unique, highly invasive pulmonary malignancy with a poor prognosis, representing 0.1–0.4% of all malignant lung tumors. Because of its highly aggressive character and propensity for frequent metastasis, PSC shows low response rates to traditional treatments such as chemotherapy, radiotherapy, and neoadjuvant therapy. In recent years, considerable progress has been made in gene sequencing, targeted therapies, and immunotherapies. One of the most promising treatment approaches is the selection of mono-targeted or multi-targeted drugs according to tumor gene-mutation sites, such as epidermal growth factor receptor or vascular endothelial growth factor receptor 2 (EGFR/VEGFR2), anaplastic lymphoma kinase (ALK), and others. Another approach is the activation of therapeutic anti-tumor immunity via pathways including programmed cell-death protein-1/programmed cell-death ligand-1 (PD-1/PD-L1), which has been used in individual cases. In this review, we will introduce the clinicopathologic features, molecular typing, and traditional treatments. We will also review the biological characteristics and the latest therapies for PSC. These novel therapies show promise in the management of PSC, and the outcomes of investigative trials will hopefully reveal a variety of treatment options for patients with PSC.

Dendritic Cells in HIV/SIV Prophylactic and Therapeutic Vaccination.

Dendritic cells (DCs) are involved in human and simian immunodeficiency virus (HIV and SIV) pathogenesis but also play a critical role in orchestrating innate and adaptive vaccine-specific immune responses. Effective HIV/SIV vaccines require strong antigen-specific CD4 T cell responses, cytotoxic activity of CD8 T cells, and neutralizing/non-neutralizing antibody production at mucosal and systemic sites. To develop a protective HIV/SIV vaccine, vaccine regimens including DCs themselves, protein, DNA, mRNA, virus vectors, and various combinations have been evaluated in different animal and human models. Recent studies have shown that DCs enhanced prophylactic HIV/SIV vaccine efficacy by producing pro-inflammatory cytokines, improving T cell responses, and recruiting effector cells to target tissues. DCs are also targets for therapeutic HIV/SIV vaccines due to their ability to reverse latency, present antigen, and augment T and B cell immunity. Here, we review the complex interactions of DCs over the course of HIV/SIV prophylactic and therapeutic immunizations, providing new insights into development of advanced DC-targeted HIV/SIV vaccines.

Abstract TMIM-068: TARGETING ER STRESS RESPONSES TO UNLEASH THERAPEUTIC IMMUNITY AGAINST OVARIAN CANCER

Abstract Harnessing the intrinsic ability of our immune system to eliminate malignant cells represents the most promising new anti-cancer strategy since the development of chemotherapy. While cancer immunotherapy has been designated a scientific breakthrough, tumor-induced immunosuppression still represents a major impediment to the success of this new approach in the vast majority of cancer patients. We found that ovarian cancer inhibits the development of protective anti-tumor immunity by inducing a state of continued “Endoplasmic Reticulum (ER) Stress” in tumor-associated dendritic cells (tDCs). Sustained activation of the IRE1-XBP1 arm of the ER stress response in DCs was necessary for the aggressive and accelerated progression of primary and metastatic ovarian cancers in various preclinical models of disease. Mechanistically, hyperactive XBP1 disrupted crucial metabolic pathways in tDCs and caused severe immune cell dysfunction at tumor sites. Accordingly, DC-specific XBP1 deletion or selective nanoparticle-mediated XBP1 silencing in tDCs restored their immunostimulatory activity in situ and extended survival by evoking protective T cell-mediated anti-tumor immunity. Our findings uncover a new regulatory role for XBP1-driven signaling in DCs of the tumor microenvironment and suggest that targeting aberrant ER stress responses may represent a new strategy to unleash protective immune responses against ovarian cancer. Citation Format: Juan R, Cubillos-Ruiz. TARGETING ER STRESS RESPONSES TO UNLEASH THERAPEUTIC IMMUNITY AGAINST OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr TMIM-068.

Self-Assembled Nanofibers Elicit Potent HPV16 E7-Specific Cellular Immunity And Abolish Established TC-1 Graft Tumor.

BackgroundVaccines are one of the most promising strategies for immunotherapy of HPV associated tumors; however, they generally lack significant clinical efficacy at present. This inefficacy might be due to inefficient generation of anti-tumor cellular immune responses.PurposeThis study aimed to assess the potential of using self-assembled nanofibers as a new vaccine platform to elicit potent HPV antigen - specific anti-tumor immunity.MethodsA HPV16 E744-62 peptide was chemically appended to the N terminus of self-assembling peptide Q11. The nanofibers were prepared and used to immunize mice through a preventive or therapeutic strategy in a TC-1 graft tumor model.ResultsPreventive immunization with nanofibers almost completely suppressed the growth of primarily grafted TC-1 tumors and even a re-challenge of tumor cells after a six-week rest. Therapeutic immunization significantly increased the levels of effector Th1 cells, CTLs and the cytokines IFN-γ and TNF-α in E7 peptide-stimulated splenocytes, and the immunization reduced Th2, MDSC and IL-4 contents compared to the controls. The nanofiber immunization significantly suppressed the growth of established tumors and achieved 66.7% and 50% tumor-free in mice carrying 2–3 mm tumors and even larger tumors with a diameter of 5–6 mm respectively. In addition, the nanofibers were more efficient than the corresponding unassembled peptides for the treatment of established larger size tumors.ConclusionThe results indicated that self-assembling nanofibers could elicit robust HPV antigen -specific anti-tumor cellular immunity and are a potent antigen delivery system for HPV related tumor vaccines.

Therapy with multi-epitope virus-like particles of B19 parvovirus reduce tumor growth and lung metastasis in an aggressive breast cancer mouse model

Triple-negative breast cancer is a major health problem that lacks molecular targets for therapy. Neoepitopes represent a viable option to induce antitumor immune responses, but they have limitations, such as low immunogenicity and tolerance induction. Parvovirus B19 virus-like particles may be used to deliver neoepitopes to prime cellular immunity. We designed and evaluated the therapeutic effect of VP2 B19-virus-like particles, with multi-neoepitopes, in a 4T1 breast cancer model. Balb/c mice received four therapeutic immunizations with multi-neoepitopes-virus-like, wild type-virus-like, vehicle, or virus-like plus Cry1Ac adjuvant particles, intraperitoneally and peritumorally. Tumor growth, lung macro-metastasis, and specific immune responses were evaluated. Therapeutic administration of multi-epitopes virus-like particles significantly delayed tumor growth and decreased the lung macro-metastasis number, in comparison to treatment with wild type-virus-like particles, which surprisingly also elicited antitumoral effects that were improved with the adjuvant. Only treatments with multi-epitope virus-like particles induced specific proliferative responses of CD8 and CD4 T lymphocytes and Granzyme-B production in lymphatic nodes local to the tumor. Treatment with recombinant multiple neoepitopes-virus-like particles induced specific cellular responses, inhibited tumor growth and macro-metastasis, thus B19-virus-like particles may function as an effective delivery system for neoepitopes for personalized immunotherapy.