An Evidence-based Medical Research on the Comparative Quantification of TGF? and Telomerase Experimentations, with their Molecular Pharmacological Analyses as Targets of Oncoimmunotherapeutic Vaccines

The basic oncotherapeutic vaccines used are cell based vaccines including whole cell vaccines, genetically modified tumour cell vaccines and dendritic cell vaccines, anti-idiotype antibody based vaccines, protein or peptide based vaccines, heat shock proteinbased vaccines, viral, bacterial or yeast vectors based vaccines, mRNA or DNA nucleic acid based vaccines, vaccines based on tumour associated antigens like overexpressed proteins, differentiation antigens, cancer-testis antigens and oncofoetal antigens, and tumour specific antigens including oncogenic viral antigens, antigen presenting cells or molecular neoantigens based vaccines with specific CD8+ T cells and, CD4+ T cells, and nanoparticles vectors based vaccines. The objective of this evidence-based medical research was the comparative quantification of TGF? and telomerase experimentations, with their molecular pharmacological analyses as targets of oncoimmunotherapeutic vaccines. A molecular pharmacological multi-variate, qualitative, analytical study of the retrieved literature derived through a thorough literature review from various available literature databases, was performed, to record, review, thoroughly analyse and delineate the molecular pharmacological basis of oncoimmunotherapeutic vaccines from a wide-ranged study literature containing molecular pharmacological researches, reviews, case presentations and varied databases about the pharmacooncoimmunotherapeutic rationale of the clinical use of vaccines in the treatment of cancer patients, with a specific emphasis on telomerase and TGF?, as molecular pharmacological targets of oncoimmunotherapeutic vaccines. After that, a multivariate evidence-based medical research study of comparative quantification and analysis of the global heterogenous multidisciplinary experimentations and study literature on telomerase and TGF?, as molecular pharmacological targets of pharmaco-oncoimmuno-therapeutic vaccines, affecting global malignant and borderline malign

IMMU-32. IDENTIFICATION OF TUMOR-ANTIGEN SPECIFIC T CELLS AND THE EFFICACY OF IMMUNOTHERAPY VACCINES FOR GLIOBLASTOMA ANTIGENS DETERMINED USING CANCER IMMUNOGENOMICS APPROACH

BACKGROUND Glioblastoma multiforme (GBM) remains a disease with debilitating survival outcomes. Owing to the heterogeneous nature and low mutation burden, identifying multiple antigens inherent to GBM that may serve as targets for immune-based therapies is attractive. Our aim is to develop a personalized immunotherapy approach using cancer immunogenomics for prospectively identifying neoantigens and uniquely expressed tumor proteins and then selectively expanding T cells against these truly tumor-specific antigens and dendritic cell vaccines to boost the T cell responses. METHODS RNAseq and WES was performed for murine KR158-luc GBM tumor. Using a cancer immunogenomics approach that we developed, called the O pen R eading Frame A ntigen N etwork (O.R.A.N.), we identified the immunogenic neoantigens and tumor-associated antigens (TAAs) including cancer testis and developmental antigens, that are aberrantly over-expressed in KR158-luc tumor. All predicted genes were subjected to a gene enrichment strategy and an mRNA library was generated containing predominantly only the target genes but had some background non-specific genes (validated by RNAseq). KR158-luc tumor bearing animals were then treated with dendritic cells loaded with the tumor antigen specific mRNA library. Tumor volume and thus progress was determined using in vivo luciferase imaging technique. Additionally, tetramers specific to several of the predicted antigens were manufactured and the frequency of antigen specific T cells was determined using flow cytometry. RESULTS The dendritic cell vaccines were effective in delaying the progression of KR158-luc tumors and we identified T cells targeting several of our predicted antigens in the tumor bearing animals. The antigen specific T cells were detected in the tumor infiltrating lymphocytes as well as in the peripheral lymph organs. CONCLUSION We developed a dendritic cell-based vaccination approach targeting all neoantigens and TAAs identified as being tumor-specific and validated our developed immunogenomics pipeline by identifying antigen-specific T cells in the tumor bearing animals against novel GBM antigens.

332 Tumor collection and establishment of tumor-initiating cell cultures as antigen source for AV-GBM-1 dendritic cell vaccines for a phase II trial in patients with newly diagnosed glioblastoma

BackgroundDespite standard aggressive therapy (maximum safe surgical resection, concurrent radiation therapy and temozolomide chemotherapy (RT/TMZ), then maintenance TMZ), 2-year survival is only about 25% for patients with newly diagnosed primary glioblastoma (GBM). Adding AV-GBM-1, a vaccine consisting of autologous dendritic cells (DC) pulsed with autologous tumor antigens (ATA) may improve survival. One objective of a multi-center phase II clinical trial was to determine the feasibility of collecting fresh GBM and establishing short-term cell cultures of GBM tumor-initiating cells (TIC) to serve as ATA source.MethodsKey eligibility criteria for tumor collection were (1) clinical suspicion of new primary GBM, (2) age 18 to 70 years (3) tentative agreement to undergo a leukapheresis procedure after recovery from surgery, and (4) tentative plans for RT/TMZ. Fresh tumor was placed in media and shipped in a transport kit by overnight courier to AIVITA where a cell suspension was placed in culture and incubated in serum-free medium with factors that favor survival and proliferation of TICS (stem cells and early progenitor cells). The intent was to produce a patient-specific DC-ATA vaccine by incubating a lysate of irradiated TICs with autologous DC for subsequent subcutaneous injection.ResultsPatients were enrolled from five sites in California, one in Kentucky and one in New Jersey. Tumors were collected between August 2018 and January 2020. 106 patients consented for tumor collection, but 15 were not GBM, 4 had insufficient tissue to send, 2 patients withdrew consent, 4 were ineligible because of age, and 1 was ineligible because of autoimmune disease. Of the 80 GBM tumors that were placed into culture, 7 were discontinued because of patient withdrawal. 71/73 (97%) resulted in a successful cell culture; two were unsuccessful because of contamination. 60/71 subsequently consented for intent-to-treat ; 46/60 (77%) had cells in culture for 28 days or less, 11 were in culture for 30 to 35 days, and the remaining 3 were cultured 46, 54, and 55 days. The average number of cells per culture at the time of irradiation was 14.0 million (range 0.78 to 63.3 million). 58/60 (97%) yielded more than 1 million TICs for irradiation for the tumor cell lysate; 36/60 (60%) had more than 10 million cells irradiated. 57 patients were subsequently treated with AV-GBM-1 after recovery from RT/TMZ.ConclusionsSelf-renewing GBM TIC cultures can be reliably and rapidly established for use as the antigen source for personal DC-ATA vaccines.Trial RegistrationClinicaltrialsgov NCT03400917Ethics ApprovalThis study was approved by the Western IRB, approval number 20182582; all participants gave written informed consent before taking part

Modification of Breast Cancer Milieu with Chemotherapy Plus Dendritic Cell Vaccines: An Approach to Select Best Therapeutic Strategies

Purpose: The addition of dendritic cell vaccines (DCV) to neoadjuvant chemotherapy (NAC) could induce immune biomarker changes in those patients with residual disease (RD) by transforming tumor microenvironment. Methods: Core diagnostic biopsies and surgical specimens from 80 patients (38 in the Vaccinated Group plus NAC (VG) and 42 in the Control Group (CG) treated only with NAC) were selected. We quantify TILs (CD8, CD4 and CD45RO) using Immunohistochemistry (IHC) and the Automated Cellular Imaging System (ACIS III) in the core-diagnostic biopsies and in the surgical specimens, to compare the amount of TILs in each group. Results: A CD8 rise in TNBC samples was observed after NAC plus DCV, changing from 4.48% in the biopsy to 6.70% in the surgical specimen, not reaching statistically significant differences (p = 0.11). TNBC patients in the CG showed a TILs drop from 2.71% in the biopsy to 0.18% in the surgical specimen (p = 0.5). We also found that 66.7% (4/6) of TNBC patients from VG registered an increase in TILs after treatment as compared to 20% (1/5) of TNBC patients in the CG (p=0.24). This phenomenon is not observed in the other biologic subtypes. An association between before NAC CD8 TILs (4% cut-off point ) and pathological complete response in the VG was found in univariate and multivariate analysis (OR=1.41, IC95% 1.05-1.90; p=0.02, and OR=2.0, IC95% 1.05-3.9; p=0.03, respectively).Conclusion: Our findings suggest that patients with TNBC especially benefit from the stimulation of the antitumor immune system by using DCV pulsed with tumor antigens.

Modification of Breast Cancer Milieu with Chemotherapy Plus Dendritic Cell Vaccines: An Approach to Select Best Therapeutic Strategies

BackgroundThe addition of Dendritic cell vaccines (DCV) to neoadjuvant chemotherapy (NAC) could induce immune biomarker changes in those patients with residual disease (RD) by transforming tumor microenvironment.MethodsCore-diagnostic biopsies and surgical specimens from 80 patients (38 in the Vaccinated Group plus NAC (VG) and 42 in the Control Group (CG) treated only with NAC) were selected. We quantify TILs (CD8, CD4 and CD45RO) using Immunohistochemistry (IHC) and the Automated Cellular Imaging System (ACIS III) in the core-diagnostic biopsies and in the surgical specimen, to compare the amount of TILs in each group.ResultsA CD8 rise in TNBC samples was observed after NAC plus DCV, changing from 4.48% in the biopsy to 6.70% in the surgical specimen, not reaching statistically significant differences (p = 0.11). TNBC patients in the CG showed a TILs drop from 2.71% in the biopsy to 0.18% in the surgical specimen (p = 0.5). We also found that a 66.7% (4/6) of TNBC patients from VG registered an increase in TILs after treatment as compared with 20% (1/5) of TNBC patients in the CG (p=0.24). This phenomenon is not observed in the other biologic subtypes.An association between before NAC CD8 TILs (4% cut-off point ) and pathological complete response in VG was found in univariate and multivariate analysis (OR=1.41, IC95% 1.05-1.90; p=0.02, and OR=2.0, IC95% 1.05-3.9; p=0.03, respectively).ConclusionOur findings suggest that patients with TNBC especially benefit from the stimulation of the antitumor immune system by using DCV pulsed with tumor antigens.Trial registration: NCT01431196. Registred 19 May 2016. EudraCT 2009- 017402-36.

Exosome-Based Vaccines: History, Current State, and Clinical Trials

Extracellular vesicles (EVs) are released by most cell types as part of an intracellular communication system in crucial processes such as inflammation, cell proliferation, and immune response. However, EVs have also been implicated in the pathogenesis of several diseases, such as cancer and numerous infectious diseases. An important feature of EVs is their ability to deliver a wide range of molecules to nearby targets or over long distances, which allows the mediation of different biological functions. This delivery mechanism can be utilized for the development of therapeutic strategies, such as vaccination. Here, we have highlighted several studies from a historical perspective, with respect to current investigations on EV-based vaccines. For example, vaccines based on exosomes derived from dendritic cells proved to be simpler in terms of management and cost-effectiveness than dendritic cell vaccines. Recent evidence suggests that EVs derived from cancer cells can be leveraged for therapeutics to induce strong anti-tumor immune responses. Moreover, EV-based vaccines have shown exciting and promising results against different types of infectious diseases. We have also summarized the results obtained from completed clinical trials conducted on the usage of exosome-based vaccines in the treatment of cancer, and more recently, coronavirus disease.

Modification of Breast Cancer Milieu With Chemotherapy Plus Dendritic Cell Vaccines: An Approach To Select Best Therapeutic Strategies

BackgroundThe addition of Dendritic cell vaccines (DCV) to neoadjuvant chemotherapy (NAC) could induce immune biomarker changes in those patients with residual disease (RD) by transforming tumor microenvironment.MethodsCore-diagnostic biopsies and surgical specimens from 80 patients (38 in the Vaccinated Group plus NAC (VG) and 42 in the Control Group (CG) treated only with NAC) were selected. We quantify TILs (CD8, CD4 and CD45RO) using Immunohistochemistry (IHC) and the Automated Cellular Imaging System (ACIS III) in the core-diagnostic biopsies and in the surgical specimen, to compare the amount of TILs in each group.ResultsA CD8 rise in TNBC samples was observed after NAC plus DCV, changing from 4.48% in the biopsy to 6.70% in the surgical specimen, not reaching statistically significant differences (p = 0.11). TNBC patients in the CG showed a TILs drop from 2.71% in the biopsy to 0.18% in the surgical specimen (p = 0.5). We also found that a 66.7% (4/6) of TNBC patients from VG registered an increase in TILs after treatment as compared with 20% (1/5) of TNBC patients in the CG (p=0.24). This phenomenon is not observed in the other biologic subtypes.An association between before NAC CD8 TILs (4% cut-off point ) and pathological complete response in VG was found in univariate and multivariate analysis (OR=1.41, IC95% 1.05-1.90; p=0.02, and OR=2.0, IC95% 1.05-3.9; p=0.03, respectively).ConclusionOur findings suggest that patients with TNBC especially benefit from the stimulation of the antitumor immune system by using DCV pulsed with tumor antigens.Trial registration: NCT01431196. Registred 19 May 2016. EudraCT 2009- 017402-36.

Vaccines Against Different Types of Cancer: Literature Review

According to the World Health Organization, in 2018, cancer was considered the second leading cause of death in the world, corresponding to 9.6 million deaths. Faced with this situation, some alternatives to combat tumors in some organs were developed, such as immunotherapy involving vaccines. Among the vaccines already developed, Sipuleucel-T (Provenge®) can be mentioned, that has been approved by the Food and Drug Administration in 2010 for cases of metastatic prostate cancer; prophylactic bivalent and quadrivalent vaccines to human papillomavirus; the nanoparticulate liposomal RNA vaccine, the melanoma FixVac (BNT111); peptide-based vaccines, such as carcinoembryonic antigen, and those that involve antigen-loaded dendritic cells for the treatment of colorectal cancer, as well as colorectal cancer stem cell-based vaccines and, for cases of ovarian cancer, dendritic cell vaccines. In relation to breast cancer, research is aimed at both immunotherapy with dendritic cells pulsed with tumor antigens and vaccines that have a combined therapy of dendritic cells and Natural Killer cells. In general, vaccines promote the induction of helper and cytotoxic cells to thereby eliminate tumor cells. This characteristic of using dendritic cells with tumor antigens already processed and presented on the cell surface allows the questioning about the use of the term “vaccine”, since it does not correspond to conventional vaccines. Thus, the studies carried out in this area of immunotherapy, although complex and expensive, show promise in the treatment of several types of cancer, with great possibilities of positively impacting the lives of all those who suffer from the disease.