Autologous Tumor Vaccine Research Articles

IMMU-61. THE LAST OF US: A FUNGI BASED DENDRITIC CELL VACCINE

Abstract BACKGROUND Glioblastoma (GBM) is the most prevalent primary malignant brain tumor in adults. The current standard treatment for newly diagnosed GBM involves maximal surgical resection followed by radiotherapy and temozolomide. Despite these interventions, the median overall survival for GBM patients remains approximately 15 months, highlighting the critical need for innovative therapeutic approaches. OBJECTIVE Our laboratory has previously developed a subcutaneous autologous tumor vaccine incorporating irradiated (IR) tumor cells with phagocytosis-stimulating ligands (Mannan-BAM), toll-like receptor (TLR) agonists, and an immunostimulant anti-CD40 antibody (collectively termed MBT). This combination has shown efficacy in mouse models of colon carcinoma, breast cancer, melanoma, and, more recently, gliomas. Our study aimed to create a dendritic cell (DC) vaccine using this strategy. METHODS To evaluate whether MBT could induce the maturation of DCs in vitro, we harvested BMDCs from mice and co-cultured them in the presence of MBT-tagged irradiated tumor cells. We then analyzed the maturation markers using flow cytometry and assessed cytokine production via ELISA. To test the efficacy of this approach in vivo, we utilized two different murine glioma models (SB28 and GL261). RESULTS Using flow cytometry, we observed a significant upregulation of important co-stimulatory molecules. Additionally, ELISA analysis demonstrated that MBT-treated DCs significantly increased the secretion of Type 1 cytokines while limiting the secretion of the regulatory cytokine IL-10. MBT-primed DCs combined with immune checkpoint inhibitor PD-1 increased mouse survival in a glioma model compared to WT mice. However, mice eventually succumbed to cerebral edema. Histology demonstrated significant treatment effects. CONCLUSION Our results demonstrate that MBT effectively matures DCs ex-vivo. Further research is required to immunophenotype the response to vaccination in glioma models and explore ways to overcome resistance.

Bis-2′-F-cGSASMP isomers encapsulated in cytidinyl/cationic lipids act as potent in situ autologous tumor vaccines

Cancer immunotherapy has greatly improved the prognosis of tumor-bearing patients. Nevertheless, cancer patients exhibit low response rates to current immunotherapy drugs, such as PD1 and PDL1 antibodies. Cyclic dinucleotide analogs are a promising class of immunotherapeutic agents. In this study, in situ autologous tumor vaccines, composed of Bis-2′-F-cGSASMP phosphonothioate isomers (FGA-di-pS-2 or FGA-di-pS-4) and cytidinyl/cationic lipids (Mix), were constructed. Intravenous (i.v.) and intratumoral (i.t.) injection of FGA-di-pS-2/Mix or FGA-di-pS-4/Mix enhanced the immunogenic cell death of tumor cells in vivo, leading to the exposure and presentation of whole tumor antigens, inhibiting tumor growth in both LLC and EO771 tumor in situ murine models and increasing their survival rates to 50% and 23%, respectively. Furthermore, the tumor-bearing mice after treatment showed potent immune memory efficacy and exhibited 100% protection against tumor rchallenge. i.v. administration of FGA-di-pS-2/Mix potently promoted DC maturation, M1 macrophage polarization and CD8+ T-cell activation and decreased the proportion of Treg cells in the tumor microenvironment. Notably, two doses of ICD-debris (generated by FGA-di-pS-2 or 4/Mix-treated LLC cells) protected 100% of mice from tumor growth. These tumor vaccines showed promising results and may serve as personalized cancer vaccinations in the future.

Hybrid Ginseng-derived Extracellular Vesicles-Like Particles with Autologous Tumor Cell Membrane for Personalized Vaccination to Inhibit Tumor Recurrence and Metastasis.

Personalized cancer vaccines based on resected tumors from patients is promising to address tumor heterogeneity to inhibit tumor recurrence or metastasis. However, it remains challenge to elicit immune activation due to the weak immunogenicity of autologous tumor antigens. Here, a hybrid membrane cancer vaccine is successfully constructed by membrane fusion to enhance adaptive immune response and amplify personalized immunotherapy, which formed a codelivery system for autologous tumor antigens and immune adjuvants. Briefly, the functional hybrid vesicles (HM-NPs) are formed by hybridizing ginseng-derived extracellular vesicles-like particles (G-EVLPs) with the membrane originated from the resected autologous tumors. The introduction of G-EVLPs can enhance the phagocytosis of autologous tumor antigens by dendritic cells (DCs) and facilitate DCs maturation through TLR4, ultimately activating tumor-specific cytotoxic T lymphocytes (CTLs). HM-NPs can indeed strengthen specific immune responses to suppress tumors recurrence and metastasis including subcutaneous tumors and orthotopic tumors. Furthermore, a long-term immune protection can be obtained after vaccinating with HM-NPs, and prolonging the survival of animals. Overall, this personalized hybrid autologous tumor vaccine based on G-EVLPs provides the possibility of mitigating tumor recurrence and metastasis after surgery while maintaining good biocompatibility.

P06.20.B LONG-TERM CLINICAL RESULTS OF 493 CASES OF NEWLY DIAGNOSED GLIOBLASTOMA AND SURVIVAL BENEFIT BY COMBINATION WITH PDT AND AFTV, AIMING TO ESTABLISH NEW STANDARD TREATMENT

Abstract BACKGROUND Glioblastoma has the worst prognosis of brain tumors. Evidence for improving prognosis by maximal tumor removal is being established, and in recent years, new treatments such as photodynamic therapy (PDT, 2014 in Japan), and TTF therapy (2018) have been approved, the treatment results are improving. In principle, our facility performs maximum tumor removal using intraoperative MRI (iMRI) follow by the standard chemoradiation. Intraoperative PDT and autologous tumor vaccine (AFTV) will be given to desired patients. We retrospectively analyzed the long-term clinical results of the patients with newly diagnosed glioblastoma who underwent surgical treatment at our facility, and the treatment results by era and treatment method. MATERIAL AND METHODS The clinical features, extent of removal (EOR), OS and PFS of the adult patients with newly diagnosed glioblastoma treated from 2001 to 2021 were analyzed retrospectively. Clinical results of those patients who received PDT and AFTV treatment was also investigated. RESULTS The number of cases was 493, median age 58 years (18-85 years), 293 males, 200 females. The median and average EOR of contrast-enhanced lesions were 98% and 96.6%, respectively. The median PFS and OS of all cases (including biopsy) were 9.4 months and 22.7 months, respectively. When the cases were analyzed separately for 2001-2006 (before TMZ), 2007-2010, 2011-2015, and 2016-2021, the median OS for each age group was 12.9 months, 22.9 months, 23 months, and 31.1 months. The treatment results improved with age (p <0.0001). In particular, the median OS of 23 cases treated with PDT and AFTV was 63.1 months. The efficacy of AFTV for newly diagnosed glioblastoma is currently being verified in a multicenter Physician-led clinical trial. CONCLUSION The treatment results for glioblastoma have improved over the years. The combination of maximal tumor removal using iMRI, PDT and AFTV may aim for a 5-year survival rate of 50%.

Converting bacteria into autologous tumor vaccine via surface biomineralization of calcium carbonate for enhanced immunotherapy

Autologous cancer vaccine that stimulates tumor-specific immune responses for personalized immunotherapy holds great potential for tumor therapy. However, its efficacy is still suboptimal due to the immunosuppressive tumor microenvironment (ITM). Here, we report a new type of bacteria-based autologous cancer vaccine by employing calcium carbonate (CaCO3) biomineralized Salmonella (Sal) as an in-situ cancer vaccine producer and systematical ITM regulator. CaCO3 can be facilely coated on the Sal surface with calcium ionophore A23187 co-loading, and such biomineralization did not affect the bioactivities of the bacteria. Upon intratumoral accumulation, the CaCO3 shell was decomposed at an acidic microenvironment to attenuate tumor acidity, accompanied by the release of Sal and Ca2+/A23187. Specifically, Sal served as a cancer vaccine producer by inducing cancer cells' immunogenic cell death (ICD) and promoting the gap junction formation between tumor cells and dendritic cells (DCs) to promote antigen presentation. Ca2+, on the other hand, was internalized into various types of immune cells with the aid of A23187 and synergized with Sal to systematically regulate the immune system, including DCs maturation, macrophages polarization, and T cells activation. As a result, such bio-vaccine achieved remarkable efficacy against both primary and metastatic tumors by eliciting potent anti-tumor immunity with full biocompatibility. This work demonstrated the potential of bioengineered bacteria as bio-active vaccines for enhanced tumor immunotherapy.

Chitosan-based nano-micelles for potential anti-tumor immunotherapy: Synergistic effect of cGAS-STING signaling pathway activation and tumor antigen absorption

Cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) signaling pathway is an essential DNA-sensing pathway to regulate the innate and adaptive immune response, which plays an important role in tumor immunotherapy. Although the STING agonists can be used, they are limited by their inability to target immune cells and systemic immunotoxicity, calling for novel strategies to accurately and effectively activate the cGAS-STING signaling pathway. Herein, mannose-modified stearic acid-grafted chitosan (M-CS-SA) micelles with the ability to activate the cGAS-STING signaling pathway and absorb tumor antigens were constructed. The chitosan-based nano-micelles showed valid dendritic cell (DCs) targeting and could escape from lysosomes leading to the activation of the cGAS-STING signaling pathway and the maturation of DCs. In addition, a combinatorial therapy was presented based on the programmed administration of oxaliplatin and M-CS-SA. M-CS-SA adsorbed tumor antigens released by chemotherapy to construct an autologous tumor vaccine and built a comprehensive antitumor immune response. In vivo, the combinatorial therapy achieved a tumor inhibition rate of 76.31 % at the oxaliplatin dose of 5 mg/kg and M-CS-SA dose of 15 mg/kg, and increased the CD3+ CD8+ T cell infiltration. This work demonstrated that M-CS-SA and its co-treatment with oxaliplatin showed great potential in tumor immunotherapy.

A multicenter, randomized, placebo-controlled phase IIb trial of an autologous formalin-fixed tumor vaccine for newly diagnosed glioblastomas.

An autologous formalin-fixed tumor vaccine (AFTV) derived from resected glioblastoma (GBM) tissue can be used against unidentified tumor antigens. Thus, the authors conducted a multicenter double-blind phase IIb trial to investigate the efficacy of an AFTV. Eligible patients were adults with supratentorial GBMs, 16-75 years of age, with Karnofsky Performance Scale (KPS) scores ≥ 60%, and no long-term steroid administration. An AFTV comprising fixed paraffin-embedded tumor tissue with immune adjuvants or an identical placebo without fixed tumor tissue was injected intradermally over three courses before and after chemoradiotherapy. The primary and secondary end points were overall survival (OS), progression-free survival (PFS), and 3-year survival rate. Sixty-three patients were enrolled. The average patient age was 61 years. The median KPS score was 80%, and the median resection rate was 95%. The full analysis set of 57 patients indicated no significant difference in OS (p = 0.64) for the AFTV group (median OS 25.6 months, 3-year OS rate 38%) compared with the placebo group (31.5 months and 41%, respectively) and no difference in PFS (median PFS 13.3 months in both groups, p = 0.98). For patients with imaging-based total tumor removal, the 3-year PFS rate was 81% in the AFTV group versus 46% in the placebo group (p = 0.067), whereas the 3-year OS rate was 80% versus 54% (p = 0.16), respectively. Similar results were obtained in the p53-negative subgroups. Severe adverse effects were not observed. The AFTV may have potential effects in certain patient subgroups. A phase III study for patients with total tumor removal remains warranted to confirm these findings. Clinical trial registration no.: UMIN000010602 (UMIN Clinical Trials Registry).

P53-negative status and gross total resection as predictive factors for autologous tumor vaccine treatment in newly diagnosed glioblastoma patients.

Among primary brain tumors, glioblastoma (GBM) is the most common and aggressive in adults, with limited treatment options. Our previous study showed that autologous formalin-fixed tumor vaccine (AFTV) contributed to prognostic improvements in newly diagnosed GBM patients. However, some patients died early despite the treatment. The discovery of predictive factors in the treatment was warranted for efficient patient recruitment and studies to overcome resistance mechanisms. Identifying prognostic factors will establish AFTV guidelines for patients who may respond to the therapy. Data from 58 patients with newly diagnosed GBM, including 29 who received standard therapy plus AFTV (AFTV group) and 29 who received standard treatment (control group) were analyzed. Several data including patient age, sex, the extent of removal, and various cell immunohistochemistry (IHC) parameters were also included in the analysis. Both univariate and multivariate analyses revealed that gross total resection (GTR) and negative p53 were associated with a better prognosis only in the AFTV group. In the IHC parameters, CD8 staining status was also one of the predictive factors in the univariate analysis. For blood cell-related data, lymphocyte counts of 1100 or more and monocyte counts of 280 or more before chemo-radiotherapy were significant factors for good prognosis in the univariate analysis. A p53-negative status in IHC and GTR were the predictive factors for AFTV treatment in newly diagnosed GBM patients. Microenvironment-targeted treatment and pretreatment blood cell status may be key factors to enhance therapy effects.

ACT-24 LONG TERM CLINICAL RESULTS OF NEWLY DIAGNOSED GLIOBLASTOMA BY AGE AND TREATMENT STRATEGY

Abstract Introduction Glioblastoma has the poorest prognosis among brain tumors, and most cases recur. On the other hand, evidence of prognosis improvement by maximal surgical removal of the tumor is being established, and in recent years, new treatments such as temozolomide (2006), photodynamic therapy (2014), and TTF therapy (2018) were approved by insurance. and patient outcome has improved. In addition, molecular targeted therapy (bevacizumab approved in 2011) and immunotherapy are also used in clinical practice. In this study, we retrospectively analyzed the long-term treatment results of newly diagnosed glioblastoma cases treated at our facility, the correlation with the resection rate, and the treatment results by age and treatment method. Methods We retrospectively analyzed the clinical characteristics, resection rate, and treatment outcomes of adult patients with primary supratentorial glioblastoma who underwent surgery and treatment at our institution during the 20-year period from 2001 to 2021. Results 493 cases, median age 58 years (18-85 years), 293 males and 200 females. The median and mean contrast-enhanced lesion resection rates in resection cases were 98% and 96.6%, respectively. Median PFS and OS for all patients (including biopsies) were 9.4 months and 22.7 months, respectively. The median OS for each age was 12.9 months, 22.9 months, 23 months, and 31.1 months when analyzed separately for 2001-2006, 2007-2010, 2011-2015, and 2016-2021 before TMZ. (p<0.0001), and treatment results improved with age. In particular, the median OS of 23 patients who combined PDT and autologous tumor vaccine (AFTV) was 63.1 months. Conclusion Treatment results for glioblastoma improve with age, and the time has come when we can aim for a 5-year survival rate of 50% by combining a high resection rate with multidisciplinary therapy including intraoperative MRI, PDT, AFTV and TTF.

CTNI-41. TRANSITION OF LONG-TERM TREATMENT RESULTS OF 493 CASES OF NEWLY DIAGNOSED GLIOBLASTOMA AND SURVIVAL BENEFIT BY COMBINATION WITH PDT AND AFTV - AIMING TO ESTABLISH NEW STANDARD TREATMENT

Abstract INTRODUCTION Glioblastoma has the worst prognosis of brain tumors. Evidence for improving prognosis by maximal tumor removal is being established, and in recent years, new treatments such as photodynamic therapy (PDT, 2014 in Japan), and TTF therapy (2018) have been approved, the treatment results are improving. In principle, our facility performs maximum tumor removal using intraoperative MRI (iMRI) follow by the standard chemoradiation. Intraoperative PDT and autologous tumor vaccine (AFTV) will be given to desired patients. We retrospectively analyzed the long-term clinical results of the patients with newly diagnosed glioblastoma who underwent surgical treatment at our facility, and the treatment results by era and treatment method. METHODS The clinical features, extent of removal (EOR), OS and PFS of the adult patients with newly diagnosed glioblastoma treated from 2001 to 2021 were analyzed retrospectively. Clinical results of those patients who received PDT and AFTV treatment was also investigated. RESULTS The number of cases was 493, median age 58 years (18-85 years), 293 males, 200 females. The median and average EOR of contrast-enhanced lesions were 98% and 96.6%, respectively. The median PFS and OS of all cases (including biopsy) were 9.4 months and 22.7 months, respectively. When the cases were analyzed separately for 2001-2006 (before TMZ), 2007-2010, 2011-2015, and 2016-2021, the median OS for each age group was 12.9 months, 22.9 months, 23 months, and 31.1 months. The treatment results improved with age ( p < 0.0001). In particular, the median OS of 23 cases treated with PDT and AFTV was 63.1 months. The efficacy of AFTV for newly diagnosed glioblastoma is currently being verified in a multicenter Investigator-led clinical trial. CONCLUSION The treatment results for glioblastoma have improved over the years. The combination of maximal tumor removal using iMRI, PDT and AFTV may aim for a 5-year survival rate of 50%.

Tumor Microenvironment-Activated Hydrogel Platform with Programmed Release Property Evokes a Cascade-Amplified Immune Response against Tumor Growth, Metastasis and Recurrence.

In situ tumor vaccines (ITV) have been recognized as a promising antitumor strategy since they contain the entire tumor-specific antigens, avoiding tumor cells from evading immune surveillance due to antigen loss. However, the therapeutic benefits of ITV are limited by obstacles such as insufficient antigen loading, inadequate immune system activation, and immunosuppressive tumor microenvironments (TME). Herein, a tumor microenvironment-activated hydrogel platform (TED-Gel) with programmed drug release property is constructed for cascaded amplification of the anti-tumor immune response elicited by ITV. Both doxorubicin (Dox) and cytosine-phosphate-guanosine oligodeoxynucleotides (CpG) are released first, in which Dox induces immunogenic tumor cell death causing additional tumor antigen release and leading the dying primary tumor cells into autologous tumor vaccine, and the released CpG promotes antigen presenting cell activation. Subsequently, the decomposed scaffold materials in conjunction with CpG, turn the anti-inflammatory M2-like macrophages into the M1 type, reversing the immunosuppressive TME. With decomposition of the TED-Gel, large amounts of macromolecule anti-PD-L1 antibodies are liberated, reinvigorating the exhausted effector T cells. In vivo studies demonstrate that TED-Gel significantly inhibits the primary, distant and rechallenged tumor growth. Overall, the simple and powerful TED-Gel provides an alternative strategy for the future development of tumor vaccines with broad application.

Bifunctional Fusion Membrane‐Based Hydrogel Enhances Antitumor Potency of Autologous Cancer Vaccines by Activating Dendritic Cells

AbstractAutologous tumor cell vaccine is an individualized tumor treatment strategy to elicit tumor‐specific immune responses. However, it is difficult to exert efficacy in “cold” tumors, which lack tumor‐infiltrating T cells and are not sensitive to immunotherapy. Here, a dendritic cells (DCs) activation hydrogel is constructed based on bifunctional fusion membrane nanoparticles (FM‐NPs) composed of autologous tumor cell membranes and Mycobacterium phlei membrane extracts. The FM‐NPs not only provide tumor antigens but also can activate DCs. Afterward, the FM‐NPs are loaded in an injectable alginate hydrogel together with granulocyte‐macrophage colony‐stimulating factor (GM‐CSF). GM‐CSF releases rapidly and recruits DCs to hydrogel, while FM‐NPs retain in hydrogel to continuously interconnected with DCs, enriching mature DCs loaded with tumor antigens. In the 4T1 mouse breast tumor model, this hydrogel promotes the maturation of DCs in tumor‐draining lymph nodes and induces sufficient effector memory T cells that migrate to the tumor microenvironment. This successfully converts the “cold” tumors to “hot”, thus exerting a significant antitumor effect synergized with the PD‐1 antibody. It is also verified the inhibitory effect of FM‐NPs using human gastric cancer organoids. Altogether, these findings demonstrate the application potential for the bifunctional fusion membrane‐based hydrogel as an autologous tumor vaccine by activating DCs.

Supramolecular cancer photoimmunotherapy based on precise peptide self-assembly design.

Combinational photoimmunotherapy (PIT) is considered to be an ideal strategy for the treatment of highly recurrent and metastatic cancer, because it can ablate the primary tumor and provide in situ an autologous tumor vaccine to induce the host immune response, ultimately achieving the goal of controlling tumor growth and distal metastasis. Significant efforts have been devoted to enhancing the immune response caused by phototherapy-eliminated tumors. Recently, supramolecular PIT nanoagents based on precise peptide self-assembly design have been employed to improve the efficacy of photoimmunotherapy by utilizing the stability, targeting capability and flexibility of drugs, increasing tumor immunogenicity and realizing the synergistic amplification of immune effects through multiple pathways and collaborative strategy. This review summarizes peptide-based supramolecular PIT nanoagents for phototherapy-synergized cancer immunotherapy and its progress in enhancing the effect of photoimmunotherapy, especially focusing on the design of peptide-based PIT nanoagents, the progress of bioactive peptides combined photoimmunotherapy, and the synergistic immune-response mechanism.

Blockading a new NSCLC immunosuppressive target by pluripotent autologous tumor vaccines magnifies sequential immunotherapy

The presence of multiple immunosuppressive targets and insufficient activation and infiltration of cytotoxic T lymphocytes (CTLs) allow tumor cells to escape immune surveillance and disable anti-PD-1/PD-L1 immunotherapy. Nanobiotechnology-engineered autologous tumor vaccines (ATVs) that were camouflaged by tumor cell membrane (TCM) were designed to activate and facilitate CTLs infiltration for killing the unprotected lung tumor cells, consequently realizing the sequential immunotherapy. PDE5 was firstly screened out as a new immunosuppressive target of lung cancer in clinical practice. Immediately afterwards, phosphodiesterase-5 (PDE5) and programmed cell death 1 ligand 1 (PD-L1) dual-target co-inhibition was proposed to unfreeze the immunosuppressive microenvironment of NSCLC. Systematic studies validated that this ATVs-unlocked sequential immunotherapy after co-encapsulating PDE5 inhibitor and NO donor (i.e., l-arginine) exerted robust anti-tumor effects through increasing inducible nitric oxide synthase (iNOS) expression, blockading PDE5 pathway and activating systematic immune responses, which synergistically eradicated local and abscopal lung cancers in either orthotopic or subcutaneous models. The pluripotent ATVs that enable PDE5 inhibition and sequential immunotherapy provide a new avenue to mitigate immunosuppressive microenvironment and magnify anti-PD-1/PD-L1 immunotherapy.

Maximum resection and immunotherapy improve glioblastoma patient survival: a retrospective single-institution prognostic analysis

Glioblastoma (GBM) is a refractory disease with a poor prognosis and various methods, including maximum resection and immunotherapy, have been tested to improve outcomes. In this retrospective study we analyzed the prognostic factors of 277 newly diagnosed GBM patients over 11 years of consecutive cases at our institution to evaluate the effect of these methods on prognosis. Various data, including the extent of removal (EOR) and type of adjuvant therapy, were examined and prognostic relationships were analyzed. The median overall survival (OS) of the entire 277-case cohort, 200 non-biopsy cases, and 77 biopsy cases was 16.6 months, 19.7 months, and 9.7 months, respectively. Gross total removal (GTR; 100% of EOR) was achieved in 32.9% of the cases. Univariate analysis revealed younger age, right side, higher Karnofsky performance status, GTR, intraoperative magnetic resonance imaging (MRI) use for removal, proton therapy, combination immunotherapy, and discharge to home as good prognostic factors. Intraoperative MRI use and EOR were closely related. In the multivariate analysis, GTR, proton therapy, and a combination of immunotherapies, including autologous formalin-fixed tumor vaccine, were the significant prognostic factors. A multivariate analysis of 91 GTR cases showed that immunotherapy contributed to prognostic improvements. The median OS and 5-year OS % values were 36.9 months and 43.3% in GTR cases receiving immunotherapy. In conclusion, GTR, proton therapy, and immunotherapy were good prognostic factors in single-center GBM cases. Tumor vaccine therapy for GTR cases achieved a notably high median survival time and long-term survival ratio, indicating its usefulness in GTR cases.

ROS Cocktails as an Adjuvant for Personalized Antitumor Vaccination?

Cancer is the second leading cause of death worldwide. Today, the critical role of the immune system in tumor control is undisputed. Checkpoint antibody immunotherapy augments existing antitumor T cell activity with durable clinical responses in many tumor entities. Despite the presence of tumor-associated antigens and neoantigens, many patients have an insufficient repertoires of antitumor T cells. Autologous tumor vaccinations aim at alleviating this defect, but clinical success is modest. Loading tumor material into autologous dendritic cells followed by their laboratory expansion and therapeutic vaccination is promising, both conceptually and clinically. However, this process is laborious, time-consuming, costly, and hence less likely to solve the global cancer crisis. Therefore, it is proposed to re-focus on personalized anticancer vaccinations to enhance the immunogenicity of autologous therapeutic tumor vaccines. Recent work re-established the idea of using the alarming agents of the immune system, oxidative modifications, as an intrinsic adjuvant to broaden the antitumor T cell receptor repertoire in cancer patients. The key novelty is the use of gas plasma, a multi-reactive oxygen and nitrogen species-generating technology, for diversifying oxidative protein modifications in a, so far, unparalleled manner. This significant innovation has been successfully used in proof-of-concept studies and awaits broader recognition and implementation to explore its chances and limitations of providing affordable personalized anticancer vaccines in the future. Such multidisciplinary advance is timely, as the current COVID-19 crisis is inexorably reflecting the utmost importance of innovative and effective vaccinations in modern times.

GM-CSF: Anti-Cancer Immune Response and Therapeutic Application

A primary focus of cancer therapeutics today is precision, or target directed, therapy. Combination treatment with precision therapy can involve both immune and signal pathway targets. One approach involving the chemokine GMCSF involves enhancement of the immune system. Herein is a review of the literature and the current therapeutic role of GM-CSF, including the proposed immune mechanisms and potential applications of GM-CSF to enhance anticancer immunotherapy. GM-CSF’s potent effects on dendritic cell activation and subsequent stimulation of T-lymphocyte activity make it an attractive potential addition to combination therapeutic regimens, including radiation therapy, oncolytic viral therapy, immune checkpoint inhibition, and autologous tumor vaccines, and warrants further clinical exploration, with an emphasis on identifying concomitant molecular pathways that mediate resistance and sensitivity to the GM-CSF effect.

1716P Vigil plasmid (VP), a dual bi-shRNA-furin/GMCSF construct from cancer to SARS-CoV-2

SARS-CoV-2 genome reveals a unique furin cleavage site change at S1/S2 junction and furin-like S2’ cleavage site which promotes membrane fusogenic pathway entry and exit to human host cells. Clinical testing of VP, used in an autologous tumor vaccine (Vigil), demonstrates >90% knockdown of TGFβ, a downstream furin protease product, elevation of GMCSF and safety and benefit in solid tumor cancer patients.

IMT-05 PHASE III RANDOMIZED CLINICAL TRIAL OF AFTV FOR NEWLY DIAGNOSED GLIOBLASTOMA

BACKGROUNDThe highly fatal glioblastoma has an extremely poor prognosis and development of a new treatment is desired. Local treatment is limited due to its high invasiveness, and immunotherapy utilizing self-immune mechanism is theoretically expected. An autologous formalin-fixed tumor vaccine (AFTV) is a vaccine that is prepared using formalin-fixed tumor tissue and recognizes tumor antigen peptides to induce cytotoxic T cells. We have previously conducted three clinical trials using AFTV for patients with newly diagnosed glioblastoma since 2004. The third trial was a double-blind multicenter phase IIb/III trial with 63 case registries, which did not make a significant difference in OS (study group 25 months, placebo group 31 months), the total removal group showed excellent clinical results (3-year survival rate; 65%, median survival; not reached). Since the study was designed to go to Phase III if the test group was not inferior to the placebo group, so it went on to go to Phase III.METHODSTarget patients will be 80 patients with newly diagnosed glioblastoma undergoing pathologic diagnosis, who have undergone total removal of contrast-enhanced lesions and receive standard chemoradiation therapy.STUDY DESIGNDouble-blind, 3-year enrollment period, 18-month observation period. Stratification factor: Photodynamic therapy (PDT), facility, age, KPS. Administration method: After standard chemoradiotherapy, in parallel with maintenance chemotherapy, a total of 9 times intradermal administration of vaccine. Primary endpoint: PFS of FAS patients, Secondary endpoints: 18 months PFS of the FAS patient, OS, PFS of the ITT analysis target case. Based on the results of the IIb trial, we limited the registered patients with total tumor removal, and in view of the fact that the prognosis of patients with combined PDT and AFTV were excellent, PDT was added to the stratification factor. We outline our efforts and problems aimed at clinical approval of AFTV for glioblastoma.

IM-01 PI3K GAMMA INHIBITOR FOR OVERCOMING TREATMENT RESISTANCE IN COMBINATION THERAPY OF TEMOZOLOMIDE AND ANTI-PDL1 ANTIBODY FOR GLIOBLASTOMA PATIENTS

PURPOSEMultidisciplinary therapies including immunotherapy in glioblastoma (GBM) patients often cause long survivor, while early relapse of GBM still remains. We should find factors associated with the immunotherapy-resistance for overcoming it. We previously reported that the infiltration of PD-1 positive cells and M2 macrophages (M2M&phi) increased in recurrent specimens compared to the initial specimens of GBMs treated with chemo-radiotherapy and autologous formalin-fixed tumor vaccine. Here we evaluate whether combination of novel immunotherapies, anti-PD-L1 antibody and M2M&phi inhibitor (IPI-549) inhibits growth of temozolomide (TMZ)-treated glioma cells rather than monotherapy. METHODSUsing murine glioma initiating cells (TS) and TMZ-resistant TS (TMZRTS) cells, PD-L1 expression and cytokine production associated with M2M&phi were evaluated. TMZRTS cells were implanted in mice flank, followed by anti-PD-L1 antibody and / or IPI-549 administration.RESULTSRelative cell proliferation rate of TMZRTS cells was lower than TS cells, while PD-L1 mRNA expression was higher. Treatment with PD-L1 antibody caused marked infiltration of M2M&phi in glioma tissue. The combination therapy strongly inhibited tumor growth in TMZRTS murine model.CONCLUSIONThe anti-PD-L1 antibody treatment altered tissue microenvironment including marked infiltration of macrophages in glioma tissue, probably associated with clinical immunotherapy-resistance in GBM. Combination therapy with anti-PD-L1 antibody and M2M&phi inhibitor could overcame it.