ATIM-09. CLINICAL TRIAL IN PROGRESS: A STUDY OF NEOADJUVANT AND ADJUVANT VB-111 FOR TREATMENT OF RECURRENT GBM

Abstract BACKGOUND Ofranergene obadenovec (VB-111) is a targeted anti-cancer viral based gene therapy with a dual mechanism: a broad antiangiogenic effect and induction of a tumor directed immune response. Previous study demonstrated a survival benefit for patients with recurrent glioblastoma (rGBM) treated with VB-111 monotherapy that was continued upon progression with combination treatment of VB-111 and bevacizumab. Glioblastoma is an immunologically “cold” microenvironment which fosters immunosuppression and antagonizes anti-tumor immune responses. The role of T-cell infiltration in combating cancer has been increasingly recognized and associated with improved participant outcomes. Based on these observations, this study will assess the hypothesis that neoadjuvant use of VB-111 will lead to a statistically significant increase in tumor infiltrating T lymphocyte (TIL) density within the tumor and enhanced systemic tumor-specific T cell responses. METHODS This is a multicenter, randomized, blinded, placebo-controlled, phase 2 surgical trial to evaluate early immunologic pharmacodynamic parameters for the viral cancer therapy VB-111 in rGBM. 45 participants with rGBM indicated for resection will randomized to one of three treatment arms: Neoadjuvant Arm: intravenous VB-111 prior to resection, and VB-111 every 6 weeks after resection. Adjuvant Arm: placebo prior to resection, and VB-111 every 6 weeks afterwards. The control arm will receive placebo prior to resection followed by standard of care. Upon evidence of contrast-enhancing progression, bevacizumab may be initiated as needed for supportive care and VB-111 will continue until progression is supported at two consecutive time points. Tumor samples will be obtained and archived at the time of surgery, and blood samples will be obtained as pharmacodynamic markers throughout the study to allow DNA sequencing of T cells. The primary endpoint is influence of neoadjuvant VB-111 on TIL density. Other endpoints include safety and tolerability, peripheral T cell response, tumor/microenvironment transcriptomic alteration, and PFS/OS. Study will open for enrolment in 2019.

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Targeting C5aR1 Increases the Therapeutic Window of Radiotherapy

10.1101/2020.10.27.358036 ◽

2020 ◽

Author(s):

Monica M. Olcina ◽

Melemenidis Stavros ◽

Dhanya K. Nambiar ◽

Ryan K. Kim ◽

Kerriann M. Casey ◽

...

Keyword(s):

T Cell ◽

Tumor Cells ◽

Normal Tissue ◽

Standard Of Care ◽

Innate Immune ◽

Therapeutic Window ◽

Functional Markers ◽

Current Standard ◽

T Cell Infiltration ◽

Radiation Induced

AbstractEngaging innate immune pathways is emerging as a productive way of achieving durable anti-tumor responses. However, systemic administration of these therapies can result in toxicity, deemed to be particularly problematic when combined with current standard-of-care cytotoxic treatments such as radiotherapy. Increasing the therapeutic window of radiotherapy may be achieved by using targeted therapies, however, few pre-clinical studies investigate both tumor and normal tissue responses in detail. Here we show that targeting innate immune receptor C5aR1 improves tumor radiation response while reducing radiation-induced normal tissue toxicity, thereby increasing the therapeutic window. Genetically or pharmacologically targeting C5aR1 increases both IL-10 expression in the small intestine and IL-10 secretion by tumor cells. Increased IL-10 attenuates RelA phosphorylation and increases apoptosis in tumor cells, leading to improved radiation responses in murine models. Of note, these radiosensitizing effects are tumor-specific since, in the gastrointestinal tract, targeting C5aR1 instead results in decreased crypt cell apoptosis reduced signs of histological damage and improved survival following total abdominal irradiation in mice. Furthermore, the potent and orally active C5aR1 inhibitor, PMX205, improves tumor radiation responses even in a context of reduced/absent CD8+ T cell infiltration. These data indicate that PMX205 can modulate cancer-cell intrinsic functions to potentiate anti-tumor radiation responses even in tumors displaying features of T-cell deficiency or exclusion. Finally, using a preclinical murine model allowing the simultaneous assessment of tumor and normal tissue radiation responses, we show that PMX205 treatment reduces histological and functional markers of small-bowel toxicity while affording a positive tumor response. Our data, therefore, suggest that targeting C5aR1 could be a promising approach for increasing the therapeutic window of radiotherapy.

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DPP4 Inhibitor Sitagliptin Enhances Lymphocyte Recruitment and Prolongs Survival in a Syngeneic Ovarian Cancer Mouse Model

Cancers ◽

10.3390/cancers13030487 ◽

2021 ◽

Vol 13 (3) ◽

pp. 487

Author(s):

Amy L. Wilson ◽

Laura R. Moffitt ◽

Kirsty L. Wilson ◽

Maree Bilandzic ◽

Mark D. Wright ◽

...

Keyword(s):

Ovarian Cancer ◽

Overall Survival ◽

T Cell ◽

Mouse Model ◽

Standard Of Care ◽

Cell Infiltration ◽

Metastatic Tumour ◽

Cell Trafficking ◽

T Regulatory Cell ◽

T Cell Infiltration

Immunity plays a key role in epithelial ovarian cancer (EOC) progression with a well-documented correlation between patient survival and high intratumoral CD8+ to T regulatory cell (Treg) ratios. We previously identified dysregulated DPP4 activity in EOCs as a potentially immune-disruptive influence contributing to a reduction in CXCR3-mediated T-cell infiltration in solid tumours. We therefore hypothesized that inhibition of DPP4 activity by sitagliptin, an FDA-approved inhibitor, would improve T-cell infiltration and function in a syngeneic ID8 mouse model of EOC. Daily oral sitagliptin at 50 mg/kg was provided to mice with established primary EOCs. Sitagliptin treatment decreased metastatic tumour burden and significantly increased overall survival and was associated with significant changes to the immune landscape. Sitagliptin increased overall CXCR3-mediated CD8+ T-cell trafficking to the tumour and enhanced the activation and proliferation of CD8+ T-cells in tumour tissue and the peritoneal cavity. Substantial reductions in suppressive cytokines, including CCL2, CCL17, CCL22 and IL-10, were also noted and were associated with reduced CD4+ CD25+ Foxp3+ Treg recruitment in the tumour. Combination therapy with paclitaxel, however, typical of standard-of-care for patients in palliative care, abolished CXCR3-specific T-cell recruitment stimulated by sitagliptin. Our data suggest that sitagliptin may be suitable as an adjunct therapy for patients between chemotherapy cycles as a novel approach to enhance immunity, optimise T-cell-mediated function and improve overall survival.

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VXM01 phase I study in patients with resectable progression of a glioblastoma.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.2061 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 2061-2061 ◽

Cited By ~ 2

Author(s):

Wolfgang Wick ◽

Antje Wick ◽

Martha Nowosielski ◽

Felix Sahm ◽

Dennis Riehl ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Response ◽

Cerebral Blood Volume ◽

Tumor Tissue ◽

Objective Response ◽

Oral Route ◽

Recurrent Glioblastoma ◽

T Cell Response

2061 Background: VXM01 consists of an attenuated Salmonella typhi Ty21a carrying a plasmid encoding for VEGFR-2. The bacterium is serving as a vector via the oral route of administration carrying the plasmid into the Peyer’s plaques. The vaccine construct elicits a systemic T-cell response targeting VEGFR-2. This trial was set up to examine safety and tolerability, clinical and immunogenic response to VXM01 after treatment with at least four vaccinations [106 or 107colony-forming units (CFU)] in patients with recurrent glioblastoma who have failed at least radiochemotherapy with temozolomide. Methods: Patients with progressive resctable glioblastoma were subjected to single oral administration of VXM01 each on day 1, 3, 5, and 7. In addition, VXM01 was allowed to be administered in 4-weekly single doses every 4 weeks during the tumor follow-up period after reoperation. Follow-up was done by weekly safety laboratories and physical examinations in the treatment period and 4-weekly thereafter, MRI including perfusion maps (days 15 and 30 and six-weekly thereafter), 12-weekly T-cell immunomonitoring in the peripheral blood, and brain tumor immunohistochemistry. Results: Eight patients have been treated according to the schedule and surgery has been performed in seven of them. Under VXM01 treatment 47 adverse events, mostly unrelated to VXM01, were observed after a median of 7 doses per patient. Four out of eight patients (50%) showed a VEGFR-2 specific T cell response. In four patients there was a relevant increase in cerebral blood volume and apparent diffusion coefficient on post-vaccination MRI. In one patient there was an objective and durable T1 response, whereas three further patients remained stable prior to surgery and thereafter. Evaluation of infiltrating T cells in the tissue from re-operation revealed an increase in CD8+ T-cells in 5 out of 7 patients relative to the primary tumor tissue. Conclusions: VXM01 was safe and produces specific peripheral immune responses as well as enumeration of tumor-infiltrating T-cells in post-vaccine tumor tissue. Post treatment MRI imply vascular normalization and there was one patient with an objective response. As a consequence of this data, an expansion cohort of this trial has been launched. Clinical trial information: NCT02718443.

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Neoadjuvant PD-1 blockade induces T cell and cDC1 activation but fails to overcome the immunosuppressive tumor associated macrophages in recurrent glioblastoma

Nature Communications ◽

10.1038/s41467-021-26940-2 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Alexander H. Lee ◽

Lu Sun ◽

Aaron Y. Mochizuki ◽

Jeremy G. Reynoso ◽

Joey Orpilla ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Cell ◽

Neoadjuvant Treatment ◽

Recurrent Glioblastoma ◽

T Cell Infiltration ◽

Treatment Paradigm ◽

Clinical Models ◽

Chemotactic Factors

AbstractPrimary brain tumors, such as glioblastoma (GBM), are remarkably resistant to immunotherapy, even though pre-clinical models suggest effectiveness. To understand this better in patients, here we take advantage of our recent neoadjuvant treatment paradigm to map the infiltrating immune cell landscape of GBM and how this is altered following PD-1 checkpoint blockade using high dimensional proteomics, single cell transcriptomics, and quantitative multiplex immunofluorescence. Neoadjuvant PD-1 blockade increases T cell infiltration and the proportion of a progenitor exhausted population of T cells found within the tumor. We identify an early activated and clonally expanded CD8+ T cell cluster whose TCR overlaps with a CD8+ PBMC population. Distinct changes are also observed in conventional type 1 dendritic cells that may facilitate T cell recruitment. Macrophages and monocytes still constitute the majority of infiltrating immune cells, even after anti-PD-1 therapy. Interferon-mediated changes in the myeloid population are consistently observed following PD-1 blockade; these also mediate an increase in chemotactic factors that recruit T cells. However, sustained high expression of T-cell-suppressive checkpoints in these myeloid cells continue to prevent the optimal activation of the tumor infiltrating T cells. Therefore, future immunotherapeutic strategies may need to incorporate the targeting of these cells for clinical benefit.

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DDIS-23. CMV-BASED PLASMID DNA VACCINE FOR GBM USING THE UNITE PLATFORM

Neuro-Oncology ◽

10.1093/neuonc/noz175.274 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi68-vi68

Author(s):

Amit Adhikari ◽

Barb Toll ◽

Yoshimi Johnson ◽

Anthony Marketon ◽

Greg Wilson ◽

...

Keyword(s):

T Cell ◽

Dna Vaccine ◽

T Cell Activation ◽

Immune Checkpoint ◽

Cell Activation ◽

Checkpoint Inhibitors ◽

Standard Of Care ◽

T Cell Response ◽

Great Opportunity ◽

Expression Platform

Abstract Glioblastoma (GBM) is an aggressive form of brain cancer with a median survival of 15 months, remaining unchanged in spite of technological advances in the standard of care. The presence of the partial CMV genome, specifically in GBM cells, provides a great opportunity for a targeted therapy. We have utilized our UNITE (UNiversal Intracellular Targeted Expression) platform to build a polyvalent DNA vaccine which includes HCMV proteins, pp65, gB and IE-1. The UNITE platform is based, in part, on a lysosomal targeting technology which can result in increased antigen presentation, a balanced T cell response, and subsequent immunologic benefit. Using an orthotopic GBM mouse model expressing CMV proteins in the CT2A cell line, we have shown up to 45% survival when treated therapeutically with the pp65-IE-1 vaccine. In order to further improve the vaccine’s efficacy, and also to understand the mechanism of action, we are evaluating the post-vaccination tumor microenvironment and testing combination therapies with immune checkpoint inhibitors. Preliminary data on treated tumors suggest an increase in the PD-1 immune checkpoint regulator and a higher number of regulatory T cells. Our immune response evaluation of the polyvalent vaccine in naïve mice showed generation of robust antigen specific T cell activation. The use of multiple antigens in this vaccine makes it better suited to prevent antigen escape by tumor cells. Encouraged by our non-clinical data and the promising outcomes from our collaborators’ clinical trials using pp65 mRNA transfected autologous dendritic cells (ATTAC and ATTAC-II), we are moving forward with a phase I trial. We believe that the immune boost from our UNITE platform combined with deactivation of the immunosuppressive microenvironment by checkpoint inhibition holds a promising treatment against GBM.

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STING Agonist Combined to a Protein-Based Cancer Vaccine Potentiates Peripheral and Intra-Tumoral T Cell Immunity

Frontiers in Immunology ◽

10.3389/fimmu.2021.695056 ◽

2021 ◽

Vol 12 ◽

Author(s):

Matteo Rossi ◽

Susanna Carboni ◽

Wilma Di Berardino-Besson ◽

Erika Riva ◽

Marie-Laure Santiago-Raber ◽

...

Keyword(s):

T Cell ◽

Cancer Vaccines ◽

T Cell Response ◽

Cd4 T Cell ◽

Mouse Tumor ◽

Therapeutic Vaccination ◽

Protein Vaccine ◽

T Cell Infiltration ◽

Cell Immunity ◽

Interferon Gene

Combining different immunotherapy approaches is currently building the future of immunotherapy, with the view to maximize anti-tumoral efficacy for larger patient population. The KISIMA™ platform allows the development of protein-based cancer vaccines able to induce tumor-specific T cell response resulting in anti-tumoral efficacy in various mouse models. Intra-tumoral administration of stimulator of interferon gene agonists (STINGa) was shown to induce a potent inflammatory response leading to the development of tumor-specific immunity. Here, we explored the efficacy and mechanisms of action of subcutaneous STINGa treatment combined with therapeutic vaccination in various mouse tumor models. This combinatory treatment highly enhanced frequency and effector function of both peripheral and intra-tumoral antigen-specific CD8 T cells, promoting potent IFNγ and TNFα production along with increased cytotoxicity. Moreover, combination therapy favorably modulated the tumor microenvironment by dampening immune-suppressive cells and increasing CD4 T cell infiltration together with their polarization toward Th1 phenotype. Combination with STINGa treatment improved the effect of therapeutic vaccination, resulting in a prolonged control and slower growth of B16-OVA and TC-1 tumors. Altogether, the results presented here highlight the potential of combining STINGa with a therapeutic protein vaccine for cancer treatment.

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Tetanus toxoid pre-conditioning in recurrent glioblastoma treated with dendritic cell immunotherapy is associated to CD8+ T cell response.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.15_suppl.e14053 ◽

2018 ◽

Vol 36 (15_suppl) ◽

pp. e14053-e14053

Author(s):

Marica Eoli ◽

Cristina Corbetta ◽

Valeria Cuccarini ◽

Elena Anghileri ◽

Simona Frigerio ◽

...

Keyword(s):

T Cell ◽

Dendritic Cell ◽

Tetanus Toxoid ◽

Cell Response ◽

Cd8 T Cell ◽

Recurrent Glioblastoma ◽

T Cell Response ◽

Cell Immunotherapy

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Neoadjuvant PD-1 blockade induces T cell and cDC1 activation but fails to overcome the immunosuppressive tumor associated macrophages in recurrent glioblastoma

10.21203/rs.3.rs-793187/v1 ◽

2021 ◽

Author(s):

Alexander Lee ◽

Lu Sun ◽

Aaron Mochizuki ◽

Jeremy Reynoso ◽

Joey Orpilla ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Cell ◽

Neoadjuvant Treatment ◽

Recurrent Glioblastoma ◽

T Cell Infiltration ◽

Treatment Paradigm ◽

Clinical Models ◽

Chemotactic Factors

Abstract Primary brain tumors, such as glioblastoma (GBM), have been remarkably resistant to immunotherapy, even though pre-clinical models suggest effectiveness. To understand this better in patients, we took advantage of our recent neoadjuvant treatment paradigm to map the infiltrating immune cell landscape of GBM and how this is altered following PD-1 checkpoint blockade using high dimensional proteomics, single cell transcriptomics, and quantitative multiplex immunofluorescence. Neoadjuvant PD-1 blockade increased T cell infiltration and proportion of a progenitor exhausted population of T cells found within the tumor. We identified an early activated and clonally expanded CD8+ T cell cluster whose TCR overlapped with a CD8+ PBMC population. Distinct changes were also observed in conventional type 1 dendritic cells that may facilitate T cell recruitment. Macrophages and monocytes still constituted the majority of infiltrating immune cells, even after anti-PD-1 therapy. Interferon-mediated changes in the myeloid population were consistently observed following PD-1 blockade; these also mediated an increase in chemotactic factors that recruit T cells. However, sustained high expression of T-cell-suppressive checkpoints in these myeloid cells continued to prevent the optimal activation of the tumor infiltrating T cells. Therefore, future immunotherapeutic strategies may need to incorporate the targeting of these cells for clinical benefit.

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Heterologous prime-boost vaccination targeting MAGE-type antigens promotes tumor T-cell infiltration and improves checkpoint blockade therapy

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-003218 ◽

2021 ◽

Vol 9 (9) ◽

pp. e003218

Author(s):

James McAuliffe ◽

Hok Fung Chan ◽

Laurine Noblecourt ◽

Ramiro Andrei Ramirez-Valdez ◽

Vinnycius Pereira-Almeida ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Response ◽

Tumor Antigens ◽

T Cell Response ◽

Checkpoint Blockade ◽

Cell Infiltration ◽

Tumor Models ◽

Murine Tumor ◽

T Cell Infiltration

BackgroundThe clinical benefit of immune checkpoint blockade (ICB) therapy is often limited by the lack of pre-existing CD8+ T cells infiltrating the tumor. In principle, CD8+ T-cell infiltration could be promoted by therapeutic vaccination. However, this remains challenging given the paucity of vaccine platforms able to induce the strong cytotoxic CD8+ T-cell response required to reject tumors. A therapeutic cancer vaccine that induces a robust cytotoxic CD8+ T-cell response against shared tumor antigens and can be combined with ICB could improve the outcome of cancer immunotherapy.MethodsHere, we developed a heterologous prime-boost vaccine based on a chimpanzee adenovirus (ChAdOx1) and a modified vaccinia Ankara (MVA) encoding MAGE-type antigens, which are tumor-specific shared antigens expressed in different tumor types. The mouse MAGE-type antigen P1A was used as a surrogate to study the efficacy of the vaccine in combination with ICB in murine tumor models expressing the P1A antigen. To characterize the vaccine-induced immune response, we performed flow cytometry and transcriptomic analyses.ResultsThe ChAdOx1/MVA vaccine displayed strong immunogenicity with potent induction of CD8+ T cells. When combined with anti-Programmed Cell Death Protein 1 (PD-1), the vaccine induced superior tumor clearance and survival in murine tumor models expressing P1A compared with anti-PD-1 alone. Remarkably, ChAdOx1/MVA P1A vaccination promoted CD8+ T-cell infiltration in the tumors, and drove inflammation in the tumor microenvironment, turning ‘cold’ tumors into ‘hot’ tumors. Single-cell transcriptomic analysis of the P1A-specific CD8+ T cells revealed an expanded population of stem-like T cells in the spleen after the combination treatment as compared with vaccine alone, and a reduced PD-1 expression in the tumor CD8+ T cells.ConclusionsThese findings highlight the synergistic potency of ChAdOx1/MVA MAGE vaccines combined with anti-PD-1 for cancer therapy, and establish the foundation for clinical translation of this approach. A clinical trial of ChadOx1/MVA MAGE-A3/NY-ESO-1 combined with anti-PD-1 will commence shortly.

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