306 The selective reduction in the production of Bmi-1 protein leads to tumor growth control in multiple tumor models

BackgroundImmune checkpoint blocker (ICB) therapy has shown survival benefits for some patients with cancer. Nevertheless, many individuals remain refractory or acquire resistance to treatment, motivating the exploration of complementary immunotherapies. Accordingly, cancer vaccines offer an attractive alternative. Optimal delivery of multiple tumor-associated antigens combined with potent adjuvants seems to be crucial for vaccine effectiveness.MethodsHere, a prototype for a generic melanoma vaccine, named TRIMELVax, was tested using B16F10 mouse melanoma model. This vaccine is made of heat shock-treated tumor cell lysates combined with the Concholepas concholepas hemocyanin as adjuvant.ResultsWhile B16F10 lysate provides appropriate melanoma-associated antigens, both a generic human melanoma cell lysate and hemocyanin adjuvant contributes with danger signals promoting conventional dendritic type 1 cells (cDC1), activation, phagocytosis and effective antigen cross-presentation. TRIMELVax inhibited tumor growth and increased mice survival, inducing cellular and humoral immune responses. Furthermore, this vaccine generated an increased frequency of intratumor cDC1s but not conventional type 2 dendritic cells (cDC2s). Augmented infiltration of CD3+, CD4+ and CD8+ T cells was also observed, compared with anti-programmed cell death protein 1 (PD-1) monotherapy, while TRIMELVax/anti-PD-1 combination generated higher tumor infiltration of CD4+ T cells. Moreover, TRIMELVax promoted an augmented proportion of PD-1lo CD8+ T cells in tumors, a phenotype associated with prototypic effector cells required for tumor growth control, preventing dysfunctional T-cell accumulation.ConclusionsThe therapeutic vaccine TRIMELVax efficiently controls the weakly immunogenic and aggressive B16F10 melanoma tumor growth, prolonging tumor-bearing mice survival even in the absence of ICB. The strong immunogenicity shown by TRIMELVax encourages clinical studies in patients with melanoma.

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Abstract P077: Composition of CD4 T cell subsets and impact on tumor growth control across mouse syngeneic tumor models

10.1158/2326-6074.tumimm21-p077 ◽

2022 ◽

Author(s):

Chunxiao Xu ◽

Lindsay Webb ◽

Sireesha Yalavarthi ◽

Clotilde Bourin ◽

Jacques Moisan

Keyword(s):

T Cell ◽

Tumor Growth ◽

Growth Control ◽

T Cell Subsets ◽

Cd4 T Cell ◽

Tumor Models ◽

Syngeneic Tumor

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208 E7777 (denileukin diftitox) enhances anti-tumor activity and significantly extends survival benefit of anti-PD-1 in syngeneic solid tumor models

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0208 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A224-A225

Author(s):

Mary Woodall-Jappe ◽

A Raghav Chari ◽

Anil Namboodiripad ◽

Chandrasekhar Goda

Keyword(s):

Overall Survival ◽

Tumor Growth ◽

Solid Tumor ◽

Therapeutic Benefit ◽

Tumor Models ◽

Treg Depletion ◽

Immune Biomarkers ◽

Group 5 ◽

Tumor Measurements ◽

Anti Tumor Activity

BackgroundRegulatory T cell (Tregs) inhibit activity of anti-tumor T cells, and have been shown to limit checkpoint inhibitor effectiveness. Depletion of Tregs seems desirable during immunotherapy, but chronic Treg depletion with antibody therapies can lead to serious autoimmune adverse events. Compared to antibodies, the fusion protein E7777 (IL-2/diphtheria toxin) has a relatively short half-life in circulation, which allows for transient and selective Treg depletion. The potential therapeutic benefit of combining E7777 with anti-PD-1 was tested in syngeneic solid tumor models.MethodsCT26 colon and H22 liver cancer tumors were implanted subcutaneously in immunocompetent BALB/c mice. E7777 (2.5 mcg/mouse, i.v.) was given on a Q7Dx3 schedule. Anti-murine PD-1 was given (100 mcg/mouse, i.v.) Q4Dx5. Groups of 16 mice received each agent as monotherapy or in combinations. Sequencing of combination administration was also varied: Group 4 started treatment on the same day; Group 5 received E7777 2 days prior to start of anti-PD-1; Group 6 received anti-PD-1 first. Tumor growth was compared across all groups. In survival studies, mice were treated for 3 weeks and observed with twice weekly tumor measurements. In other experiments, tumors, tumor-draining lymph nodes, and spleens were examined by IHC and by flow cytometry of immune cells from dissociated tissues at defined points, for immune biomarkers.ResultsFigure 1 shows additive benefit from the E7777 + anti-PD-1 combinations over either monotherapy. Most importantly, figure 2 and table 1 show significantly enhanced overall survival from a 3 week course of combinations compared to either agent alone (p<0.005) or to vehicle controls (p<0.000001). There was no clear distinction among different sequencing regimens. Benefit correlated with enhanced CD8:Treg ratios in tumors.Abstract 208 Figure 1Tumor growth in s.c. syngeneic solid tumors. N=16/groupAbstract 208 Figure 2Overall survival in s.c. syngeneic models. N=16/groupAbstract 208 Table 1Calculated median survivalConclusionsDepletion of Tregs by E7777 significantly increased anti-tumor activity and durably extended overall survival compared to treatment with anti-PD-1 alone in syngeneic solid tumor models. Clinical studies of a combination of the two agents are planned.Ethics ApprovalAll studies were conducted at Crown Bio, and were approved by the Crown Bio IACUC.

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Therapeutic Application of Brain-Specific Angiogenesis Inhibitor 1 for Cancer Therapy

Cancers ◽

10.3390/cancers13143562 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3562

Author(s):

Mitra Nair ◽

Chelsea Bolyard ◽

Tae Jin Lee ◽

Balveen Kaur ◽

Ji Young Yoo

Keyword(s):

Angiogenesis Inhibitor ◽

Suppressor Gene ◽

Chemotherapeutic Agents ◽

Tumor Models ◽

In Vivo Models ◽

Herpes Simplex Viruses ◽

Multiple Tumor ◽

And Function

Brain-specific angiogenesis inhibitor 1 (BAI1/ADGRB1) is an adhesion G protein-coupled receptor that has been found to play key roles in phagocytosis, inflammation, synaptogenesis, the inhibition of angiogenesis, and myoblast fusion. As the name suggests, it is primarily expressed in the brain, with a high expression in the normal adult and developing brain. Additionally, its expression is reduced in brain cancers, such as glioblastoma (GBM) and peripheral cancers, suggesting that BAI1 is a tumor suppressor gene. Several investigators have demonstrated that the restoration of BAI1 expression in cancer cells results in reduced tumor growth and angiogenesis. Its expression has also been shown to be inversely correlated with tumor progression, neovascularization, and peri-tumoral brain edema. One method of restoring BAI1 expression is by using oncolytic virus (OV) therapy, a strategy which has been tested in various tumor models. Oncolytic herpes simplex viruses engineered to express the secreted fragment of BAI1, called Vasculostatin (Vstat120), have shown potent anti-tumor and anti-angiogenic effects in multiple tumor models. Combining Vstat120-expressing oHSVs with other chemotherapeutic agents has also shown to increase the overall anti-tumor efficacy in both in vitro and in vivo models. In the current review, we describe the structure and function of BAI1 and summarize its application in the context of cancer treatment.

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Abstract 688: Anti-CNTN4 antibody, GENA-104A07 suppresses tumor growth in murine syngeneic tumor models by regulating T cell function

10.1158/1538-7445.am2021-688 ◽

2021 ◽

Author(s):

Mi Young Cha ◽

Youn Kyung Houh ◽

Yun Yeon Kim ◽

Hyunuk Kim ◽

Joo-Yeon Chung ◽

...

Keyword(s):

T Cell ◽

Tumor Growth ◽

Cell Function ◽

Tumor Models ◽

T Cell Function ◽

Syngeneic Tumor

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Abstract P001: The anti-angiogenic antibody BD0801 demonstrates better anti-tumor activity than bevacizumab and synergize with chemotherapies in multiple tumor models

10.1158/1535-7163.targ-21-p001 ◽

2021 ◽

Author(s):

Liting Xue ◽

Jianxing Tang ◽

Yuyin Ding ◽

Lei Song ◽

Shansen Xu ◽

...

Keyword(s):

Tumor Models ◽

Multiple Tumor ◽

Anti Tumor Activity

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Efficacy of KD033, an anti-human-PD-L1-IL-15 bispecific protein, in human-PD-L1 positive and negative murine tumor models.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e14556 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e14556-e14556

Author(s):

Stella Martomo ◽

Dan Lu ◽

Zhanna Polonskaya ◽

Xenia Luna ◽

Zhikai Zhang ◽

...

Keyword(s):

Fusion Protein ◽

Tumor Growth ◽

Nk Cells ◽

Immune Cell ◽

Clinical Stage ◽

Tumor Models ◽

T Cell Infiltration ◽

Negative Tumor ◽

Tumor Expression ◽

The Impact

e14556 Background: KD033 is a clinical-stage bispecific fusion molecule consisting of a high-affinity anti-human-PD-L1 antibody and human IL-15. Preclinical studies have demonstrated that targeting IL-15 with anti-PD-L1 antibody resulted in increased efficacy, safety and maximal tolerated dose of the fusion protein compared to administration of free IL-15, as well as reduction of tumor growth in both PD-L1 positive and negative tumor models (1). The goal of the current study is to directly compare KD033 efficacy when PD-L1 is present or absent on the surface of the same tumor. Methods: KD033 was administered in the human-PD-L1/PD-1 transgenic C57/Bl6 mice subcutaneously transplanted with human-PD-L1 positive and negative MC38 colon carcinoma cells. This animal model allowed the evaluation of the impact of the presence or absence of human-PD-L1 expression on the tumor cell surface without altering human-PD-L1 expression on immune cells. Results: KD033 treatment resulted in significant tumor growth reduction in both human-PD-L1 positive and negative MC38 tumors. Analysis of peripheral immune cell populations showed similar increases of CD8 T and NK cells between human-PD-L1 positive and negative MC38- bearing mice after KD033 administration. Immunohistochemistry demonstrated a significant increase in CD8 T-cell infiltration into the human-PD-L1 positive MC38 tumors, whereas NK cells infiltration was more pronounced in the human-PD-L1 negative MC38 tumors. Analysis of tumor gene transcription after KD033 treatment highlighted differences in gene signatures between human-PD-L1 positive and negative MC38 tumors following KD033 treatment. Conclusions: These results showed that the efficacy of anti-PD-L1-IL-15 fusion protein is not limited to PD-L1 tumor expression as KD033 was efficacious in both PD-L1 positive and negative tumors. Mol Cancer Ther February 1 2021 (20) (2) 347-356; DOI: 10.1158/1535-7163.MCT-20-0457

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A Tumor-Peptide–Based Nanoparticle Vaccine Elicits Efficient Tumor Growth Control in Antitumor Immunotherapy

Molecular Cancer Therapeutics ◽

10.1158/1535-7163.mct-18-0764 ◽

2019 ◽

Vol 18 (6) ◽

pp. 1069-1080 ◽

Cited By ~ 9

Author(s):

Carolin Heße ◽

Sebastian Kollenda ◽

Olga Rotan ◽

Eva Pastille ◽

Alexandra Adamczyk ◽

...

Keyword(s):

Tumor Growth ◽

Growth Control ◽

Antitumor Immunotherapy

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Gamma Knife Radiosurgery for the Treatment of Cavernous Sinus Meningiomas

Neurosurgery ◽

10.1227/01.neu.0000047814.18819.9f ◽

2003 ◽

Vol 52 (3) ◽

pp. 517-524 ◽

Cited By ~ 111

Author(s):

Yoshiyasu Iwai ◽

Kazuhiro Yamanaka ◽

Tomoya Ishiguro

Keyword(s):

Tumor Growth ◽

Gamma Knife ◽

Cavernous Sinus ◽

Tumor Regression ◽

Gamma Knife Radiosurgery ◽

Growth Control ◽

Neurological Deficits ◽

Surgical Removal ◽

Tumor Diameter

Abstract OBJECTIVE We report on the efficacy of gamma knife radiosurgery for cavernous sinus meningiomas. METHODS Between January 1994 and December 1999, we used gamma knife radiosurgery for the treatment of 43 patients with cavernous sinus meningiomas. Forty-two patients were followed up for a mean of 49.4 months (range, 18–84 mo). The patients' average age was 55 years (range, 18–81 yr). Twenty-two patients (52%) underwent operations before radiosurgery, and 20 patients (48%) underwent radiosurgery after the diagnosis was made by magnetic resonance imaging. The tumor volumes ranged from 1.2 to 101.5 cm3 (mean, 14.7 cm3). The tumors either compressed or were attached to the optic apparatus in 17 patients (40.5%). The marginal radiation dose was 8 to 15 Gy (mean, 11 Gy), and the optic apparatus was irradiated with 2 to 12 Gy (mean, 6.2 Gy). Three patients with a mean tumor diameter greater than 4 cm were treated by two-stage radiosurgery. RESULTS Thirty-eight patients (90.5%) demonstrated tumor growth control during the follow-up period after radiosurgery. Tumor regression was observed in 25 patients (59.5%), and growth was unchanged in 13 patients (31%). Regrowth or recurrence occurred in four patients (9.5%). The actual tumor growth control rate at 5 years was 92%. Only one patient (2.4%) experienced regrowth within the treatment field; in other patients, regrowth occurred at sites peripheral to or outside the treatment field. Twelve patients (28.6%) had improved clinically by the time of the follow-up examination. None of the patients experienced optic neuropathy caused by radiation injury or any new neurological deficits after radiosurgery. CONCLUSION Gamma knife radiosurgery may be a useful option for the treatment of cavernous sinus meningiomas not only as an adjuvant to surgery but also as an alternative to surgical removal. We have shown it to be safe and effective even in tumors that adhere to or are in close proximity to the optic apparatus.

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