scholarly journals 141 PBMC-based cancer vaccines generated with microfluidics squeezing demonstrate synergistic and durable tumor reduction in combination with PD1 checkpoint and FAP targeted IL-2 variants

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A155-A155
Author(s):  
Matthew Booty ◽  
Adam Stockmann ◽  
Olivia Pryor ◽  
Melissa Myint ◽  
Christine Trumpfheller ◽  
...  
Keyword(s):  
T Cells ◽  
Combination Therapy ◽  
Median Survival ◽  
Cancer Vaccine ◽  
Cd8 T Cells ◽  
Cancer Vaccines ◽  
Tumor Model ◽  
Mechanistic Study ◽  
Engineering System ◽  
Tumor Implant

BackgroundWe engineered unfractionated peripheral blood mononuclear cells (PBMCs) to function as antigen presenting cells (APCs) that generate potent CD8+ T cell responses. We investigated the combined efficacy of PBMC-based cancer vaccine with targeted interleukin 2 variants (IL2v); anti-Programmed Cell Death Protein 1 (muPD1-IL2v) and anti-Fibroblast Activation Protein (muFAP-IL2v).MethodsWe generated PBMC-based cancer vaccine with microfluidic cell engineering system (Cell Squeeze®), which facilitates direct cytosolic antigen delivery and enables cell subsets within PBMCs to function as APCs. The immunocytokines used contain IL2v fused with antibody counterparts that enable targeting to tumor-associated stroma or immune cells (aFAP and aPD-1, respectively) with modified FcR binding. The IL2v moiety, compared with wild-type IL-2, has abolished binding to IL-2Ra (CD25) resulting in IL-2Rgb binding only, thus fully maintaining activity on NK and CD8+ T cells, while avoiding Treg activity and CD25 mediated toxicity.ResultsIn the murine TC-1 HPV tumor model, SQZ-PBMC-based vaccines show efficacy as monotherapy (1e6 cells administered iv on day 14 post-tumor implant), while SQZ combination therapy with targeted immunocytokines, muPD1-IL2v and muFAP-IL2v (2 mg/kg or 1 mg/kg, respectively, administered iv on days 21, 28, and 35 post-tumor implant) significantly delayed tumor growth and improved survival in murine TC-1 HPV tumor model. Median survival of combination treated groups remained undefined at day 84 post-tumor implant, while the monotherapy treated groups had calculated median survival times of 36.5, 42, and 70 days for the muFAP-IL2v, muPD1-IL2v, and SQZ monotherapy groups, respectively. Following initial tumor clearance, tumor-free mice (2/12 animals for SQZ monotherapy; 8/12 animals for SQZ with muFAP-IL2v; 11/11 animals for SQZ with muPD1-IL2v) were all re-challenged at day 84 and all remained tumor free at least 7 weeks post re-challenge, suggesting the generation of anti-tumor memory response. In a mechanistic study, SQZ-PBMCs in combination with muPD1-IL2v resulted in increased expansion of intra-tumoral, antigen-specific CD8+ T cells compared with separate administration of either therapy (~3.6-fold over SQZ alone; ~2000-fold over muPD1-IL2v alone; per mg of tumor). Combination therapy also resulted in improved IFNγ and TNFα cytokine production by SQZ-elicited CD8+ T cells (~1.7-fold and ~9-fold, respectively, over SQZ monotherapy).ConclusionsMonotherapy with SQZ-PBMC-based cancer vaccines can drive anti-tumor responses in murine systems. These responses are enhanced by combined administration of targeted immunocytokines. Monotherapy with SQZ-PBMC-HPV is currently under clinical evaluation for HPV16+ tumor indications. These preclinical data support the combination of SQZ-PBMC with FAP-IL2v or PD1-IL2v targeted immunocytokine as promising cancer immunotherapies.

452 Combination treatment using KISIMATM protein-based cancer vaccine and systemic STING agonist results in profound modulation of tumor microenvironment and improved tumor control

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A479-A479
Author(s):  
Matteo Rossi ◽  
Elodie Belnoue ◽  
Susanna Carboni ◽  
Wilma Besson-Di Berardino ◽  
Erika Riva ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Combination Therapy ◽  
Cancer Vaccine ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Tumor Control ◽  
Therapeutic Vaccination ◽  
Potent Tumor

BackgroundKISIMATM platform allows the development of protein-based cancer vaccines able to induce a potent, tumor-specific CD8 and CD4 T cells response. While the cell penetrating peptide and the Anaxa portions confer, respectively, the cell delivery and self-adjuvanticity properties, the multiantigenic domain allows the targeting of different cancer antigens, resulting in anti-tumoral efficacy in different murine models.1 The first clinical candidate developed from KISIMATM is currently tested, together with anti-PD-1 blockade, in a phase I study in metastatic colorectal cancer patients. Stimulator of interferon genes agonists (STINGa) were shown to induce a potent type I interferon response in preclinical studies. The intratumoral administration of STINGa, to promote tumor inflammation, was shown to result in a protective spontaneous immune response in several murine tumor models. However, the encouraging preclinical results are not supported by recent clinical data, challenging the efficacy of unspecific monotherapy.As it is more and more clear that an effective cancer immunotherapy will require the combination of different treatment strategies, we investigate here the efficacy of combining KISIMATM cancer vaccine with STINGa treatment.MethodsMice were vaccinated with subcutaneous (s.c.) injection of KISIMATM vaccine combined with s.c. administration of STINGa. Safety and immunogenicity were assessed by measuring temperature, serum cytokines and the peripheral antigen-specific response. Anti-tumoral efficacy as well as in depth monitoring of TILs and tumor microenvironment modulation were assessed following therapeutic vaccination in a HPV16 E6 and E7 expressing TC-1 cold tumor model.ResultsCombination treatment was well tolerated and promoted the development of circulating antigen-specific CD8 T cells. In TC-1 tumor bearing mice, KISIMATM therapeutic vaccination resulted in the infiltration of both antigen-specific CD8 and CD4 T cells within the tumor, as well as a switch of tumor associated macrophages polarization toward the more inflammatory type 1. Combination therapy further increased the tumor microenvironment modulation induced by KISIMATM vaccine, promoting the polarization of inflammatory Thelper 1 CD4 T cells and increasing the effector function of antigen-specific CD8 T cells. The profound modulation of the tumor microenvironment induced by combination therapy enhanced the beneficial effect of KISIMATM vaccination, resulting in a prolonged tumor control.ConclusionsCombination of KISIMATM cancer vaccine with systemic STINGa treatment induces the development of a potent, tumor-specific immune response resulting in a profound modulation of the TME. As check-point inhibitor (CPI) therapy is ineffective on poorly infiltrated tumors, combination with therapies able to highly enhance tumor infiltration by T cells could expand CPI indications.Ethics ApprovalThe study was approved by the Canton of Geneva Ethic Board, under the license number GE165/19ReferenceBelnoue E, et al. Targeting self and neo-epitopes with a modular self-adjuvanting cancer vaccine. JCI Insight 2019. 4:11.

scholarly journals Tumor Inhibition by DepoVax-Based Cancer Vaccine Is Accompanied by Reduced Regulatory/Suppressor Cell Proliferation and Tumor Infiltration

ISRN Oncology ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Mohan Karkada ◽  
Tara Quinton ◽  
Rachelle Blackman ◽  
Marc Mansour
Keyword(s):  
T Cells ◽  
Cancer Vaccine ◽  
Cd8 T Cells ◽  
Cancer Vaccines ◽  
Suppressor Cells ◽  
Suppressor Cell ◽  
Vaccine Platform ◽  
Efficient Induction ◽  
Suppressive Cytokine ◽  
Treg Lymphocytes

A successful cancer vaccine needs to overcome the effects of immune-suppressor cells such as Treg lymphocytes, suppressive cytokine-secreting Tr1 cells, and myeloid-derived suppressor cells (MDSCs), while enhancing tumor-specific immune responses. Given the relative poor efficacy associated with current cancer vaccines, a novel vaccine platform called DepoVaxTM (DPX) was developed. C3 tumor-challenged mice were immunized with HPV-E7 peptide in DPX- or conventional-emulsion- (CE-) based vaccine. While control mice showed marked increase in Treg/MDSCs in spleen and blood, in mice treated with DPX-E7 the levels remained similar to tumor-free naive mice. Such differences were also seen within the tumor. Antigen-specific IL10-secreting CD4/CD8 T cells and TGF-β+CD8+ T cell frequencies were increased significantly in CE-treated and control mice in contrast to DPX-E7-immunized mice. Analysis of tumor-infiltrating cells revealed higher frequency of suppressor cells in untreated controls than in DPX-E7 group while the converse was true for tumor-infiltrating CD8 T cells. Immunization of tumor-bearing HLA-A2 transgenic mice with human vaccine DPX-0907, a peptide-based vaccine for breast/ovarian/prostate cancers, showed efficient induction of immune response to cancer peptides despite the presence of suppressor cells. Thus, this study provides the rationale for using DPX-based cancer vaccines in immune-suppressed cancer patients, to induce effective anticancer immunity.

scholarly journals IMMU-19. TARGETING GLIOBLASTOMA IMMUNOSUPPRESSION AND TREATMENT RESISTANCE WITH IBRUTINIB IN COMBINATION WITH STEREOTACTIC RADIATION AND IMMUNE CHECKPOINT BLOCKADE

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii108-ii108
Author(s):  
Jayeeta Ghose ◽  
Baisakhi Raychaudhuri ◽  
Kevin Liu ◽  
William Jiang ◽  
Pooja Gulati ◽  
...  
Keyword(s):  
T Cells ◽  
Combination Therapy ◽  
Median Survival ◽  
Immune Checkpoint ◽  
Survival Benefit ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Control Group ◽  
Triple Combination ◽  
Triple Combination Therapy

Abstract BACKGROUND Glioblastoma (GBM) is associated with systemic and intratumoral immunosuppression. Part of this immunosuppression is mediated by myeloid derived suppressor cells (MDSCs). Preclinical evidence shows that ibrutinib, a tyrosine kinase inhibitor FDA approved for use in chronic lymphocytic leukemia and known to be CNS penetrant, can decrease MDSC generation and function. Also, focal radiation therapy (RT) synergizes with anti-PD-1 therapy in mouse GBM models. Thus, we aimed to test the combination of these approaches on immune activation and survival in a preclinical immune-intact GBM mouse model. METHODS C57BL/6 mice intracranially implanted with the murine glioma cell line GL261-Luc2 were divided into 8 groups consisting of treatments with ibrutinib, RT (10 Gy SRS), or anti-PD-1 individually or in each combination (along with a no treatment control group). Immune cell subset changes (flow-cytometry) and animal survival (Kaplan-Meier) were assessed (n=10 mice per group). RESULTS Median survival of the following groups including control (28 days), ibrutinib (27 days), RT (30 days) or anti-PD-1 (32 days) showed no significant differences. However, a significant improvement in median survival was seen in mice given combinations of ibrutinib+RT (35 days), ibrutinib+anti-PD-1 (38 days), and triple therapy with ibrutinib+RT+anti-PD-1 (48 days, p < 0.05) compared to controls or single treatment groups. The reproducible survival benefit of triple combination therapy was abrogated in the setting of CD4+ and CD8+ T cell depletion. Contralateral intracranial tumor re-challenge in long-term surviving mice suggested generation of tumor-specific immune memory responses. The immune profile of the tumor microenvironment (TME) showed increased cytotoxic CD8+ T cells and decreased MDSCs and regulatory T cells in the triple combination therapy mice compared to controls. CONCLUSION The combination of ibrutinib, focal RT, and anti-PD-1 immune checkpoint blockade led to a significant survival benefit compared to controls in a preclinical model of GBM.

Increases in T Cell Telomere Length in HIV Infection after Antiretroviral Combination Therapy for HIV-1 Infection Implicate Distinct Population Dynamics in CD4+ and CD8+ T Cells

1999 ◽  
Vol 92 (1) ◽  
pp. 14-24 ◽  
Author(s):  
Sumesh Kaushal ◽  
Alan L. Landay ◽  
Michael M. Lederman ◽  
Elizabeth Connick ◽  
John Spritzler ◽  
...  
Keyword(s):  
T Cells ◽  
Population Dynamics ◽  
T Cell ◽  
Combination Therapy ◽  
Hiv Infection ◽  
Telomere Length ◽  
Cd8 T Cells ◽  
Distinct Population ◽  
Hiv 1

scholarly journals Combination Treatment of Topical Imiquimod Plus Anti-PD-1 Antibody Exerts Significantly Potent Antitumor Effect

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3948
Author(s):  
Kazumasa Oya ◽  
Yoshiyuki Nakamura ◽  
Zhu Zhenjie ◽  
Ryota Tanaka ◽  
Naoko Okiyama ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Combination Therapy ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Antitumor Effect ◽  
Skin Lesions ◽  
Ifn Γ ◽  
Deficient Mice

The exact mechanisms of the imiquimod (IMQ)-induced antitumor effect have not been fully understood. Although both topical IMQ treatment and anti-PD-1 antibody may be used for primary skin lesions or skin metastases of various cancers, the efficacy of each monotherapy for these lesions is insufficient. Using a murine tumor model and human samples, we aimed to elucidate the detailed mechanisms of the IMQ-induced antitumor effect and analyzed the antitumor effect of combination therapy of topical IMQ plus anti-PD-1 antibody. Topical IMQ significantly suppressed the tumor growth of MC38 in wildtype mice. IMQ upregulated interferon γ (IFN-γ) expression in CD8+ T cells in both the lymph nodes and the tumor, and the antitumor effect was abolished in both Rag1-deficient mice and IFN-γ-deficient mice, indicating that IFN-γ produced by CD8+ T cells play a crucial role in the IMQ-induced antitumor effect. IMQ also upregulated PD-1 expression in T cells as well as PD-L1/PD-L2 expression in myeloid cells, suggesting that IMQ induces not only T-cell activation but also T-cell exhaustion by enhanced PD-1 inhibitory signaling. Combination therapy of topical IMQ plus anti-PD-1 antibody exerted a significantly potent antitumor effect when compared with each single therapy, indicating that the combination therapy is a promising therapy for the skin lesions of various cancers.

scholarly journals A microbial-based cancer vaccine for induction of EGFRvIII-specific CD8+ T cells and anti-tumor immunity

PLoS ONE ◽  
2019 ◽  
Vol 14 (1) ◽  
pp. e0209153 ◽  
Author(s):  
Lauren Zebertavage ◽  
Shelly Bambina ◽  
Jessica Shugart ◽  
Alejandro Alice ◽  
Kyra D. Zens ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Immunity ◽  
Cancer Vaccine ◽  
Cd8 T Cells

scholarly journals T cell-mediated eradication of murine metastatic melanoma induced by targeted interleukin 2 therapy.

1996 ◽  
Vol 183 (5) ◽  
pp. 2361-2366 ◽  
Author(s):  
J C Becker ◽  
J D Pancook ◽  
S D Gillies ◽  
K Furukawa ◽  
R A Reisfeld
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Nk Cell ◽  
Interleukin 2 ◽  
Tumor Model ◽  
Melanoma Metastases ◽  
Tumor Eradication

Induction of a T-cell mediated antitumor response is the ultimate goal for tumor immunotherapy. We demonstrate here that antibody-targeted IL2 therapy is effective against established pulmonary and hepatic melanoma metastases in a syngeneic murine tumor model. The effector mechanisms involved in this tumor eradication are not dependent on NK cells, since the therapeutic effect of antibody-IL2 fusion protein was not altered in NK cell-deficient mice. In contrast, T cells are essential for the observed antitumor effect, since therapy with antibody IL2 fusion proteins is unable to induce tumor eradication in T cell-deficient SCID mice. In vivo depletion studies characterized the essential effector cell population further as CD8 + T cells. Such CD8 + T cells, isolated from tumor bearing mice after antibody-directed IL2 therapy, exerted a MHC class I-restricted cytotoxicity against the same tumor in vitro. These data demonstrate the ability of antibody-targeted IL2 delivery to induce a T cell-dependent host immune response that is capable of eradicating established melanoma metastases in clinically relevant organs.

scholarly journals The Combination of Anti-Tigit and Lenalidomide Promotes Synergistic Myeloma-Specific Immunity after ASCT

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 328-328
Author(s):  
Simone A Minnie ◽  
Nicole S Nemychenkov ◽  
Kathleen S Ensbey ◽  
Christine R Schmidt ◽  
Gregory Driessens ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Median Survival ◽  
Cd8 T Cells ◽  
Research Funding ◽  
Molecular Transport ◽  
Immunomodulatory Drugs ◽  
Preclinical Models ◽  
Specific Immunity

Abstract Multiple myeloma is a largely incurable bone marrow (BM) resident plasma cell malignancy that is increasing in incidence. Autologous stem cell transplantation (ASCT) is the current standard consolidation therapy and a subset of patients achieve durable progression free survival that is suggestive of long-term immune control. Utilizing novel preclinical models, we have provided definitive evidence that this is largely mediated by T cell-dependent myeloma-specific immunity. In both patients and preclinical models, myeloma progression is associated with T cell dysfunction and expression of multiple inhibitory receptors suggesting a loss of immunosurveillance. In mice, we have demonstrated potent anti-myeloma efficacy of TIGIT blockade in both ASCT and non-transplant settings. Here we utilized identical TIGIT Abs that do or do not Fc bind to demonstrate that immunological efficacy after ASCT was absolutely dependent on ADCC (median survival was unreached (>110 days) in Fc-binding vs 73 days in Fc-dead and 71 days in control Ig (cIg)-treated mice). Since TIGIT inhibition does not protect against myeloma relapse in all mice, it is apparent that combinational approaches are required to target non-responders. Therefore, we hypothesized that TIGIT blockade could be combined with immunomodulatory drugs (IMiDs) to provide synergistic anti-myeloma activity after ASCT. To that end, we utilized CRBN transgenic mice to investigate the efficacy of TIGIT blockade in combination with lenalidomide, the standard of care IMiD used in maintenance therapy after clinical ASCT. Briefly, B6 Vk*MYC myeloma-bearing (MM-bearing) mice were lethally irradiated and transplanted with B6 bone marrow (BM) and a suboptimal dose of T cells followed by anti-TIGIT or control Ig (100 mg twice weekly) for 5 weeks with lenalidomide (50 mg/kg daily gavage) or control diluent from D+14 for 3 weeks (Figure 1A). The combination of anti-TIGIT and lenalidomide provided synergistic anti-myeloma efficacy evidenced by prolonged median survival (109 days in combination vs < 60 days in monotherapy/control-treated mice, p<0.01; Figure B). Myeloma M bands were also suppressed in the combination treated mice relative to monotherapy or cIg-treated mice (p<0.01; Figure 1). Analysis of BM CD8 T cells 6 weeks after ASCT demonstrated that combination therapy significantly decreased terminal exhaustion (TOX + TIM3 + CD101 + PD-1 + DNAM-1 ─) with an average of only 20% of CD8 T cells with an exhausted phenotype in the combination group compared to greater than 50% exhausted CD8 T cells in monotherapy or cIg-treated mice (p<0.05; Figure 1C-D). The combination also increased the frequency of central memory and tissue-resident memory subsets (CD49b +CD69 +; p<0.05; Figure 1C-D), and increased IFNγ production from activated (PD-1 +; p<0.05; Figure 1E) cells compared to monotherapy or control Ig-treated mice. Importantly, these phenotypic changes were specific to the BM tumor microenvironment as we observed no effect of combination or monotherapy treatment on CD8 or CD4 T cells in peripheral blood. In sum, these data provide a strong rationale for combining TIGIT inhibition with immunomodulatory drugs to prevent the progression of myeloma. Figure 1 Figure 1. Disclosures Driessens: iTeos Therapeutics: Current Employment, Current equity holder in publicly-traded company. Holmberg: Up-To-Date: Patents & Royalties; Bristol Myers Squibb: Research Funding; Janssen: Research Funding; Merck: Research Funding; Millennium-Takeda: Research Funding; Sanofi: Research Funding; Seattle Genetics: Research Funding. Hill: NeoLeukin Therapeutics: Consultancy; Compass Therapeutics: Research Funding; NapaJen Pharma: Consultancy; Generon Corporation: Consultancy; Roche: Research Funding; iTeos Therapeutics: Consultancy, Research Funding; Syndax Pharmaceuticals: Research Funding; Applied Molecular Transport: Research Funding.

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