746 Vectorized Treg-depleting anti-CTLA-4 elicits antigen cross-presentation and CD8+ T cell immunity to reject “cold” tumors

BackgroundImmune checkpoint blockade (ICB) is a clinically proven concept to treat cancer. Still, a majority of cancer patients including those with poorly immune infiltrated “cold” tumors are resistant to currently available ICB therapies. CTLA-4 is one of few clinically validated targets for ICB, but toxicities linked to efficacy in approved anti-CTLA-4 regimens have restricted their use and precluded full therapeutic dosing. At a mechanistic level, accumulating preclinical and clinical data indicate dual mechanisms for anti-CTLA-4; immune checkpoint blockade and Treg depletion are both thought to contribute efficacy and toxicity in available, systemic, anti-CTLA-4 regimens. Accordingly, strategies to deliver highly effective, yet safe, anti-CTLA-4 therapies have been lacking. Here, BioInvent and Transgene present and preclinically characterize a highly efficacious and potentially safe strategy to target CTLA-4 in the context of oncolytic virotherapy.MethodsA novel human IgG1 CTLA-4 antibody (4-E03) was identified using function-first screening for mAbs and targets associated with superior Treg depleting activity. A tumor-selective oncolytic Vaccinia vector was then engineered to encode this novel, strongly Treg-depleting, checkpoint-blocking, anti-CTLA-4 antibody and GM-CSF (VVGM-ahCTLA4, BT-001). Viruses encoding a matching Treg-depleting mouse surrogate antibody were additionally generated, enabling proof-of-concept studies in syngeneic immune competent mouse tumor models.ResultsOur studies demonstrate that intratumoral (i.t.) administration of VVGM-aCTLA4 achieved tumor-restricted CTLA-4 receptor saturation and Treg-depletion, which elicited antigen cross-presentation and stronger systemic expansion of tumor-specific CD8+ T cells and antitumor immunity compared with systemic anti-CTLA-4 antibody therapy. Efficacy correlated with FcgR-mediated intratumoral Treg-depletion and the reduction of exhausted CD8+ T cells. Remarkably, in a clinically relevant mouse model resistant to systemic immune checkpoint blockade, i.t. VVGM-aCTLA4 synergized with anti-PD-1 to reject “cold” tumors.ConclusionsOur findings demonstrate in vivo proof-of-concept for spatial restriction of strongly Treg-depleting, immune checkpoint blocking, vectorized anti-CTLA-4 as a highly effective and safe strategy to target CTLA-4 which is able to overcome current limitations of approved anti-CTLA-4 regimens. A clinical trial evaluating i.t. VVGM-ahCTLA4 (BT-001) alone and in combination with anti-PD-1 in metastatic or advanced solid tumors has commenced.Ethics ApprovalAll mouse experiments were approved by the local ethical committee for experimental animals (Malmö/Lunds djurförsöksetiska nämnd); at BioInvent under permit numbers 17196/2018 or 2934/2020; or at Transgene APAFIS Nr21622 project 2019072414343465 and performed in accordance with local ethical guidelines.

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Radiotherapy-Mediated Immunomodulation and Anti-Tumor Abscopal Effect Combining Immune Checkpoint Blockade

Cancers ◽

10.3390/cancers12102762 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2762 ◽

Cited By ~ 1

Author(s):

Xinrui Zhao ◽

Chunlin Shao

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Immune Checkpoint ◽

Tumor Regression ◽

Combined Therapy ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Abscopal Effect ◽

Specific Circumstance

Radiotherapy (RT) is a conventional method for clinical treatment of local tumors, which can induce tumor-specific immune response and cause the shrinkage of primary tumor and distal metastases via mediating tumor infiltration of CD8+ T cells. Ionizing radiation (IR) induced tumor regression outside the radiation field is termed as abscopal effect. However, due to the mobilization of immunosuppressive signals by IR, the activated CD8+T cells are not sufficient to maintain a long-term positive feedback to make the tumors regress completely. Eventually, the “hot” tumors gradually turn to “cold”. With the advent of emerging immunotherapy, the combination of immune checkpoint blockade (ICB) and local RT has produced welcome changes in stubborn metastases, especially anti-PD-1/PD-L1 and anti-CTLA-4 which have been approved in clinical cancer treatment. However, the detailed mechanism of the abscopal effect induced by combined therapy is still unclear. Therefore, how to formulate a therapeutic schedule to maximize the efficacy should be took into consideration according to specific circumstance. This paper reviewed the recent research progresses in immunomodulatory effects of local radiotherapy on the tumor microenvironment, as well as the unique advantage for abscopal effect when combined with ICB, with a view to exploring the potential application value of radioimmunotherapy in clinic.

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Cytotoxic CD8+ T cells in myeloma are in a state of telomere-independent senescence rather than an exhausted or anergic state: Implication for immune checkpoint blockade

Clinical Lymphoma Myeloma & Leukemia ◽

10.1016/j.clml.2015.07.211 ◽

2015 ◽

Vol 15 ◽

pp. e66

Author(s):

H. Suen ◽

D. Joshua ◽

R. Brown ◽

S. Yang ◽

P.J. Ho ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Immune Checkpoint ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade

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Radiation combines with immune checkpoint blockade to enhance T cell priming in a murine model of poorly immunogenic pancreatic cancer

Open Biology ◽

10.1098/rsob.210245 ◽

2021 ◽

Vol 11 (11) ◽

Author(s):

Courtney T. Stump ◽

Kevin Roehle ◽

Nataly Manjarrez Orduno ◽

Stephanie K. Dougan

Keyword(s):

Pancreatic Cancer ◽

T Cells ◽

Cd8 T Cells ◽

Immune Checkpoint ◽

Stereotactic Body Radiation Therapy ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Growth Delay ◽

T Cell Priming ◽

Effects Of Radiation

Radiation has been a pillar of cancer therapy for decades. The effects of radiation on the anti-tumour immune response are variable across studies and have not been explicitly defined in poorly immunogenic tumour types. Here, we employed combination checkpoint blockade immunotherapy with stereotactic body radiation therapy and examined the effect on tumour growth and immune infiltrates in subcutaneous and orthotopic mouse models of pancreatic cancer. Although immune checkpoint blockade and radiation were ineffective alone, their combination produced a modest growth delay in both irradiated and non-irradiated tumours that corresponded with significant increases in CD8+ T cells, CD4+ T cells and tumour-specific T cells as identified by IFNγ ELISpot. We conclude that radiation enhances priming of tumour-specific T cells in poorly immunogenic tumours and that the frequency of these T cells can be further increased by combination with immune checkpoint blockade.

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Combination anti–CTLA-4 plus anti–PD-1 checkpoint blockade utilizes cellular mechanisms partially distinct from monotherapies

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1821218116 ◽

2019 ◽

Vol 116 (45) ◽

pp. 22699-22709 ◽

Cited By ~ 38

Author(s):

Spencer C. Wei ◽

Nana-Ama A. S. Anang ◽

Roshan Sharma ◽

Miles C. Andrews ◽

Alexandre Reuben ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Combination Therapy ◽

Cd8 T Cells ◽

Immune Checkpoint ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Cell Populations ◽

Mass Cytometry ◽

Therapy Targets

Immune checkpoint blockade therapy targets T cell-negative costimulatory molecules such as cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1). Combination anti–CTLA-4 and anti–PD-1 blockade therapy has enhanced efficacy, but it remains unclear through what mechanisms such effects are mediated. A critical question is whether combination therapy targets and modulates the same T cell populations as monotherapies. Using a mass cytometry-based systems approach, we comprehensively profiled the response of T cell populations to monotherapy and combination anti–CTLA-4 plus anti–PD-1 therapy in syngeneic murine tumors and clinical samples. Most effects of monotherapies were additive in the context of combination therapy; however, multiple combination therapy-specific effects were observed. Highly phenotypically exhausted cluster of differentiation 8 (CD8) T cells expand in frequency following anti–PD-1 monotherapy but not combination therapy, while activated terminally differentiated effector CD8 T cells expand only following combination therapy. Combination therapy also led to further increased frequency of T helper type 1 (Th1)-like CD4 effector T cells even though anti–PD-1 monotherapy is not sufficient to do so. Mass cytometry analyses of peripheral blood from melanoma patients treated with immune checkpoint blockade therapies similarly revealed mostly additive effects on the frequencies of T cell subsets along with unique modulation of terminally differentiated effector CD8 T cells by combination ipilimumab plus nivolumab therapy. Together, these findings indicate that dual blockade of CTLA-4 and PD-1 therapy is sufficient to induce unique cellular responses compared with either monotherapy.

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Zika virus oncolytic activity requires CD8+ T cells and is boosted by immune checkpoint blockade

JCI Insight ◽

10.1172/jci.insight.144619 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Sharmila Nair ◽

Luciano Mazzoccoli ◽

Arijita Jash ◽

Jennifer Govero ◽

Sachendra S. Bais ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Immune Checkpoint ◽

Zika Virus ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Oncolytic Activity

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Immune checkpoint blockade impairs immunosuppressive mechanisms of regulatory T cells in B-cell lymphoma

Translational Oncology ◽

10.1016/j.tranon.2021.101170 ◽

2021 ◽

Vol 14 (9) ◽

pp. 101170

Author(s):

Vera Bauer ◽

Fatima Ahmetlić ◽

Nadine Hömberg ◽

Albert Geishauser ◽

Martin Röcken ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

B Cell ◽

Immune Checkpoint ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade

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

Neuro-Oncology ◽

10.1093/neuonc/noaa215.449 ◽

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.

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