Bryan Irving

The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells

Here we have identified a surface protein, TIGIT, containing an immunoglobulin variable domain, a transmembrane domain and an immunoreceptor tyrosine-based inhibitory motif that was expressed on regulatory, memory and activated T cells. Poliovirus receptor, which is expressed on dendritic cells, bound TIGIT with high affinity. A TIGIT-Fc fusion protein inhibited T cell activation in vitro, and this was dependent on the presence of dendritic cells. The binding of poliovirus receptor to TIGIT on human dendritic cells enhanced the production of interleukin 10 and diminished the production of interleukin 12p40. Knockdown of TIGIT with small interfering RNA in human memory T cells did not affect T cell responses. TIGIT-Fc inhibited delayed-type hypersensitivity reactions in wild-type but not interleukin 10–deficient mice. Our data suggest that TIGIT exerts immunosuppressive effects by binding to poliovirus receptor and modulating cytokine production by dendritic cells.

Molecular Pathways: Next Generation Immunotherapy: Inhibiting Programmed Death-Ligand 1 and Programmed Death-1

The aim of T-cell–based immune therapy for cancer has been to generate durable clinical benefit for patients. Following a generation of therapies that largely showed minimal activity, substantial toxicity, and no biomarkers to identify which patients benefit from treatment, early studies are showing signs that programmed death-ligand 1 (PD-L1) and programmed death-1 (PD-1) inhibitors are highly active. Preclinical and early data from clinical studies suggest that targeting this pathway can induce durable clinical responses in patients in a variety of tumor types, including lung and colon cancer. Furthermore, correlations with tumor PD-L1 expression may enable selection of patients most likely to benefit from treatment. The emerging data not only offer the hope of better cancer therapy but also provide evidence that changes our understanding of how the host immune system interacts with human cancer. Clin Cancer Res; 18(24); 6580–7. ©2012 AACR.

MAP Kinase Inhibition Promotes T Cell and Anti-tumor Activity in Combination with PD-L1 Checkpoint Blockade

Targeted inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) can induce regression of tumors bearing activating mutations in the Ras pathway but rarely leads to tumor eradication. Although combining MEK inhibition with T-cell-directed immunotherapy might lead to more durable efficacy, T cell responses are themselves at least partially dependent on MEK activity. We show here that MEK inhibition did profoundly block naive CD8(+) T cell priming in tumor-bearing mice, but actually increased the number of effector-phenotype antigen-specific CD8(+) T cells within the tumor. MEK inhibition protected tumor-infiltrating CD8(+) T cells from death driven by chronic TCR stimulation while sparing cytotoxic activity. Combining MEK inhibition with anti-programmed death-ligand 1 (PD-L1) resulted in synergistic and durable tumor regression even where either agent alone was only modestly effective. Thus, despite the central importance of the MAP kinase pathway in some aspects of T cell function, MEK-targeted agents can be compatible with T-cell-dependent immunotherapy.

B cells regulate macrophage phenotype and response to chemotherapy in squamous carcinomas.

B cells foster squamous cell carcinoma (SCC) development through deposition of immunoglobulin-containing immune complexes in premalignant tissue and Fcγ receptor-dependent activation of myeloid cells. Because human SCCs of the vulva and head and neck exhibited hallmarks of B cell infiltration, we examined B cell-deficient mice and found reduced support for SCC growth. Although ineffective as a single agent, treatment of mice bearing preexisting SCCs with B cell-depleting αCD20 monoclonal antibodies improved response to platinum- and Taxol-based chemotherapy. Improved chemoresponsiveness was dependent on altered chemokine expression by macrophages that promoted tumor infiltration of activated CD8(+) lymphocytes via CCR5-dependent mechanisms. These data reveal that B cells, and the downstream myeloid-based pathways they regulate, represent tractable targets for anticancer therapy in select tumors.

Bruton Tyrosine Kinase–Dependent Immune Cell Cross-talk Drives Pancreas Cancer

UNLABELLED Pancreas ductal adenocarcinoma (PDAC) has one of the worst 5-year survival rates of all solid tumors, and thus new treatment strategies are urgently needed. Here, we report that targeting Bruton tyrosine kinase (BTK), a key B-cell and macrophage kinase, restores T cell-dependent antitumor immune responses, thereby inhibiting PDAC growth and improving responsiveness to standard-of-care chemotherapy. We report that PDAC tumor growth depends on cross-talk between B cells and FcRγ(+) tumor-associated macrophages, resulting in T(H)2-type macrophage programming via BTK activation in a PI3Kγ-dependent manner. Treatment of PDAC-bearing mice with the BTK inhibitor PCI32765 (ibrutinib) or by PI3Kγ inhibition reprogrammed macrophages toward a T(H)1 phenotype that fostered CD8(+) T-cell cytotoxicity, and suppressed PDAC growth, indicating that BTK signaling mediates PDAC immunosuppression. These data indicate that pharmacologic inhibition of BTK in PDAC can reactivate adaptive immune responses, presenting a new therapeutic modality for this devastating tumor type. SIGNIFICANCE We report that BTK regulates B-cell and macrophage-mediated T-cell suppression in pancreas adenocarcinomas. Inhibition of BTK with the FDA-approved inhibitor ibrutinib restores T cell-dependent antitumor immune responses to inhibit PDAC growth and improves responsiveness to chemotherapy, presenting a new therapeutic modality for pancreas cancer.

Antitumor Efficacy of a Bispecific Antibody That Targets HER2 and Activates T Cells

Clinical results from the latest strategies for T-cell activation in cancer have fired interest in combination immunotherapies that can fully engage T-cell immunity. In this study, we describe a trastuzumab-based bispecific antibody, HER2-TDB, which targets HER2 and conditionally activates T cells. HER2-TDB specifically killed HER2-expressing cancer cells at low picomolar concentrations. Because of its unique mechanism of action, which is independent of HER2 signaling or chemotherapeutic sensitivity, HER2-TDB eliminated cells refractory to currently approved HER2 therapies. HER2-TDB exhibited potent antitumor activity in four preclinical model systems, including MMTV-huHER2 and huCD3 transgenic mice. PD-L1 expression in tumors limited HER2-TDB activity, but this resistance could be reversed by anti-PD-L1 treatment. Thus, combining HER2-TDB with anti-PD-L1 yielded a combination immunotherapy that enhanced tumor growth inhibition, increasing the rates and durability of therapeutic response.

Tumour and host cell PD-L1 is required to mediate suppression of anti-tumour immunity in mice

Expression of PD-L1, the ligand for T-cell inhibitory receptor PD-1, is one key immunosuppressive mechanism by which cancer avoids eradication by the immune system. Therapeutic use of blocking antibodies to PD-L1 or its receptor PD-1 has produced unparalleled, durable clinical responses, with highest likelihood of response seen in patients whose tumour or immune cells express PD-L1 before therapy. The significance of PD-L1 expression in each cell type has emerged as a central and controversial unknown in the clinical development of immunotherapeutics. Using genetic deletion in preclinical mouse models, here we show that PD-L1 from disparate cellular sources, including tumour cells, myeloid or other immune cells can similarly modulate the degree of cytotoxic T-cell function and activity in the tumour microenvironment. PD-L1 expression in both the host and tumour compartment contribute to immune suppression in a non-redundant fashion, suggesting that both sources could be predictive of sensitivity to therapeutic agents targeting the PD-L1/PD-1 axis.

MTRX1011A, a humanized anti-CD4 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: a Phase I randomized, double-blind, placebo-controlled study incorporating pharmacodynamic biomarker assessments

IntroductionThe purpose of this study was to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of the humanized anti-CD4 monoclonal antibody MTRX1011A in a randomized, double-blind placebo-controlled Phase 1 study in patients with rheumatoid arthritis (RA).MethodsIn the single ascending dose (SAD) portion of the study, patients received single doses of a placebo or MTRX1011A at 0.3, 1.0, 3.5 and 7.0 mg/kg intravenously (IV) or 1.0 and 3.5 mg/kg subcutaneously (SC), followed by five weeks of evaluation. In the multi-dose (MD) portion of the study, placebo or MTRX1011A was administered weekly for eight doses at 1.5 or 3.5 mg/kg SC, or 5 mg/kg IV, followed by eight weeks of evaluation.ResultsMTRX1011A was well tolerated in the SAD phase up to 7 mg/kg IV and in the MD phase up to 1.5 mg/kg SC. At weekly doses of 3.5 mg/kg SC and 5 mg/kg IV, a moderate pruritic papular rash was observed in some MTRX1011A-treated patients, which was considered a dose-limiting toxicity for this clinical indication. No serious adverse events occurred in any cohort. Reduction in disease activity was modest. PD assessments demonstrated that MTRX1011A induced a dose-dependent down-modulation of CD4 expression on peripheral blood CD4 T cells, CD4 receptor occupancy, increases in serum sCD4-MTRX1011A complexes and up-regulation of CD69 on T cells, but was non-depleting.ConclusionsThe maximum tolerated dose of MTRX1011A was 1.5 mg/kg SC administered weekly. At this dose MTRX1011A did not achieve maximum PD activity expected to be required for reduction in disease activity.

Abstract 2941: Local tumor irradiation combined with α-PDL-1 immune checkpoint inhibition results in local and systemic anti-tumor responses: Successful translation of a mouse model to a human case series

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Introduction: Tumor irradiation induces innate and adaptive immune responses which, rarely, lead to tumor regression at distant sites, the abscopal effect. We have previously demonstrated that immunotherapy including Toll-like-receptor agonists (CpG) and checkpoint inhibitors (anti-CTLA4) both preclinically and clinically ([NCT00185965][1] & [NCT01769222][2]) can significantly increase the rate of systemic, abscopal responses (Kim, Blood 2012 & Brody, JCO 2010). Here we provide the first report of a preclinical murine model and patient case series following local radiation and systemic anti-PD-L1 ([NCT01375842][3]). Methods: Preclinical modeling was performed in a two-tumor, syngenic, A20, lymphoma BALB/c model combining fractionated single tumor radiation and systemic (i.p.) anti-PD-L1. Patients receiving MPDL3280A, a human mAb containing an engineered Fc-domain, as part of the phase 1 clinical trial with mixed responses or asymptomatic progression of disease were eligible for the addition of local radiation therapy. Murine and human immune responses including cell phenotype and function, specifically assessing expression of PD-L1 and production of IFNγ were determined by standard flow cytometry and time of flight mass cytometry (CyTOF). Results: Fractionated radiation delayed tumor growth at the treated site only, and systemic anti-PD-L1 reduced tumor growth rate at both sites, however despite prolonged survival all mice died by day 38 following either monotherapy (radiation or anti-PD-L1). In contrast, combination local fractionated radiation and systemic anti-PD-L1 flattened tumor growth at both the irradiated and un-irradiated site, and prolonged survival with 50% survival at day 48 post-tumor inoculation. Modulation of PD-L1 expression post-radiation and tumor-specific augmentation of IFNγ secretion correlated with the enhanced anti-tumor activity. Five patients including four with solid tumors received fractionated, non-definitive dose radiation with at least stabilization of systemic progression in all patients and a RECIST partial response at systemic sites in 1 patient, notably with a synovial sarcoma. Transient, grade 1-2 inflammatory adverse events (fevers, flu-like symptoms) occurred with no DLTs or serious immune-related toxicities. Modulation of PD-L1 expression, T cell phenotype and IFNγ secretion was observed and updated clinical and immune response will be presented. Conclusion: We provide the first report of combination local radiotherapy with anti-PD-L1 demonstrating synergy in a preclinical model and clinical activity in a limited case series. The magnitude of the immune response and abscopal response rate in mice and humans provides proof-of-concept that anti-PD-L1 may be an equally if not more potent combination immunotherapy with radiation compared to our experience with CpG and/or anti-CTLA4. Citation Format: Idit Sagiv-Barfi, Amanda Rajapaksa, Debra Czerwinski, Serena Chang, Jonathan Hebb, Cariad Chester, Erin Waller, Gregg Fine, Daniel Chen, Marcin Kowanetz, Bryan Irving, Ronald Levy, Holbrook Kohrt. Local tumor irradiation combined with α-PDL-1 immune checkpoint inhibition results in local and systemic anti-tumor responses: Successful translation of a mouse model to a human case series. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2941. doi:10.1158/1538-7445.AM2014-2941 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00185965&atom=%2Fcanres%2F74%2F19_Supplement%2F2941.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01769222&atom=%2Fcanres%2F74%2F19_Supplement%2F2941.atom [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01375842&atom=%2Fcanres%2F74%2F19_Supplement%2F2941.atom

New Cancer Immunotherapy Agents in Development: a report from an associated program of the 31stAnnual Meeting of the Society for Immunotherapy of Cancer, 2016

This report is a summary of ‘New Cancer Immunotherapy Agents in Development’ program, which took place in association with the 31st Annual Meeting of the Society for Immunotherapy of Cancer (SITC), on November 9, 2016 in National Harbor, Maryland. Presenters gave brief overviews of emerging clinical and pre-clinical immune-based agents and combinations, before participating in an extended panel discussion with multidisciplinary leaders, including members of the FDA, leading academic institutions and industrial drug developers, to consider topics relevant to the future of cancer immunotherapy.