Treatment with a VEGFR-2 antibody results in intra-tumor immune modulation and enhances anti-tumor efficacy of PD-L1 blockade in syngeneic murine tumor models.

Prolonged activation of vascular endothelial growth factor receptor-2 (VEGFR-2) due to mis-regulation of the VEGF pathway induces aberrant blood vessel expansion, which supports growth and survival of solid tumors. Therapeutic interventions that inhibit the VEGFR-2 pathway have therefore become a mainstay of cancer treatment. Non-clinical studies have recently revealed that blockade of angiogenesis can modulate the tumor microenvironment and enhance the efficacy of concurrent immune therapies.

The Folate Pathway Inhibitor Pemetrexed Pleiotropically Enhances Effects of Cancer Immunotherapy.

Purpose: Combination strategies leveraging chemotherapeutic agents and immunotherapy have held the promise as a method to improve benefit for patients with cancer. However, most chemotherapies have detrimental effects on immune homeostasis and differ in their ability to induce immunogenic cell death (ICD). The approval of pemetrexed and carboplatin with anti-PD-1 (pembrolizumab) for treatment of non-small cell lung cancer represents the first approved chemotherapy and immunotherapy combination.

FcγRIIIa-dependent IFN-γ release in whole blood assay is predictive of therapeutic IgG1 antibodies safety.

Immunomodulatory monoclonal IgG1 antibodies developed for cancer and autoimmune disease have an inherent risk of systemic release of pro-inflammatory cytokines. In vitro cytokine release assays are currently used to predict cytokine release syndrome (CRS) risk, but the validation of these preclinical tools suffers from the limited number of characterized CRS-inducing IgG1 antibodies and the poor understanding of the mechanisms regulating cytokine release. Here, we incubated human whole blood from naïve healthy volunteers with four monoclonal IgG1 antibodies with different proven or predicted capacity to elicit CRS in clinic and measured cytokine release using a multiplex assay.

Targeting the TGFβ pathway with galunisertib, a TGFβRI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as monotherapy and in combination with checkpoint blockade.

Background: TGFβ signaling plays a pleotropic role in tumor biology, promoting tumor proliferation, invasion and metastasis, and escape from immune surveillance. Inhibiting TGFβ's immune suppressive effects has become of particular interest as a way to increase the benefit of cancer immunotherapy. Here we utilized preclinical models to explore the impact of the clinical stage TGFβ pathway inhibitor, galunisertib, on anti-tumor immunity at clinically relevant doses.

The CDK4/6 Inhibitor Abemaciclib Induces a T Cell Inflamed Tumor Microenvironment and Enhances the Efficacy of PD-L1 Checkpoint Blockade.

Abemaciclib, an inhibitor of cyclin dependent kinases 4 and 6 (CDK4/6), has recently been approved for the treatment of hormone receptor-positive breast cancer. In this study, we use murine syngeneic tumor models and in vitro assays to investigate the impact of abemaciclib on T cells, the tumor immune microenvironment and the ability to combine with anti-PD-L1 blockade. Abemaciclib monotherapy resulted in tumor growth delay that was associated with an increased T cell inflammatory signature in tumors.

Blockade of surface-bound TGF-β on regulatory T cells abrogates suppression of effector T cell function in the tumor microenvironment.

Regulatory T cells (T) suppress antitumor immunity by inhibiting the killing of tumor cells by antigen-specific CD8 T cells. To better understand the mechanisms involved, we used ex vivo three-dimensional collagen-fibrin gel cultures of dissociated B16 melanoma tumors. This system recapitulated the in vivo suppression of antimelanoma immunity, rendering the dissociated tumor cells resistant to killing by cocultured activated, antigen-specific T cells.

Targeting tumor-necrosis factor receptor pathways for tumor immunotherapy.

With the success of ipilimumab and promise of programmed death-1 pathway-targeted agents, the field of tumor immunotherapy is expanding rapidly. Newer targets for clinical development include select members of the tumor necrosis factor receptor (TNFR) family. Agonist antibodies to these co-stimulatory molecules target both T and B cells, modulating T-cell activation and enhancing immune responses.

GITR pathway activation abrogates tumor immune suppression through loss of regulatory T cell lineage stability.

Ligation of GITR (glucocorticoid-induced tumor necrosis factor (TNF) receptor-related gene, or TNFRSF18) by agonist antibody has recently entered into early phase clinical trials for the treatment of advanced malignancies. Although the ability of GITR modulation to induce tumor regression is well-documented in preclinical studies, the underlying mechanisms of action, particularly its effects on CD4(+)foxp3(+) regulatory T cells (Treg), have not been fully elucidated. We have previously demonstrated that GITR ligation in vivo by agonist antibody DTA-1 causes a >50% reduction of intra-tumor Treg with down modulation of Foxp3 expression.

Biomarkers for immunostimulatory monoclonal antibodies in combination strategies for melanoma and other tumor types.

Modulation of the immune system by targeting coinhibitory and costimulatory receptors has become a promising new approach of immunotherapy for cancer. The recent approval of the CTLA-4-blocking antibody ipilimumab for the treatment of melanoma was a watershed event, opening up a new era in the field of immunotherapy. Ipilimumab was the first treatment to ever show enhanced overall survival (OS) for patients with stage IV melanoma.

Modulation of GITR for cancer immunotherapy.

Modulation of co-inhibitory and co-stimulatory receptors of the immune system has become a promising new approach for immunotherapy of cancer. With the recent FDA approval of CTLA-4 blockade serving as an important proof of principal, many new targets are now being translated into the clinic. Preclinical research has demonstrated that targeting glucocorticoid-induced tumor necrosis factor (TNF) receptor related gene (GITR), a member of TNF receptor superfamily, by agonist antibodies or natural ligand, can serve as an effective anti-tumor therapy.

Hiding the road signs that lead to tumor immunity.

Tumors exploit many strategies to evade T cell-mediated destruction. For example, tumors can prevent T cell infiltration by modifying gene expression in the endothelial cells and pericytes that form their vasculature. New work showing that the T cell-attracting chemokine CCL2 can be posttranslationally modified in the tumor microenvironment adds another mechanism to the already formidable arsenal of immunoevasion tactics used by solid tumors.

Detection of intra-tumor self antigen recognition during melanoma tumor progression in mice using advanced multimode confocal/two photon microscope.

Determining how tumor immunity is regulated requires understanding the extent to which the anti-tumor immune response "functions" in vivo without therapeutic intervention. To better understand this question, we developed advanced multimodal reflectance confocal/two photon fluorescence intra-vital imaging techniques to use in combination with traditional ex vivo analysis of tumor specific T cells. By transferring small numbers of melanoma-specific CD8+ T cells (Pmel-1), in an attempt to mimic physiologic conditions, we found that B16 tumor growth alone was sufficient to induce naive Pmel-1 T cell proliferation and acquisition of effector phenotype.

Anti-GITR antibodies--potential clinical applications for tumor immunotherapy.

Since the development of the first vaccines, modern medicine has been consistently aiming to improve the efficacy of immune responses. Traditionally, adjuvants have been used as non-specific immune modulators to enhance recognition and activation against a desired antigen. By providing 'danger' signals to the immune system, adjuvants activate innate immunity, which enhances the development of protective and therapeutic adaptive immune responses.

Agonist anti-GITR monoclonal antibody induces melanoma tumor immunity in mice by altering regulatory T cell stability and intra-tumor accumulation.

In vivo GITR ligation has previously been shown to augment T-cell-mediated anti-tumor immunity, yet the underlying mechanisms of this activity, particularly its in vivo effects on CD4+ foxp3+ regulatory T cells (Tregs), have not been fully elucidated. In order to translate this immunotherapeutic approach to the clinic it is important gain better understanding of its mechanism(s) of action. Utilizing the agonist anti-GITR monoclonal antibody DTA-1, we found that in vivo GITR ligation modulates regulatory T cells (Tregs) directly during induction of melanoma tumor immunity.