Immuno-pharmacodynamics for evaluating mechanism of action and developing immunotherapy combinations

Co-stimulatory signals induced by ligands of the tumor necrosis factor superfamily (TNFSF) play a central role in T cell activation and have emerged as a promising strategy in cancer immunotherapy. Here, we established a novel class of bifunctional co-stimulatory fusion proteins with the aim to boost T cell activation at the level of T cell – antigen-presenting cell (APC) interaction. These novel dual-acting cytokine fusion proteins were created by connecting two different homotrimeric TNFSF ligands to form homotrimeric bifunctional molecules (Duokines) or by connecting single-chain derivatives of two different homotrimeric TNFSF with a single, flexible linker (single-chain Duokines, scDuokines). By linking the TNFSF ligands 4-1BBL, OX40L and CD27L in all possible combinations, cis-acting Duokines were generated that act on the same or adjacent T cells, while combining CD40L with 4-1BBL, OX40L and CD27L resulted in trans-acting Duokines acting simultaneously on APCs and T cells. In vitro, co-stimulation of T cells was seen for cis- and trans-acting Duokines and scDuokines in an antigen-independent as well as antigen-specific setting. Trans-acting molecules furthermore activated B cells, which represent a subclass of APCs. In a pilot experiment using the syngeneic B16-FAP mouse tumor model scDuokines displayed antitumoral activity in vivo in combination with a primary T cell-activating bispecific antibody, evident from reduced number of lung metastasis compared to the antibody-only treated group. Our data show that the bifunctional, co-stimulatory duokines are capable to enhance T cell-mediated anti-tumor immune responses, suggesting that they can serve as a new class of immuno-stimulatory molecules for use in cancer immunotherapy strategies.

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“…These studies should also resolve duokine pharmacokinetic profiles and the immuno-pharmacodynamic effects on different immune cell subsets. 27 …”

Section: Discussionmentioning

confidence: 99%

Duokines: a novel class of dual-acting co-stimulatory molecules acting in cis or trans

et al. 2018

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“…Cancer vaccines are highlighted in the era of cancer immunotherapy as they can induce immune responses in “cold” tumors that do not appear immunogenic on their own, potentially converting them to “hot” tumors amenable to checkpoint blockade therapy. Hot tumors are defined as ones in which the tumor itself has induced an immune response of infiltrating T cells that are not able to function because of various checkpoints such as PD-1, CTLA-4, LAG3, TIM3, TIGIT, or other immunoregulatory mechanisms involving regulatory cells (regulatory T cells, myeloid-derived suppressor cells (MDSCs), M2 macrophages, regulatory natural killer (NK) T cells, and so on) or regulatory cytokines (transforming growth factor-beta [TGFβ]), interleukin-10 (IL-10), and IL-13) 2, 3 . A cold tumor is one that is not sufficiently immunogenic to induce such infiltrating T cells on its own, or has excluded these cells.…”

Section: Introductionmentioning

confidence: 99%

Strategies for developing and optimizing cancer vaccines

Maeng

Berzofsky

2019

F1000Res

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With the spotlight on cancer immunotherapy and the expanding use of immune checkpoint inhibitors, strategies to improve the response rate and duration of current cancer immunotherapeutics are highly sought. In that sense, investigators around the globe have been putting spurs on the development of effective cancer vaccines in humans after decades of efforts that led to limited clinical success. In more than three decades of research in pursuit of targeted and personalized immunotherapy, several platforms have been incorporated into the list of cancer vaccines from live viral or bacterial agents harboring antigens to synthetic peptides with the hope of stronger and durable immune responses that will tackle cancers better. Unlike adoptive cell therapy, cancer vaccines can take advantage of using a patient’s entire immune system that can include more than engineered receptors or ligands in developing antigen-specific responses. Advances in molecular technology also secured the use of genetically modified genes or proteins of interest to enhance the chance of stronger immune responses. The formulation of vaccines to increase chances of immune recognition such as nanoparticles for peptide delivery is another area of great interest. Studies indicate that cancer vaccines alone may elicit tumor-specific cellular or humoral responses in immunologic assays and even regression or shrinkage of the cancer in select trials, but novel strategies, especially in combination with other cancer therapies, are under study and are likely to be critical to achieve and optimize reliable objective responses and survival benefit. In this review, cancer vaccine platforms with different approaches to deliver tumor antigens and boost immunity are discussed with the intention of summarizing what we know and what we need to improve in the clinical trial setting.

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“…Recent studies indicate that various tumorigenic signaling pathways are involved in ESCC, such as tumor growth, cell cycle, angiogenesis, invasion and apoptosis [ 7 – 9 ], so targeting these signaling pathways may be strategies for treating ESCC. Target therapy also showed exciting effect when combined with immunotherapy [ 10 – 12 ]. However, there is no specific agent for targeted therapy in ESCC.…”

Section: Introductionmentioning

confidence: 99%

Establishment and genomic characterizations of patient-derived esophageal squamous cell carcinoma xenograft models using biopsies for treatment optimization

et al. 2018

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BackgroundSquamous cell carcinoma is the dominant type of esophageal cancer in China with many patients initially diagnosed at advanced stage. Patient-derived xenografts (PDX) models have been developed to be an important platform for preclinical research. This study aims to establish and characterize PDX models using biopsy tissue from advanced esophageal cancer patients to lay the foundation of preclinical application.MethodsFresh endoscopic biopsy tissues were harvested from patients with advanced esophageal cancer and implanted subcutaneously into NOD/SCID mice. Then, the PDXs were serially passaged for up to four generations. Transplantation was analyzed and genomic characteristics of xenografts were profiled using next-generation sequencing.ResultsTwenty-five PDX models were established (13.3%, 25/188). The latency period was 75.12 ± 19.87 days (50–120 days) for the first passage and it decreased with increasing passaging. Other than tumor stages, no differences were found between transplantations of xenografts and patient characteristics, irrespective of chemotherapy. Histopathological features and chemosensitivity of PDXs were in great accordance with primary patient tumors. Each PDX was assessed for molecular characteristics including copy number variations, somatic mutations, and signaling pathway abnormalities and these were similar to patient results.ConclusionsOur PDX models were established from real time biopsies and molecularly profiled. They might be promising for drug development and individualized therapy.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1379-9) contains supplementary material, which is available to authorized users.

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Immuno-pharmacodynamics for evaluating mechanism of action and developing immunotherapy combinations

Cited by 9 publications

References 98 publications

Duokines: a novel class of dual-acting co-stimulatory molecules acting in cis or trans

Duokines: a novel class of dual-acting co-stimulatory molecules acting in cis or trans

Strategies for developing and optimizing cancer vaccines

Establishment and genomic characterizations of patient-derived esophageal squamous cell carcinoma xenograft models using biopsies for treatment optimization

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