Dive into desmoplasia, the dense "shield" surrounding tumors, with the Cukierman Lab. Their 3D model unveils the hidden "symphony" of fibroblasts and fibroblastic cell-generated ECM, revealing how these units influence cancer, immune, and other cells. Their key? The Harmonic Output of Stromal Traits, or HOST-Factor, a tool to understand the stromal "score" and rewrite it for treatment. Witness the Cukierman Lab's quest to reorchestrate pancreatic cancer onset and progression!

There is a significant need for therapeutics that drive immune cells into tumors. For drug discovery, this requires high-throughput models of the tumor microenvironment (TME) that recapitulate physiologically-relevant barriers to immune infiltration. Here, we attempt to induce formation of an immune-excluded TME by co-culturing relevant cell types in 3D culture. A high-throughput, human TME model would enable drug screening and identification of new targets broadly applicable to solid tumors.

The VISTA-101 clinical trial is a first-in-human, Phase 1/2 open-label, safety, PK, and pharmacodynamic evaluation of KVA12123, both as monotherapy and in combination with pembrolizumab, in adult patients with advanced solid tumors. KVA12123 is a human IgG1 monoclonal antibody that specifically binds to VISTA at neutral and acidic pHs. It was designed to improve pharmacokinetic characteristics as well as reduce the risk of cytokine release syndrome.

Translational research efforts to define the tumor microenvironment and uncover biomarkers in clinical trials samples depends on variables such as trial design, tissue sampling plan, and available technologies. Considerations and examples of these variables will be discussed.

• What are the major drivers of immunosuppression in the tumor microenvironment?
• What are the strategies to overcome immunosuppression?
• What are the promising new targets?
• Which combination strategies should be considered to restore an effective antitumor immune response?​

• What aspects of the TME require ex vivo modeling?
• What are the challenges in modeling tumor immune responses?
• What are the unique advantages of ex vivo TME models?
• How do we advance ex vivo TME models for drug discovery and mechanistic studies?
  

The “hypoxic gradient” is a critical aspect of the colorectal cancer (CRC) microenvironment and has long been hypothesized to guide cancer growth and invasion but has yet to be studied ex vivo. Here we introduce a system capable of manipulating and profiling oxygen gradients across 3D cultures. This system achieves a hypoxic region of < 5µM and a steep gradient exceeding 20 µM/mm. Utilizing this technology, we are pursuing two main avenues: 1) Investigating the role of the oxygen gradient in guiding cancer growth and invasion using patient-derived CRC organoids, and 2) Establishing a stable anaerobe-epithelium coculture ex vivo to understand the interaction between bacterial growth dynamics and CRC progression.

We have developed a novel therapeutic platform for durably retaining immunostimulatory agents within tumors through complexation with aluminum hydroxide; this retention leads to improved efficacy and safety. Following local delivery of an IL-12 based therapy, known as ANK-101, potent anti-tumor activity is observed with abscopal effects; these effects are associated with profound reprogramming of the tumor microenvironment, leading to activation of both innate and adaptive immunity.

Deka Biosciences has developed a tumor microenvironment–targeted therapeutic platform that combines highly potent but toxic cytokines with IL-10 to concentrate the cytokines in the TME to improve potency and reduce toxicity. The lead asset that combines IL-2, IL-10 with EGFR targeting (termed DK210 (EGFR)) has been dosed in 28 patients and illustrates toxicological proof of concept, achieving high exposures with no vascular/capillary leak nor cytokine release syndromes.

Blockade of the PD-1 immune checkpoint has revolutionized therapy of immune-infiltrated “hot” tumors, but lacks efficacy in “cold” tumors in which T cells are largely excluded. We developed a dual-specific PD-L1/PD-L2 that provides the equivalent of combined PD-1 and PD-L1 antibody blockade in a single drug. By engineering this antibody to also mediate killing of PD-L1 and PD-L2+ target cells, we found that it could efficiently deplete immune suppressive and T cell exclusionary stroma thereby promoting curative immunity against “cold” cancers entire refractory to traditional PD-1 blockade.

Despite its promising potential, CAR T cell therapy faces challenges due to the tumor microenvironment (TME), which harbors immunosuppressive factors and physical barriers that hinder CAR T cell efficacy. To overcome this resistance, strategies are being developed to enhance CAR T cell fitness, engineer them to resist the TME, and target multiple tumor antigens. By addressing these challenges, CAR T cell therapy holds the promise of achieving more durable responses and better patient outcomes.

Tumor interferon gamma (IFNg) transcriptional signatures are associated with the efficacy of cancer immunotherapy. Yet, our knowledge as it pertains to cancer cell-intrinsic plasticity in response to IFNg in the context of tumor genetic and transcriptional heterogeneity can be summarized as little to none. We leverage >70 patient-derived organoid models and paired primary tumors across different cancers to identify tumor-intrinsic molecular signatures of IFNg sensitivity.