Genetic Engineering & Biotechnology News

JUL 2018

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14 | JULY 2018 | Genetic Engineering & Biotechnology News | tumorigenesis, which is essentially a campaign to transform the body's internal ecosystems so that they may serve destructive rather than life-sustaining processes. The conference highlighted ecosystem restoration options such as: • Neutralizing semaphorin 4D, a transmembrane protein, to block its TME-sustaining functions, which include the restriction of immune-cell infiltration and activity at tumor margins. • Targeting the ubiquitin-proteasome pathway to deplete immunosuppressive regulatory T cells. • Using TME gene signatures to optimize therapies that incorporate chimeric antigen receptor–engineered T cells. • Developing agents to reoxygenate typically hypoxic malignant tissues. Shifting the Immune Balance One of cancer's nefarious strategies is to manipulate host defenses to mask a tumor's presence or to enhance immune suppression. To counter this strategy, scientists at Vaccinex are targeting semaphorin 4D (SEMA4D), a large cell surface antigen found on the resting T cell and overexpressed in a variety of tumor cell types. SEMA4D has been implicated in vascular growth, tumor progression, invasion, and immune cell regulation. "SEMA4D is highly expressed at tumor margins, where it promotes immune suppression in the TME by restricting im- mune cell infiltration and immunoactivity," noted Elizabeth Evans, Ph.D., one of the speakers at the conference and a vice president of preclinical research at Vaccinex. Dr. Evans offered this observation in a discussion devoted to target vali- dation and prioritization. SEMA4D regulates the migration and differentiation of cells, especially immune cells expressing its major receptors, plexin-B1 and plexin-B2. Company scientists found that an- tibody blockade of SEMA4D restores the ability of dendritic cells and cytotoxic T cells to migrate into the tumor, while simultaneously reducing the function of multiple immuno- suppressive cell lineages in the TME. "These coordinated changes in the tumoral immune context are associated with durable tumor rejection and im- munologic memory in several murine carcinoma models," asserted Dr. Evans. "Importantly, anti-SEMA4D treatment enhances the activity of co-administered immunotherapies, including immune checkpoint inhibitors, chemotherapy, and epigenetic modulating agents." These preclinical findings encouraged Vaccinex to initi- ate a clinical trial to evaluate the company's pepinemab (VX15/2503), a humanized immunoglobulin G4 monoclo- nal antibody against SEME4D, in combination with Ave- lumab, an inhibitor of the immune checkpoint PD-L1, in non-small cell lung carcinoma (NCT03268057). This trial is being carried out in collaboration with Merck (Darmstadt), one of Avelumab's developers. Vaccinex' preclinical collaborators included Antoni Ri- bas, M.D., Ph.D., and Siwen Hu-Lieskovan, M.D., Ph.D., researchers affiliated with the Jonsson Comprehensive Cancer Center. This research center is currently sponsoring a trial to evaluate pepinemab in patients with anti-PD-1/ PD-L1 refractory melanoma (NCT03425461). In addition, a neoadjuvant trial is recruiting pancreatic and colorec- tal cancer patients to evaluate clinical and pathological responses to pepinemab in combination with PD-1- and/ or CTLA-4-directed therapies (NCT03373188). Finally, a Phase I/II trial of pepinemab is recruiting pediatric patients with recurrent or refractory solid tumors, including osteo- sarcoma (NCT03320330). According to Dr. Evans, pepinemab synergizes with other immunomodulatory agents to enhance antitumor responses. "Inhibition of SEMA4D," she explained, "represents a novel OMICS Tumors characteristically develop hypoxia, which drives immunosuppression and malignant invasion. Omniox is developing therapeutic compounds to oxygenate malignant tissue to restore the body's anticancer defenses. Reclaim the Tumor Microenvironment via "Immunoforming" Continued from page 1 Cross-talk between a nascent tumor and infiltrating immune cells contributes to the creation of an immunosuppressive microenvironment that helps cancerous cells avoid host defenses. This deleteri- ous cross-talk can be modified, however, to hinder tumorigenesis. The benefit of intervening in deleterious cross-talk is underscored by the success of check- point immunotherapies and the con- tinuing rise of immuno-oncology, notes Paul Volden, Ph.D., field application sci- entist, Taconic Biosciences. To improve translation of novel immuno-oncology therapies, Taconic focuses on models that enable repro- duction of the human tumor microenvi- ronment (TME) in a murine system. For example, Taconic's super-immunode- ficient CIEA NOG mouse® may serve as a foundation for next-generation NOG models. According to Dr. Volden, such models may express human cytokines to support dual engraftment of the most challenging patient-derived can- cers and human immune cells. With the help of the new cytokine- transgenic models, therapies targeting immunosuppressive tumor-associated macrophages can now be studied with- in a human tumor microenvironment (Ito et al. 2013. J. Immunol. 191(6): 2890–9). Human-specific antibody therapeutics that target natural killer cells can now be investigated in vivo, facilitated by NOG mice expressing human IL-15 (Hanazawa et al. 2018. Front. Immunol. 9: 152.) And as a first in any rodent model, patient responses to a microenvironment-derived immuno- therapy have been reproduced using NOG mice expressing human IL-2 cytokine (Jespersen et al. 2017. Nat. Commun. 8(1): 707). These examples illustrate Taconic's approach to enabling TME research through next-generation humanized models. Models that reproduce the human TME can help researchers translate therapies that intervene in pathologic microenvironment interactions. n Taconic Biosciences, a leader in genetically engineered rodent models and services, enables customers to acquire, custom generate, breed, precondition, test, and distribute valuable research models worldwide. Website: Modeling the Human Tumor Microenvironment

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