Safety, PK/PD, and anti-tumor activity of RO6874281, an engineered variant of interleukin-2 (IL-2v) targeted to tumor-associated fibroblasts via binding to fibroblast activation protein (FAP).

Soerensen, Morten Mau; Ros, Willeke; Rodríguez-Ruiz, María E.; Robbrecht, Debbie G.J.; Rohrberg, Kristoffer Staal; Martín-Liberal, Juan; Lassen, Ulrik; Melero, Ignacio; Lolkema, Martijn P.; Tabernero, Josep; Boetsch, Christophe; Piper-Lepoutre, Hanna; Waldhauer, Inja; Charo, Jehad; Evers, Stefan; Teichgräber, Volker; Schellens, Jan H.M.

doi:10.1200/jco.2018.36.15_suppl.e15155

Cited by 36 publications

(28 citation statements)

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“…A recent pioneer study investigated the use of a bispecific antibody (RO6874281) consisting of an interleukin-2 variant (IL-2v) domain that binds the IL-2 receptor on immune cells and a FAPα-specific domain, which tracks the antibody-drug conjugate inside the tumor and reduces efflux. RO6874281 showed an acceptable safety profile and displayed monotherapy activity in tumor types not previously reported to respond to IL-2 [138] A phase II trial (NCT02627274) of RO6874281 together with atezolizumab is currently ongoing. CAFs and their immunosuppressive network present an interesting therapeutic target, however non-specificity of molecular markers incorporates a major hurdle and needs further exploration.…”

Section: Clinical Translationmentioning

confidence: 99%

Overcoming immunotherapy resistance in non-small cell lung cancer (NSCLC) - novel approaches and future outlook

et al. 2020

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Immunotherapy (IO) has revolutionized the therapy landscape of non-small cell lung cancer (NSCLC), significantly prolonging the overall survival (OS) of advanced stage patients. Over the recent years IO therapy has been broadly integrated into the first-line setting of non-oncogene driven NSCLC, either in combination with chemotherapy, or in selected patients with PD-L1high expression as monotherapy. Still, a significant proportion of patients suffer from disease progression. A better understanding of resistance mechanisms depicts a central goal to avoid or overcome IO resistance and to improve patient outcome. We here review major cellular and molecular pathways within the tumor microenvironment (TME) that may impact the evolution of IO resistance. We summarize upcoming treatment options after IO resistance including novel IO targets (e.g. RIG-I, STING) as well as interesting combinational approaches such as IO combined with anti-angiogenic agents or metabolic targets (e.g. IDO-1, adenosine signaling, arginase). By discussing the fundamental mode of action of IO within the TME, we aim to understand and manage IO resistance and to seed new ideas for effective therapeutic IO concepts.

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Section: Clinical Translationmentioning

confidence: 99%

Overcoming immunotherapy resistance in non-small cell lung cancer (NSCLC) - novel approaches and future outlook

et al. 2020

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“…Intralesional IL-2 (NCT03474497) increases PD-L1 expression and promotes CD8 + T cell infiltration (114). RO6874281 (NCT03386721), an engineered IL2v moiety, maintains its affinity for IL-2Rβγ, thus activating effector CD8 T cells and NK cells and reducing Treg activity (115).…”

Section: Potential Strategies To Overcome Tme-mediated Drug Resistancementioning

confidence: 99%

Targeting the Immune Microenvironment in the Treatment of Head and Neck Squamous Cell Carcinoma

2019

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Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive solid tumor, with a 5-year mortality rate of ~50%. The development of immunotherapies has improved the survival of patients with HNSCC, but, the long-term prognosis of patients with recurrent or metastatic HNSCC remains poor. HNSCC is characterized by intratumoral infiltration of regulatory T cells, dysfunctional natural killer cells, an elevated Treg/CD8+ T cell ratio, and increased programmed cell death ligand 1 protein on tumor cells. This leads to an immunocompromised niche in favor of the proliferation and treatment resistance of cancer cells. To achieve an improved treatment response, several potential combination strategies, such as increasing the neoantigens for antigen presentation and therapeutic agents targeting components of the tumor microenvironment, have been explored and have shown promising results in preclinical studies. In addition, large-scale bioinformatic studies have also identified possible predictive biomarkers of HNSCC. As immunotherapy has shown survival benefits in recent HNSCC clinical trials, a comprehensive investigation of immune cells and immune-related factors/cytokines and the immune profiling of tumor cells during the development of HNSCC may provide more insights into the complex immune microenvironment and thus, facilitate the development of novel immunotherapeutic agents.

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“…RG-7461 (RO6874281) is a recombinant fusion protein comprising a mAb directed against the tumor-associated fibroblast activation protein linked to an rhIL-2 variant that does not bind to IL-2Rα (75). The antibody portion mediates the retention and accumulation of the molecule in malignant tissue given the strong expression of fibroblast activation protein on tumor-associated fibroblasts; administration is accompanied by the activation and intratumoral accumulation of CD8 + T and NK cells but reduced activity of Tregs (75) demonstrated an acceptable safety profile; rapidly expanded Teffs and NK cells, but not Tregs, in peripheral blood and tumors; and elicited objective long-lasting (>6 months) responses in three patients with metastatic solid tumors (75). Several phase I/II trials of RG-7461 in combination with other targeted therapies are currently recruiting.…”

Section: Non-mentioning

confidence: 99%

Engineering IL-2 to Give New Life to T Cell Immunotherapy

2021

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Interleukin-2 (IL-2) is integral to immune system regulation. Its opposing immunostimulatory and immunosuppressive actions make it an attractive therapeutic target for cancer and autoimmune diseases. A challenge in developing IL-2-directed anticancer therapies has been how to stimulate effector T cells (Teffs) without inducing regulatory T cells (Tregs) in the tumor microenvironment; conversely, IL-2 therapy for autoimmune diseases requires Treg induction without further stimulation of Teffs. High-dose IL-2 is approved for melanoma and renal cell carcinoma, but its therapeutic value is limited by a need for frequent dosing at specialist centers, its short half-life, severe toxicity, and a lack of efficacy in most patients. Re-engineered IL-2 therapeutics are designed to have longer in vivo half-lives, target specific IL-2 receptor conformations to stimulate specific T cell subsets, or localize to target tissues to optimize efficacy and reduce toxicity. We discuss recent studies that elucidate the potential of newly engineered IL-2-based therapeutics for cancer and autoimmune diseases. Expected final online publication date for the Annual Review of Medicine, Volume 72 is January 27, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Safety, PK/PD, and anti-tumor activity of RO6874281, an engineered variant of interleukin-2 (IL-2v) targeted to tumor-associated fibroblasts via binding to fibroblast activation protein (FAP).

Cited by 36 publications

References 0 publications

Overcoming immunotherapy resistance in non-small cell lung cancer (NSCLC) - novel approaches and future outlook

Overcoming immunotherapy resistance in non-small cell lung cancer (NSCLC) - novel approaches and future outlook

Targeting the Immune Microenvironment in the Treatment of Head and Neck Squamous Cell Carcinoma

Engineering IL-2 to Give New Life to T Cell Immunotherapy

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