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Abstract
Background Antibodies (Abs) agonizing the CD40 immune receptor hold promise for cancer treatment by activating anti-tumor immune responses.1–3 However, clinical implementation has been limited due to minimal on-target activity and significant toxicity.4–7 We previously investigated the bases if these issues and discovered that the interaction between the antibody (Ab) Fc domain and the inhibitory Fc-gamma receptor FcγRIIB is crucial for the in vivo activity of anti-CD40 antibodies, and that previous antibodies were not optimized for this interaction.8–10 To address this, we developed 2141 -V11, a human anti-CD40 Ab engineered to enhance FcγRIIB binding. In several tumor models, 2141-V11 enhanced dendritic cell (DC) activation and antigen-specific T cell responses, showing superior antitumor activity compared to other clinical CD40 Abs. Additionally, intratumoral administration of 2141-V11 reduced systemic toxicity associated with CD40 agonism and mediated abscopal responses in non-injected tumors.10–12 Here, we present the results of a first-in-human, phase 1 study,13 investigating the safety and preliminary clinical activity of intratumoral administration of 2141-V11 (NCT04059588), coupled with in vivo mechanistic studies in a humanized mouse model for CD40 and FcγRs (hCD40/hFcγR mice).
Methods Primary endpoints of the clinical trial included safety and maximum tolerated dose (MTD). Secondary objectives included preliminary clinical activity and correlative studies from biospecimens. Reverse translational studies were also performed in hCD40/hFcgR mice using a breast cancer model.
Results A total of 12 patients with metastatic solid tumors and identifiable metastatic lesions in the skin, amenable to intratumoral injection, were enrolled in the study. 2141-V11 was well-tolerated without dose-limiting toxicities, all treatment related adverse events were mild (Grade 1–2). In ten evaluable patients with metastatic cancer, the overall response rate was 20%, with complete responses in two patients (melanoma and hormone positive breast carcinoma) and stable disease in six patients (figure 1A). 2141-V11 induced tumor regression in both injected and non-injected lesions (figure 1B-C and figure 2), with increased leukocyte infiltration and tertiary lymphoid structures (TLS) formation in post-treatment biopsies of complete responders (figure 3). In hCD40/hFcγR mice, 2141-V11 induced TLS formation in mice bearing orthotopic breast carcinoma, correlating with local and abscopal antitumor effects, systemic immune activation, and immune memory (figure 4).
Conclusions Intratumoral administration of 2141-V11 is safe and effective, warranting phase 2 studies that are currently ongoing. Correlative and in vivo studies suggest TLS formation as a unique mechanism of action for this Fc-enhanced immunotherapy.
Acknowledgements We acknowledge Jim Ackland for his consulting on regulatory affairs, and Dr. Sarah J. Schlesinger and Arlene Hurley for assisting with protocol updates and reports to the IRB. We thank the Pharmacy and Hospital staff, and of course the patients and families who contributed to this trial. We thank Carlo M. Sevilla and Alessandra E. Marino for their excellent technical assistance. We also thank all the members of the J.V.R. Laboratory of Molecular Genetics and Immunology for 804 helpful discussions and sharing experiment materials.
Trial Registration NCT04059588.
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Ethics Approval Studies were approved by the institutional review board (IRB) of the Rockefeller University (DKN-0993).
Preliminary clinical activity of 2141-V11. Waterfall plot displaying best percent change from baseline in sum of lesion diameters (SoD). a) Best overall response; b) Injected target lesions; c) Non-injected target lesions
Induction of tumor shrinkage in remote sites, in complete responders to 2141-V11. Representative photographs of the lesions from responders a) Melanoma patient; b) Breast cancer patient. Injected (red arrows) and non-injected target lesions (green arrows) are indicated. c-d) Radiographic and cancer markers from breast ca. patient
Formation of tertiary lymphoid structures in complete responders to 2141-V11. a-b) Representative images of H&E stained slides of tumor samples from two responding patients. c-d) IHC of FFPE sections after treatment with 2141-V11. e-f) Representative mIF images from responding patients. g-i) Quantification of TLS & immune cells
Intratumoral administration of 2141-V11 leads to antitumor immunity, resulting in primary tumor regression, an abscopal effect, and induction of long-term immune memory. a-b) Scheme and results of experiment showing antitumor effect of 2141-V11 in orthotopic breast cancer model. c-d) Scheme and results of rechallenge experiment with 2141-V11. d) Representative image and results of abscopal effect of 2141-V11
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