Search

BackgroundT-cell redirecting bispecific antibodies (bsAbs) are therapeutics that recognize two distinct antigens: a tumor-associated antigen on tumor cells to promote recruitment of T-cells to the tumor, and a receptor on T-cells to potentiate anti-tumor activity. REGN7075 is a human immunoglobulin G4-based costimulatory bsAb designed to bridge epidermal growth factor receptor (EGFR) positive tumor cells with CD28 positive T-cells and to provide amplified T-cell receptor-CD3 complex-mediated T-cell activation within the tumor, through the activation of CD28 co-stimulation. In genetically humanized immunocompetent mouse models, REGN7075 in combination with anti–PD-1 (antibody directed against programmed cell death-1 receptor) improved anti-tumor activity compared with either single agent alone.1MethodsThis is an open label, Phase I/II, first-in-human study evaluating the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of REGN7075 (EGFRxCD28) alone and in combination with cemiplimab in patients with advanced solid tumors (NCT04626635). Patients must have a protocol-defined advanced solid tumor, be ≥18 years of age (≥20 years in Japan), have an Eastern Cooperative Oncology Group performance status of 0 or 1, and be naïve to anti–PD-1/anti–PD-ligand(L)1.This study includes dose escalation (a 4+3 design modified from 3+3; Part 1) and expansion phases (Part 2). In Part 1, patients will receive a lead-in of REGN7075 monotherapy for 3 weeks followed by combination therapy with cemiplimab 350 mg every 3 weeks. Study therapies are administered until disease progression, intolerable adverse events, withdrawal of consent, or other stopping criterion is met. Once a recommended Phase 2 dose is determined in Part 1, four tumor-specific expansion cohorts will be opened: non-small cell lung cancer (PD-L1 ≥50%), triple-negative breast cancer, colorectal cancer (microsatellite stable), and cutaneous squamous cell carcinoma. Primary endpoints are safety and tolerability of REGN7075 alone or in combination with cemiplimab for Part 1, and objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 for Part 2. This study is currently open to enrollment.Trial RegistrationClinicalTrials.gov identifier NCT04626635.ReferencesWaite JC, Wang B, Haber L, et al. Tumor-targeted CD28 bispecific antibodies enhance the antitumor efficacy of PD-1 immunotherapy. Sci Transl Med 2020;12:2325.Ethics ApprovalThis study was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. The study protocol and all amendments were approved by the institutional review board/ethics committee at each participating study site.ConsentAll patients provided written informed consent.

The in-step plantar fasciotomy has remained a viable option for treatment of plantar fasciitis. The level of the in-step procedure has previously been described as 1.5 cm distal to the anterior heel fat pad. The authors are unaware of any study defining mean width and thickness of the plantar fascia at specific distances from its insertion. The authors performed a standardized cadaveric dissection of 25 fresh frozen cadaveric specimens from a local region in Pennsylvania. Each fascial band width and thickness of the plantar fascia was measured at the fascial insertion, 2 cm distal from insertion, and 3 cm distal from insertion. The mean (± standard deviation) width of the medial, central, and lateral band of the plantar fascia 3 cm from its insertion was 25.3 ± 5.3, 25 ± 3.41, and 23.3 ± 4.49 mm, respectively. At the same anatomic distance, the band thicknesses were 1.5 ± 0.82, 3.3 ± 0.85, and 1.9 ± 0.33 mm, respectively. The literature describes 2 techniques. The first is transecting between one-third to two-thirds of the plantar fascia during a fasciotomy from medial to lateral. The second is identifying, isolating, and releasing the central band. Our study allows to further quantify this, equating to 24.5 to 49 mm in total medial to lateral transection at 3 cm distal from insertion and an isolated central band equating to 25 ± 3.41 mm. With quantitative measurements of transection length, the surgeon will avoid having to estimate and potentially overtransect. This may help in preventing postoperative sequela related to overcorrection.

Antigen immunization studies in cynomolgus monkeys (cyno) provide an opportunity to study in vivo immune responses in a higher order species. Such models can also be useful for testing candidate immunomodulatory drugs which lack rodent cross-reactivity. Here, we have optimized and validated eight, 6-7 color panels of cyno-human cross-reactive antibodies allowing extensive flow cytomtric phenotyping of immune cell populations under steady state, Tetatanus Toxoid (TT), or Keyhole limpet hemocyanin (KLH) primed conditions. Comparisons were made between fresh & overnight cells in Na/Hep tubes to cells phenotypically stabilized in Cytochex tubes. We followed 17 distinct lymphocyte subsets including T, B & NK cells and tracked their activation status over 85 days following primary or secondary immunization. Similar to humans, cyno B & T cell compartments demonstrated a history of prior stimulation evidenced by elevated memory:naive cell ratios and significant baseline expression of CD95, GrB, Ki-67, PD-1, CXCR3, CCR6 and CD11c. In response to immunization, frequencies of circulating Ki67+ B & T cells increased, followed by an elevation of T dependent Ab titers. Changes in Th1 and Th17 subset frequencies as well as CD25 and CD69 expression following immunization were also observed. Direct application of these Ab panels to leukocytes from Rheumatoid Arthritis patients has recapitulated published observations supporting the utility of modeling immune responses in cyno.

The female reproductive tract (FRT) is a heterogenous mucosal tissue that is exposed to commensal flora, undergoes periodic remodeling, and supports fertilization, yet serves as a major site of microbial infection. Due to its unique physiology and vulnerability to microbes, it is important to have a better understanding of the dynamics of the adaptive immune response within the FRT. We paired flow cytometric analyses with immunofluorescence microscopy in order to characterize the kinetics, localization, phenotype and function of antigen specific CD8 T cells present in the FRT during a systemic infection. Effector CD8 T cells migrated into the vagina, cervix, uterine horns and ovaries, where they localized within the lamina propria, epithelium, or unexpectedly, in large lymphoid aggregates where they were associated with CD11c/MHCII+ cells. After pathogen clearance, maintenance of memory CD8 T cells varied greatly based on location within the FRT. Memory CD8 T cell phenotype was also heterogenous; only a subset retained high levels of granzyme B after pathogen clearance. The cellularity of the lymphoid aggregates changed dramatically throughout the response. We are now exploiting local challenge models to visualize the role of these structures in CD8 T cell migration, antigen trafficking and presentation, and supporting in situ recall responses. These studies should be highly relevant for understanding protective cell-mediated immunity within the female genital mucosa.