Identifying MAGE-A4-positive tumors for TCR T cell therapies in HLA-A∗02-eligible patients.

T cell receptor (TCR) T cell therapies target tumor antigens in a human leukocyte antigen (HLA)-restricted manner. Biomarker-defined therapies require validation of assays suitable for determination of patient eligibility. For clinical trials evaluating TCR T cell therapies targeting melanoma-associated antigen A4 (MAGE-A4), screening in studies NCT02636855 and NCT04044768 assesses patient eligibility based on: (1) high-resolution HLA typing and (2) tumor MAGE-A4 testing via an immunohistochemical assay in HLA-eligible patients. The HLA/MAGE-A4 assays validation, biomarker data, and their relationship to covariates (demographics, cancer type, histopathology, tissue location) are reported here. HLA-A∗02 eligibility was 44.8% (2,959/6,606) in patients from 43 sites across North America and Europe. While HLA-A∗02:01 was the most frequent HLA-A∗02 allele, others (A∗02:02, A∗02:03, A∗02:06) considerably increased HLA eligibility in Hispanic, Black, and Asian populations. Overall, MAGE-A4 prevalence based on clinical trial enrollment was 26% (447/1,750) across 10 solid tumor types, and was highest in synovial sarcoma (70%) and lowest in gastric cancer (9%). The covariates were generally not associated with MAGE-A4 expression, except for patient age in ovarian cancer and histology in non-small cell lung cancer. This report shows the eligibility rate from biomarker screening for TCR T cell therapies and provides epidemiological data for future clinical development of MAGE-A4-targeted therapies.

Phase 1 Clinical Trial Evaluating the Safety and Anti-Tumor Activity of ADP-A2M10 SPEAR T-Cells in Patients With MAGE-A10+ Head and Neck, Melanoma, or Urothelial Tumors.

Background: ADP-A2M10 specific peptide enhanced affinity receptor (SPEAR) T-cells are genetically engineered autologous T-cells that express a high-affinity melanoma-associated antigen (MAGE)-A10-specific T-cell receptor (TCR) targeting MAGE-A10-positive tumors in the context of human leukocyte antigen (HLA)-A*02. ADP-0022-004 is a phase 1, dose-escalation trial to evaluate the safety and anti-tumor activity of ADP-A2M10 in three malignancies (https://clinicaltrials.gov: NCT02989064). Methods: Eligible patients were HLA-A*02 positive with advanced head and neck squamous cell carcinoma (HNSCC), melanoma, or urothelial carcinoma (UC) expressing MAGE-A10. Patients underwent apheresis; T-cells were isolated, transduced with a lentiviral vector containing the MAGE-A10 TCR, and expanded. Patients underwent lymphodepletion with fludarabine and cyclophosphamide prior to receiving ADP-A2M10. ADP-A2M10 was administered in two dose groups receiving 0.1×109 and >1.2 to 6×109 transduced cells, respectively, and an expansion group receiving 1.2 to 15×109 transduced cells. Results: Ten patients (eight male and two female) with HNSCC (four), melanoma (three), and UC (three) were treated. Three patients were treated in each of the two dose groups, and four patients were treated in the expansion group. The most frequently reported adverse events grade ≥3 were leukopenia (10), lymphopenia (10), neutropenia (10), anemia (nine), and thrombocytopenia (five). Two patients reported cytokine release syndrome (one each with grade 1 and grade 3), with resolution. Best response included stable disease in four patients, progressive disease in five patients, and not evaluable in one patient. ADP-A2M10 cells were detectable in peripheral blood from patients in each dose group and the expansion group and in tumor tissues from patients in the higher dose group and the expansion group. Peak persistence was greater in patients from the higher dose group and the expansion group compared with the lower dose group. Conclusions: ADP-A2M10 has shown an acceptable safety profile with no evidence of toxicity related to off-target binding or alloreactivity in these malignancies. Persistence of ADP-A2M10 in the peripheral blood and trafficking of ADP-A2M10 into the tumor was demonstrated. Because MAGE-A10 expression frequently overlaps with MAGE-A4 expression in tumors and responses were observed in the MAGE-A4 trial (NCT03132922), this clinical program closed, and trials with SPEAR T-cells targeting the MAGE-A4 antigen are ongoing.

Evaluation of the depth and duration of anesthesia from heated lidocaine/tetracaine (Synera) patches compared with placebo patches applied to healthy adult volunteers.

BACKGROUND: The heated lidocaine/tetracaine patch (Synera; ZARS Pharma, Inc, Salt Lake City, UT) is among the local topical anesthetic formulations used to prevent procedural pain. This study was conducted to determine the depth and duration of anesthesia provided by the patch and to evaluate safety and tolerability. METHODS: This randomized, double-blind, placebo-controlled, 2-period crossover study was conducted in healthy subjects. Subjects were randomized to receive either the heated lidocaine/tetracaine patch (active patch) in period 1 and placebo patch in period 2 or vice versa. Patches were applied for 30 mins to the volar aspect of the forearm. Pain and sensory depths were measured at baseline and at 30, 60, 90, and 150 mins after patch application. Duration of anesthesia was measured at 40, 70, 110, and 130 mins after patch application by evaluating thermal and mechanical sensation. RESULTS: A total of 25 subjects were enrolled in the study. Twenty-four subjects completed the study. Pain and sensory depths with the active patch were greater than with placebo (P < 0.001) at all postdose time points. Maximum mean pain depth achieved with the active patch was 8.22 mm; anesthesia lasted at least 100 mins after patch removal. Cool and warm sensations and hot pain thresholds were increased compared with placebo (P < 0.001). Light touch and pinprick were detectable by most subjects. CONCLUSIONS: The heated lidocaine/tetracaine patch is well tolerated, and it provides favorable depth and duration of anesthesia without significant sensory loss for superficial venous access and minor dermatological procedures after a 30-min application.