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.

Afamitresgene autoleucel for advanced synovial sarcoma and myxoid round cell liposarcoma (SPEARHEAD-1): an international, open-label, phase 2 trial.

BACKGROUND: Afamitresgene autoleucel (afami-cel) showed acceptable safety and promising efficacy in a phase 1 trial (NCT03132922). The aim of this study was to further evaluate the efficacy of afami-cel for the treatment of patients with HLA-A*02 and MAGE-A4-expressing advanced synovial sarcoma or myxoid round cell liposarcoma. METHODS: SPEARHEAD-1 was an open-label, non-randomised, phase 2 trial done across 23 sites in Canada, the USA, and Europe. The trial included three cohorts, of which the main investigational cohort (cohort 1) is reported here. Cohort 1 included patients with HLA-A*02, aged 16-75 years, with metastatic or unresectable synovial sarcoma or myxoid round cell liposarcoma (confirmed by cytogenetics) expressing MAGE-A4, and who had received at least one previous line of anthracycline-containing or ifosfamide-containing chemotherapy. Patients received a single intravenous dose of afami-cel (transduced dose range 1·0 × 109-10·0 × 109 T cells) after lymphodepletion. The primary endpoint was overall response rate in cohort 1, assessed by a masked independent review committee using Response Evaluation Criteria in Solid Tumours (version 1.1) in the modified intention-to-treat population (all patients who received afami-cel). Adverse events, including those of special interest (cytokine release syndrome, prolonged cytopenia, and neurotoxicity), were monitored and are reported for the modified intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT04044768; recruitment is closed and follow-up is ongoing for cohorts 1 and 2, and recruitment is open for cohort 3. FINDINGS: Between Dec 17, 2019, and July 27, 2021, 52 patients with cytogenetically confirmed synovial sarcoma (n=44) and myxoid round cell liposarcoma (n=8) were enrolled and received afami-cel in cohort 1. Patients were heavily pre-treated (median three [IQR two to four] previous lines of systemic therapy). Median follow-up time was 32·6 months (IQR 29·4-36·1). Overall response rate was 37% (19 of 52; 95% CI 24-51) overall, 39% (17 of 44; 24-55) for patients with synovial sarcoma, and 25% (two of eight; 3-65) for patients with myxoid round cell liposarcoma. Cytokine release syndrome occurred in 37 (71%) of 52 of patients (one grade 3 event). Cytopenias were the most common grade 3 or worse adverse events (lymphopenia in 50 [96%], neutropenia 44 [85%], leukopenia 42 [81%] of 52 patients). No treatment-related deaths occurred. INTERPRETATION: Afami-cel treatment resulted in durable responses in heavily pre-treated patients with HLA-A*02 and MAGE-A4-expressing synovial sarcoma. This study shows that T-cell receptor therapy can be used to effectively target solid tumours and provides rationale to expand this approach to other solid malignancies. FUNDING: Adaptimmune.

Autologous T cell therapy for MAGE-A4+ solid cancers in HLA-A*02+ patients: a phase 1 trial.

Affinity-optimized T cell receptors can enhance the potency of adoptive T cell therapy. Afamitresgene autoleucel (afami-cel) is a human leukocyte antigen-restricted autologous T cell therapy targeting melanoma-associated antigen A4 (MAGE-A4), a cancer/testis antigen expressed at varying levels in multiple solid tumors. We conducted a multicenter, dose-escalation, phase 1 trial in patients with relapsed/refractory metastatic solid tumors expressing MAGE-A4, including synovial sarcoma (SS), ovarian cancer and head and neck cancer ( NCT03132922 ). The primary endpoint was safety, and the secondary efficacy endpoints included overall response rate (ORR) and duration of response. All patients (N = 38, nine tumor types) experienced Grade ≥3 hematologic toxicities; 55% of patients (90% Grade ≤2) experienced cytokine release syndrome. ORR (all partial response) was 24% (9/38), 7/16 (44%) for SS and 2/22 (9%) for all other cancers. Median duration of response was 25.6 weeks (95% confidence interval (CI): 12.286, not reached) and 28.1 weeks (95% CI: 12.286, not reached) overall and for SS, respectively. Exploratory analyses showed that afami-cel infiltrates tumors, has an interferon-γ-driven mechanism of action and triggers adaptive immune responses. In addition, afami-cel has an acceptable benefit-risk profile, with early and durable responses, especially in patients with metastatic SS. Although the small trial size limits conclusions that can be drawn, the results warrant further testing in larger studies.

Phase I Study of Safety, Tolerability, and Efficacy of Tebentafusp Using a Step-Up Dosing Regimen and Expansion in Patients With Metastatic Uveal Melanoma.

PURPOSE: This phase I study aimed to define the recommended phase II dose (RP2D) of tebentafusp, a first-in-class T-cell receptor/anti-CD3 bispecific protein, using a three-week step-up dosing regimen, and to assess its safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity in patients with metastatic uveal melanoma (mUM). METHODS: In this open-label, international, phase I/II study, HLA-A*02 or HLA-A*02:01+ patients with mUM received tebentafusp 20 µg once in week 1 and 30 µg once in week 2. Dose escalation (starting at 54 µg) began at week 3 in a standard 3 + 3 design to define RP2D. Expansion-phase patients were treated at the RP2D (20-30-68 µg). Blood and tumor samples were collected for pharmacokinetics/pharmacodynamics assessment, and treatment efficacy was evaluated for all patients with baseline efficacy data as of December 2017. RESULTS: Between March 2016 and December 2017, 42 eligible patients who failed a median of two previous treatments were enrolled: 19 in the dose escalation cohort and 23 in an initial dose expansion cohort. Of the dose levels investigated, 68 µg was identified as the RP2D. Most frequent treatment-emergent adverse events regardless of attribution were pyrexia (91%), rash (83%), pruritus (83%), nausea (74%), fatigue (71%), and chills (69%). Toxicity attenuated following the first three doses. The overall response rate was 11.9% (95% CI, 4.0 to 25.6). With a median follow-up of 32.4 months, median overall survival was 25.5 months (range, 0.89-31.1 months) and 1-year overall survival rate was 67%. Treatment was associated with increased tumor T-cell infiltration and transient increases in serum inflammatory mediators. CONCLUSION: Using a step-up dosing regimen of tebentafusp allowed a 36% increase in the RP2D compared with weekly fixed dosing, with a manageable side-effect profile and a signal of efficacy in mUM.

Tebentafusp, A TCR/Anti-CD3 Bispecific Fusion Protein Targeting gp100, Potently Activated Antitumor Immune Responses in Patients with Metastatic Melanoma.

PURPOSE: Tebentafusp is a first-in-class bispecific fusion protein designed to target gp100 (a melanoma-associated antigen) through a high affinity T-cell receptor (TCR) binding domain and an anti-CD3 T-cell engaging domain, which redirects T cells to kill gp100-expressing tumor cells. Here, we report a multicenter phase I/II trial of tebentafusp in metastatic melanoma (NCT01211262) focusing on the mechanism of action of tebentafusp. PATIENTS AND METHODS: Eighty-four patients with advanced melanoma received tebentafusp. Treatment efficacy, treatment-related adverse events, and biomarker assessments were performed for blood-derived and tumor biopsy samples obtained at baseline and on-treatment. RESULTS: Tebentafusp was generally well-tolerated and active in both patients with metastatic uveal melanoma and patients with metastatic cutaneous melanoma. A 1-year overall survival rate of 65% was achieved for both patient cohorts. On-treatment cytokine measurements were consistent with the induction of IFNγ pathway-related markers in the periphery and tumor. Notably, tebentafusp induced an increase in serum CXCL10 (a T-cell attractant) and a reduction in circulating CXCR3+ CD8+ T cells together with an increase in cytotoxic T cells in the tumor microenvironment. Furthermore, increased serum CXCL10 or the appearance of rash (likely due to cytotoxic T cells targeting gp100-expressing skin melanocytes) showed a positive association with patient survival. CONCLUSIONS: These data suggest that redirecting T cells using a gp100-targeting TCR/anti-CD3 bispecific fusion protein may provide benefit to patients with metastatic melanoma. Furthermore, the activity observed in these two molecularly disparate melanoma classes hints at the broad therapeutic potential of tebentafusp.

Measurement properties of the neck disability index: a systematic review.

STUDY DESIGN: Systematic review of clinical measurement. OBJECTIVE: To find and synthesize evidence on the psychometric properties and usefulness of the neck disability index (NDI). BACKGROUND: The NDI is the most commonly used outcome measure for neck pain, and a synthesis of knowledge should provide a deeper understanding of its use and limitations. METHODS AND MEASURES: Using a standard search strategy (1966 to September 2008) and 4 databases (Medline, CINAHL, Embase, and PsychInfo), a structured search was conducted and supplemented by web and hand searching. In total, 37 published primary studies, 3 reviews, and 1 in-press paper were analyzed. Pairs of raters conducted data extraction and critical appraisal using structured tools. Ranking of quality and descriptive synthesis were performed. RESULTS: Horizon estimation suggested the potential for 1 missed paper. The agreement between raters on quality assessments was high(kappa = 0.82). Half of the studies reached a quality level greater than 70%. Failures to report clear psychometric objectives/hypotheses or to rationalize the sample size were the most common design flaws. Studies often focused on less clinically applicable properties, like construct validity or group reliability, than transferable data, like known group differences or absolute reliability (standard error of measurement [SEM] or minimum detectable change [MDC]). Most studies suggest that the NDI has acceptable reliability, although intraclass correlation coefficients (ICCs) range from 0.50 to 0.98. Longer test intervals and the definition of stable can influence reliability estimates. A number of high-quality published (Korean, Dutch, Spanish, French, Brazilian Portuguese) and commercially supported translations are available. The NDI is considered a 1-dimensional measure that can be interpreted as an interval scale. Some studies question these assumptions. The MDC is around 5/50 for uncomplicated neck pain and up to 10/50 for cervical radiculopathy. The reported clinically important difference (CID) is inconsistent across different studies ranging from 5/50 to 19/50. The NDI is strongly correlated (>0.70) to a number of similar indices and moderately related to both physical and mental aspects of general health. CONCLUSION: The NDI has sufficient support and usefulness to retain its current status as the most commonly used self-report measure for neck pain. More studies of CID in different clinical populations and the relationship to subjective/work/function categories are required.

G-protein-coupled receptor heterodimerization: assay technologies to clinical significance.

The concept of G-protein-coupled receptor (GPCR) oligomerization has existed for many years, but has only recently received scrutiny from the pharmaceutical industry. The new interest in this theory has arisen not only because technologies to exploit GPCR oligomers are now available, but also because GPCR oligomerization has the potential to explain previously anomalous pharmacology and to provide an array of new therapeutic targets. The emergence of higher order GPCR organization adds a layer of complexity in the context of cellular control, and indeed drug discovery. This review outlines the current knowledge surrounding the oligomerization of GPCRs and describes effective assays for exploiting oligomerization in drug discovery. The clinical significance of oligomerization and the most promising strategies for therapeutically targeting GPCR oligomers are discussed.