Chimeric antigen receptor T-cell therapy targeting a MAGE A4 peptide and HLA-A*02:01 complex for unresectable advanced or recurrent solid cancer: protocol for a multi-institutional phase 1 clinical trial.

INTRODUCTION: Adoptive cell transfer of genetically engineered T cells is a promising treatment for malignancies; however, there are few ideal cancer antigens expressed on the cell surface, and the development of chimeric antigen receptor T cells (CAR-T cells) for solid tumour treatment has been slow. CAR-T cells, which recognise major histocompatibility complex and peptide complexes presented on the cell surface, can be used to target not only cell surface antigens but also intracellular antigens. We have developed a CAR-T-cell product that recognises the complex of HLA-A*02:01 and an epitope of the MAGE-A4 antigen equipped with a novel signalling domain of human GITR (investigational product code: MU-MA402C) based on preclinical studies. METHODS AND ANALYSIS: This is a dose-escalation, multi-institutional, phase 1 study to evaluate the tolerability and safety of MU-MA402C for patients with MAGE A4-positive and HLA-A*02:01-positive unresectable advanced or recurrent solid cancer. Two dose cohorts are planned: cohort 1, MU-MA402C 2×108/person; cohort 2, MU-MA402C 2×109/person. Prior to CAR-T-cell infusion, cyclophosphamide (CPA) and fludarabine (FLU) will be administered as preconditioning chemotherapy. Three evaluable subjects per cohort, for a total of 6 subjects (maximum of 12 subjects), will be recruited for this clinical trial. The primary endpoints are safety and tolerability. The severity of each adverse event will be evaluated in accordance with Common Terminology Criteria for Adverse Events V.5.0. The secondary endpoint is efficacy. Antitumour response will be evaluated according to Response Evaluation Criteria in Solid Tumours V.1.1. ETHICS AND DISSEMINATION: This clinical trial will be conducted in accordance with the current version of Good Clinical Practice. The protocol was approved by the Clinical Research Ethics Review Committee of Mie University Hospital (approval number F-2021-017). The trial results will be published in peer-reviewed journals and/or disseminated through international conferences. TRIAL REGISTRATION NUMBER: jRCT2043210077.

Tebentafusp for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma.

INTRODUCTION: Metastatic uveal melanoma is associated with poor prognosis and few treatment options. Tebentafusp recently became the first FDA-approved agent for metastatic uveal melanoma. AREAS COVERED: In this review, we describe the mechanism of action of tebentafusp as well as preclinical data showing high tumor specificity of the drug. We also review promising early-phase trials in which tebentafusp demonstrated activity in metastatic uveal melanoma patients with an acceptable toxicity profile that included cytokine-mediated, dermatologic-related, and liver-related adverse events. Finally, we summarize findings from a pivotal phase III randomized trial in which tebentafusp demonstrated significant improvement in overall survival in comparison with investigator choice therapy. EXPERT OPINION: Tebentafusp has transformed the treatment paradigm for metastatic uveal melanoma and should be the preferred frontline agent for most HLA-A*0201 positive patients. However, patients with rapidly progressing disease or high tumor benefit may not derive the same benefit. Areas of future study should focus on its role in the adjuvant setting as well as strategies to improve the efficacy of tebentafusp in the metastatic setting.

Spectrum of Spondyloarthritis Among Chinese Populations.

PURPOSE OF REVIEW: This review aims to emphasize interesting and important new findings with a focus on the spectrum of spondyloarthritis (SpA) in China. RECENT FINDINGS: Over the past decade, significant advances have been made in the investigation of SpA epidemiology, the exploration of genetic and environmental risk factors, the identification of clinical features, and the updating of treatment protocols in the Chinese population. The prevalence of ankylosing spondylitis (AS) in China is 0.20-0.42%, and the prevalence of HLA-B27 in AS patients is 88.8-89.4%. HLA-B*2704 is the most common subtype in Chinese AS patients, followed by HLA-B*2705. HLA-A*01, more precisely HLA-A*01:01, may be associated with psoriatic arthritis (PsA). Tumor necrosis factor inhibitors and IL-17A inhibitors have been shown to be effective and safe for AS patients in China. Juvenile-onset AS is relatively rare, accounting for only 9.1% of the AS population. The prevalence of arthritis related to inflammatory bowel disease is 6.9 to 7.2%. A Chinese study showed that the most frequently prescribed medication was methotrexate (66.4%). Biological agents were prescribed in only16.4% of patients with PsA. This review summarizes the latest research in the epidemiology, pathogenesis, clinical manifestations, and management of SpA among Chinese populations. Multiple HLA associations with SpA have also been described, and it is hoped that discoveries of such ethnic-specific risk factor(s) and understanding of their pathological mechanisms may potentially lead to newer targeted therapies for the Chinese populations worldwide.

Tebentafusp: First Approval.

Tebentafusp (tebentafusp-tebn; Kimmtrak®) is a first-in-class, bispecific gp100 peptide-HLA-A*02:01 directed T cell receptor (TCR) CD3 T cell engager being developed by Immunocore for the treatment of uveal melanoma and malignant melanoma. The TCR arm of tebentafusp binds to HLA-A*02:01-positive uveal melanoma cells and activates polyclonal T cells, through CD3, to release inflammatory cytokines and cytolytic proteins, resulting in the direct lysis of tumour cells. In January 2022, tebentafusp received its first approval in the USA for the treatment of HLA-A*02:01-positive adults with unresectable or metastatic uveal melanoma, and in February 2022 received a Positive Opinion from the EU Committee for Medicinal Products for Human Use for the treatment of uveal melanoma. Tebentafusp is under regulatory review for the treatment of metastatic uveal melanoma in the UK, Australia and Canada. Clinical studies of tebentafusp are underway for uveal melanoma and cutaneous melanoma in several countries worldwide. This article summarizes the milestones in the development of tebentafusp leading to this first approval for unresectable or metastatic uveal melanoma.

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.

Chronic ocular sequelae in Stevens-Johnson syndrome: a genetic association study.

Purpose: This study sought to investigate the association of molecular markers with chronic ocular sequelae in Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Methods: One hundred SJS/TEN patients (200 eyes) with confirmed diagnosis were enrolled between July 2011 and July 2015 from a tertiary eye-care hospital, and their clinical histories were noted. Each eye was scored for severity of manifestation on a scale of 0-5. Peripheral blood samples were collected for DNA followed by screening for interleukin (IL-4, IL-13, IL-4R) polymorphisms, HLA-A locus allele typing, and sera to detect levels of the apoptotic markers granulysin and sFas L. Results: Of the 100 enrolled patients (53 males/47 females; age range: 6-58 years), the incriminating drugs were non-steroidal anti-inflammatory (52%), antibiotics (10%), sulphonamides (8%), anti-epileptics (6%), and unknown (24%). Significant differences in the frequencies of IL-4R polymorphism, HLA-A*3301, HLA-A*02, and HLA-A*2402 alleles, and elevated levels of granulysin and sFas L were observed in patients compared to controls. The ocular complications of conjunctival keratinization (p=0.004) showed an association with IL-13 promoter region (IL-13a) genotypes. Conclusions: The study highlights the possible association of interleukin-13 with severity-graded chronic sequelae and the role of HLA-A alleles- HLA-A*3301, HLA-A*02, and HLA-A*2402 in SJS/TEN causation and manifestation. Screening of these alleles may help caregivers to identify markers associated with severe and lifelong ocular complications, and help in appropriate treatment and management of the condition.

A multivalent and cross-protective vaccine strategy against arenaviruses associated with human disease.

Arenaviruses are the causative pathogens of severe hemorrhagic fever and aseptic meningitis in humans, for which no licensed vaccines are currently available. Pathogen heterogeneity within the Arenaviridae family poses a significant challenge for vaccine development. The main hypothesis we tested in the present study was whether it is possible to design a universal vaccine strategy capable of inducing simultaneous HLA-restricted CD8+ T cell responses against 7 pathogenic arenaviruses (including the lymphocytic choriomeningitis, Lassa, Guanarito, Junin, Machupo, Sabia, and Whitewater Arroyo viruses), either through the identification of widely conserved epitopes, or by the identification of a collection of epitopes derived from multiple arenavirus species. By inoculating HLA transgenic mice with a panel of recombinant vaccinia viruses (rVACVs) expressing the different arenavirus proteins, we identified 10 HLA-A02 and 10 HLA-A03-restricted epitopes that are naturally processed in human antigen-presenting cells. For some of these epitopes we were able to demonstrate cross-reactive CD8+ T cell responses, further increasing the coverage afforded by the epitope set against each different arenavirus species. Importantly, we showed that immunization of HLA transgenic mice with an epitope cocktail generated simultaneous CD8+ T cell responses against all 7 arenaviruses, and protected mice against challenge with rVACVs expressing either Old or New World arenavirus glycoproteins. In conclusion, the set of identified epitopes allows broad, non-ethnically biased coverage of all 7 viral species targeted by our studies.

Vaccination of hormone-refractory prostate cancer patients with peptide cocktail-loaded dendritic cells: results of a phase I clinical trial.

BACKGROUND: Immunotherapies might represent promising alternatives for the treatment of patients with hormone-refractory prostate cancer (HRPC). In a Phase I clinical trial, we evaluated a vaccination with dendritic cells (DCs) loaded with a cocktail consisting of HLA-A*0201-restricted peptides derived from five different prostate cancer-associated antigens [prostate-specific antigen (PSA), prostate-specific membrane antigen (PSMA), survivin, prostein, transient receptor potential p8 (trp-p8)]. METHODS: Eight HRPC patients received a total of four vaccinations every other week. Clinical and immunological responses were monitored by the determination of the serum PSA levels and by enzyme linked immunospot (ELISPOT) analyses, respectively. RESULTS: Apart from local skin reactions no side effects were noted. One patient displayed a partial response (PR; PSA decrease >50%) and three other patients showed stable PSA values or decelerated PSA increases. In ELISPOT analyses, three of four PSA responders also showed antigen-specific CD8+ T-cell activation against prostein, survivin, and PSMA. CONCLUSIONS: The described protocol represents a safe and feasible concept for the induction of clinical and immunological responses. The application of a peptide cocktail-derived from different antigens as a novel treatment modality is supposed to allow for the genetic and biologic heterogeneity of PCa.

Immunization of HLA-A*0201 and/or HLA-DPbeta1*04 patients with metastatic melanoma using epitopes from the NY-ESO-1 antigen.

HLA class I-restricted peptides are often used in peptide vaccine regimens. There is strong evidence that many of these peptides can generate specific CD8 T-cell responses in vivo; however, only occasional objective clinical responses have been reported. To test whether provision of "help" would enhance antitumor immunity, the authors initiated a clinical trial in which patients with metastatic melanoma were immunized against the NY-ESO-1 tumor antigen, using an HLA-A2-restricted peptide (ESO-1:165V), an HLA-DP4-restricted peptide (NY-ESO-1:161-180), or both peptides given concomitantly. The first cohorts received only ESO-1:165V, using three vaccination schedules. Immunologically, most patients developed immune responses to the HLA-A2-restricted native ESO-1 epitope after vaccination. Peptide vaccine given daily for 4 days appeared to induce immunologic responses more rapidly than if given once a week or once every 3 weeks. In contrast, vaccination using the NY-ESO-1:161-180 peptide induced immune responses in only a few patients. Clinically, one patient who received NY-ESO-1:161-180 peptide alone had a partial response lasing 12 months. Concomitant vaccination with the HLA class II-restricted peptide did not alter the immune response to the HLA class I-restricted peptide form NY-ESO-1. However, vaccination with the HLA-A2-restricted epitope generated primarily T cells that did not recognize tumor after in vitro sensitization. This result raises questions about the use of synthetic peptides derived from NY-ESO-1 as a sole form of immunization.

Protective efficacy of multiepitope human leukocyte antigen-A*0201 restricted cytotoxic T-lymphocyte peptide construct against challenge with human T-cell lymphotropic virus type 1 Tax recombinant vaccinia virus.

Human T-cell lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia. Multiepitope T-cell vaccines are more likely to generate a broad long-lasting immune response than those composed of single epitopes. We recently reported a novel multivalent cytotoxic T-lymphocyte peptide construct derived from the Tax protein of HTLV-1 separated by arginine spacers that elicited high cellular responses against individual epitopes simultaneously in human leukocyte antigen (HLA)-A*0201 transgenic mice. We now report the effect of epitope orientation on the processing of the multiepitope construct by 20s proteasomes and the effect of the processing rates on the immunogenicity of the intended epitopes. A positive correlation was found between processing rates and the immunogenicity of the intended epitopes. The construct with the highest immunogenicity for each epitope was tested for protective efficacy in a preclinical model of infection using HTLV-1 Tax recombinant vaccinia virus and HLA-A*0201 transgenic mice. Mice vaccinated with the multiepitope construct displayed a statistically significant reduction in viral replication that was dependent on CD8 T cells. Reduction in viral replication was also confirmed to be specific to Tax-vaccinia virus. These results demonstrate the activation of Tax-specific CD8+ T cells by vaccination and are supportive of a multivalent peptide vaccine approach against HTLV-1 infections.

WT1 peptide-based immunotherapy for patients with lung cancer: report of two cases.

The Wilms' tumor gene WT1 is overexpressed in various types of solid tumors, including lung and breast cancer and WT1 protein is a tumor antigen for these malignancies. In phase I clinical trials of WT1 peptide-based cancer immunotherapy, two patients with advanced lung cancer were intradermally injected with 0.3 mg of an HLA-A*2402-restricted, 9-mer WT1 peptide emulsified with Montanide ISA51 adjuvant. Consecutive WT1 vaccination at 2-week intervals resulted in a reduction in tumor markers such as chorio-embryonic antigen (CEA) and sialyl Lewis (x) (SLX) and by a transient decrease in tumor size. No adverse effects except for local erythema at the injection sites of WT1 vaccine were observed. These results provided us with the first clinical evidence demonstrating that WT1 peptide-based immunotherapy should be a promising treatment for patients with lung cancer.

Wilms tumor gene peptide-based immunotherapy for patients with overt leukemia from myelodysplastic syndrome (MDS) or MDS with myelofibrosis.

The Wilms tumor gene, WT1, is overexpressed not only in leukemias and myelodysplastic syndrome (MDS) but also in various types of solid tumors, including lung and breast cancer, and the WT1 protein is a tumor antigen for these malignancies. In clinical trials of WT1 peptide-based cancer immunotherapy, patients with overt leukemia from MDS or MDS with myelofibrosis were injected intradermally with 0.3 mg of an HLA-A*2402-restricted, 9-mer WT1 peptide emulsified with Montanide ISA51 adjuvant. Only a single dose of WT1 vaccination resulted in an increase in WT1-specific cytotoxic T-lymphocytes, which was followed by a rapid reduction in leukemic blast cells. Severe leukopenia and local erythema at the injection sites of WT1 peptide were observed as adverse effects. These results have provided us with the first clinical evidence suggesting that WT1 peptide-based immunotherapy is an attractive treatment for patients with leukemias or MDS.