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Identifying MAGE-A4-positive tumors for TCR T cell therapies in HLA-A∗02-eligible patients
Tianjiao Wang1, Jean-Marc Navenot1, Stavros Rafail2
1Clinical Biomarkers & Companion Diagnostics, Adaptimmune, Philadelphia, PA, USA.
Abstract:
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.
Insights
Biomarker screening for T cell receptor (TCR) T cell therapies targeting MAGE-A4 found HLA-A*02 eligibility in 44.8% of patients. MAGE-A4 prevalence was 26% across 10 tumor types, with variations by cancer and ethnicity.
Area of Science:
- Oncology
- Immunotherapy
- Genetics
Background:
- T cell receptor (TCR) T cell therapies are a promising cancer treatment approach.
- These therapies target specific tumor antigens in a human leukocyte antigen (HLA)-restricted manner.
- Validating patient eligibility assays is crucial for biomarker-defined therapies.
Purpose of the Study:
- To report on the validation of human leukocyte antigen (HLA) and melanoma-associated antigen A4 (MAGE-A4) assays.
- To present biomarker data and eligibility rates for TCR T cell therapies targeting MAGE-A4.
- To analyze the relationship between biomarker expression and patient covariates.
Main Methods:
- High-resolution HLA typing was performed to determine patient eligibility.
- Tumor MAGE-A4 expression was assessed using immunohistochemical assays in HLA-eligible patients.
- Data from clinical trials NCT02636855 and NCT04044768 were analyzed, including demographic and histopathological information.
Main Results:
- HLA-A*02 eligibility was observed in 44.8% of 6,606 patients across North America and Europe.
- While HLA-A*02:01 was most common, other HLA-A*02 alleles increased eligibility in diverse ethnic populations.
- MAGE-A4 prevalence was 26% across 10 solid tumor types, with highest rates in synovial sarcoma (70%) and lowest in gastric cancer (9%).
Conclusions:
- This study provides essential eligibility rates from biomarker screening for MAGE-A4-targeted TCR T cell therapies.
- The findings highlight the importance of diverse HLA alleles for broader patient eligibility.
- Epidemiological data on MAGE-A4 prevalence offer valuable insights for future clinical development.
