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. 2024 May 14;32(2):101265.
doi: 10.1016/j.omtm.2024.101265. eCollection 2024 Jun 13.

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

Tianjiao Wang  1 , Jean-Marc Navenot  1 , Stavros Rafail  2 , Cynthia Kurtis  1 , Mark Carroll  3 , Marian Van Kerckhoven  4 , Sofie Van Rossom  4 , Kelly Schats  4 , Konstantinos Avraam  5 , Robyn Broad  6 , Karen Howe  7 , Ashley Liddle  6 , Amber Clayton  7 , Ruoxi Wang  3 , Laura Quinn  8 , Joseph P Sanderson  8 , Cheryl McAlpine  6 , Carly Carozza  9 , Eric Pimpinella  9 , Susan Hsu  9 , Francine Brophy  10 , Erica Elefant  10 , Paige Bayer  10 , Dennis Williams  11 , Marcus O Butler  12 , Jeffrey M Clarke  13 , Justin F Gainor  14 , Ramaswamy Govindan  15 , Victor Moreno  16 , Melissa Johnson  17 , Janet Tu  18 , David S Hong  19 , George R Blumenschein Jr  20
Affiliations

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

Tianjiao Wang et al. Mol Ther Methods Clin Dev. .

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.

Keywords: HLA; MAGE-A4; T cell receptor; T cell therapy; assay validation; biomarker; clinical trial; immunotherapy; patient screening; precision medicine.

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Conflict of interest statement

T.W., J.-M.N., S.R., C.K., M.C., R.B., K.H., A.L., A.C., R.W., L.Q., J.P.S., C.M., F.B., E.E., P.B., and D.W. are or were employees of Adaptimmune at the time of the study and may own stock/stock options in Adaptimmune. M.V.K., S.V.R., K.S., and K.A. are employees of CellCarta NV, Antwerp, Belgium, and were involved in the development and validation of the MAGE-A4 IHC assay. G.B.J. received consulting fees from AbbVie, Daiichi Sankyo, Eli Lilly, Genzyme, Gilead, Merck Sharp & Dohme, Novartis, Regeneron; expenses from Regeneron; research funding from AstraZeneca, BeiGene, Bristol Myers Squibb, Daiichi Sankyo, Exelixis, Genentech, Incyte, Merck Sharp & Dohme, Novartis, Regeneron. M.O.B. received grant support from Merck, Takara Bio; quality improvement support from Novartis; is on the advisory board of Adaptimmune, Bristol Myers Squibb, GlaxoSmithKline, IDEAYA, Instil Bio, Iovance, La Roche Possey, Medison, Merck, Novartis, Pfizer, Regeneron, Sanofi, Sun Pharma; oral presentations given for Bristol Myers Squibb, Merck, Novartis, Pfizer, Sanofi. J.M.C. received grant/research support from AbbVie, Adaptimmune, Array, AstraZeneca, Bayer, Bristol Myers Squibb, CBMG, Genentech, GlaxoSmithKline, Grid Therapeutics, Medpacto, Moderna, Spectrum; consultant for Amgen, Corbus, G1 Therapeutics, Novartis, Omega, Sanofi, Turning Point, Vivacitas; speaker’s bureau for AstraZeneca. J.F.G. was compensated consultant or received honoraria from AI Proteins, AstraZeneca, Blueprint Medicines, Bristol Myers Squibb, Curie Therapeutics, Genentech/Roche, Gilead, iTeos, Jounce, Karyopharm, Loxo/Lilly, Merck, Merus Pharmacueticals, Mirati, Moderna, Novartis, Novocure, Nuvalent, Pfizer, Silverback Therapeutics, Takeda; research support from Genentech/Roche, Novartis, Takeda; institutional research support from Adaptimmune, Alexo, Array Biopharma, Bristol Myers Squibb, Blueprint Medicines, Jounce, Merck, Moderna, Novartis, Palleon, Tesaro; equity in AI Proteins; and has an immediate family member who is an employee with equity at Ironwood Pharmaceuticals. V.M. received consulting fees from Affimed, AstraZeneca, Bayer, Bristol Myers Squibb, Janssen, Roche, Syneos; was principal investigator – institutional funding from AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca, Bayer, BeiGene, BioInvent International AB, Bristol Myers Squibb, Boehringer, Boston, Celgene, Daichii Sankyo, DEBIOPHARM, Eisai, e-Terapeutics, Exelisis, Forma Therapeutics, Genmab, GlaxoSmithKline, Harpoon, Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Kirin, Lilly, Loxo, MedSir, Menarini, Merck, Merus, Millennium, MSD, Nanobiotix, Nektar, Novartis, Odonate Therapeutics, Pfizer, Pharma Mar, PharmaMar, Principia, PsiOxus, Puma, Regeneron, Rigontec, Roche, Sanofi, Sierra Oncology, Synthon, Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics, Upshersmith. M.J. received research funding (institutional) from AbbVie, Acerta, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, Atreca, BeiGene, BerGenBio, BioAtla, Black Diamond, Boehringer Ingelheim, Bristol Myers Squibb, Calithera Biosciences, Carisma Therapeutics, Checkpoint Therapeutics, City of Hope National Medical Center, Corvus Pharmaceuticals, Curis, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, Dynavax, Eli Lilly, Elicio Therapeutics, EMD Serono, EQRx, Erasca, Exelixis, Fate Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Harpoon, Helsinn Healthcare SA, Hengrui Therapeutics, Hutchison MediPharma, IDEAYA Biosciences, IGM Biosciences, Immunitas Therapeutics, Immunocore, Incyte, Janssen, Jounce Therapeutics, Kadmon Pharmaceuticals, Kartos Therapeutics, Loxo Oncology, Lycera, Memorial Sloan Kettering, Merck, Merus, Mirati Therapeutics, Mythic Therapeutics, NeoImmune Tech, Neovia Oncology, Novartis, Numab Therapeutics, Nuvalent, OncoMed Pharmaceuticals, Palleon Pharmaceuticals, Pfizer, PMV Pharmaceuticals, Rain Therapeutics, RasCal Therapeutics, Regeneron Pharmaceuticals, Relay Therapeutics, Revolution Medicines, Ribon Therapeutics, Rubius Therapeutics, Sanofi, Seven and Eight Biopharmaceuticals/Birdie Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, Stem CentRx, Syndax Pharmaceuticals, Takeda Pharmaceuticals, Tarveda, TCR2 Therapeutics, Tempest Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, Turning Point Therapeutics, University of Michigan, Vyriad, WindMIL Therapeutics, Y-mAbs Therapeutics; had a consulting/advisory role (institutional) for AbbVie, Amgen, Arcus Biosciences, Arrivent, Astellas, AstraZeneca, Black Diamond, Boehringer Ingelheim, Calithera Biosciences, Daiichi Sankyo, EcoR1, Genentech/Roche, Genmab, Genocea Biosciences, Gilead Sciences, GlaxoSmithKline, Gritstone Oncology, Ideaya Biosciences, Immunocore, iTeos, Janssen, Jazz Pharmaceuticals, Merck, Mirati Therapeutics, Molecular Axiom, Normunity, Novartis, Oncorus, Pyramid Biosciences, Regeneron Pharmaceuticals, Revolution Medicines, Sanofi-Aventis, SeaGen, Synthekine, Takeda Pharmaceuticals, Turning Point Therapeutics, VBL Therapeutics. D.S.H. received travel, accommodations, expenses from AACR, ASCO, CLCC, Bayer, Genmab, SITC, Telperian; had consulting, speaker, or advisory role with 28Bio, AbbVie, Acuta, Adaptimmune, Alkermes, Alpha Insights, Amgen, Affini-T, Astellas, Aumbiosciences, Axiom, Baxter, Bayer, Boxer Capital, BridgeBio, CARSgen, CLCC, COG, COR2ed, Cowen, EcoR1, Erasca, Fate Therapeutics, F. Hoffmann-La Roche, Genentech, Gennao Bio, Gilead, GLG, Group H, Guidepoint, HCW Precision Oncology, Immunogenesis, InduPro, Janssen, Liberium, MedaCorp, Medscape, Numab, Oncologia Brasil, ORI Capital, Pfizer, Pharma Intelligence, POET Congress, Prime Oncology, Projects in Knowledge, Quanta, RAIN, Ridgeline, SeaGen, Stanford, STCube, Takeda, Tavistock, Trieza Therapeutics, Turning Point Therapeutics, WebMD, YingLing Pharma, Ziopharm; has other ownership interests in Molecular Match (advisor), OncoResponse (founder, advisor), Telperian (founder, advisor); received institutional research/grant funding from AbbVie, Adaptimmune, Adlai-Nortye, Amgen, AstraZeneca, Bayer, Biomea, Bristol Myers Squibb, Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Endeavor, Erasca, F. Hoffmann-La Roche, Fate Therapeutics, Genentech, Genmab, Immunogenesis, Infinity, Kyowa Kirin, Merck, Mirati, Navier, NCI-CTEP, Novartis, Numab, Pfizer, Pyramid Bio, Revolution Medicine, SeaGen, STCube, Takeda, TCR2, Turning Point Therapeutics, VM Oncology.

Figures

None
Graphical abstract
Figure 1
Figure 1
Relative contribution of HLA-A∗02 inclusion alleles to HLA eligibility for afamitresgene autoleucel by race and ethnicity Overall, most HLA-eligible participants were eligible based on the expression of A∗02:01 or one of its P-group members (in blue, e.g., 02:09 or 02:642), either as the only inclusion allele (heterozygous or homozygous), or combined with another inclusion allele. However, some participants were eligible based only on the expression of other inclusion alleles: A∗02:02 (orange), 02:03 (gray), 02:06 (yellow), or both 02:03 and 02:06 (red). The percentage of eligible participants exclusively expressing these inclusion alleles varied greatly by race and ethnicity. HLA, human leukocyte antigen.
Figure 2
Figure 2
Representative images of histological and MAGE-A4 staining in different cancers screened Tissues from patients with esophagogastric junction (A), melanoma (B), non-small cell lung sarcoma (C), urothelial (D), head and neck (E), myxoid/round cell liposarcoma (F), synovial sarcoma (G), esophageal (H), ovarian (I), or gastric (J) cancers. The cancer tissue was stained with H&E, anti-MAGE-A4 antibody (MAGE-A4), and isotype control (IgG), visualized in the left, middle, and right columns, respectively. MAGE-A4 immunoreactivity demonstrated specific expression in each cancer tissue. Magnification of the images: 40×. H&E, hematoxylin and eosin; IgG, immunoglobulin G; MAGE-A4, melanoma-associated antigen A4.
Figure 3
Figure 3
MAGE-A4 positivity and expression level by tissue location (primary or metastatic) across cancer types (A) MAGE-A4 positivity. (B) MAGE-A4 expression level. an = 199 HNSCC, n = 1 “other” head and neck cancer histology. The dotted line represents the cutoff value of the P score indicating MAGE-A4 positivity. EGJ, esophagogastric junction cancer; HNSCC, head and neck squamous cell carcinoma; M, metastatic; MAGE-A4, melanoma-associated antigen A4; MRCLS, myxoid/round cell liposarcoma; NSCLC, non-small cell lung cancer; P, primary; P score, protein score; SyS, synovial sarcoma.
Figure 4
Figure 4
MAGE-A4 positivity and expression level by histopathology (A) MAGE-A4 positivity. (B) MAGE-A4 expression level. AC, adenocarcinoma; MAGE-A4, melanoma-associated antigen A4; MAGE-A4+, MAGE-A4 positive; NSCLC, non-small cell lung cancer; P score, protein score; SCC, squamous cell carcinoma.
Figure 5
Figure 5
Effect of patient age on MAGE-A4 positivity and expression level across cancer types (A) MAGE-A4 positivity. (B) MAGE-A4 expression level. an = 199 HNSCC, n = 1 “other” head and neck cancer histology. bPatient age was determined at biopsy collection. The dotted line represents the cutoff value of the P score indicating MAGE-A4 positivity. EGJ, esophagogastric junction cancer; HNSCC, head and neck squamous cell carcinoma; MAGE-A4, melanoma-associated antigen A4; MAGE-A4+, MAGE-A4 positive; MRCLS, myxoid/round cell liposarcoma; NSCLC, non-small cell lung cancer; P score, protein score; SyS, synovial sarcoma.
See this image and copyright information in PMC

References

    1. Creelan B.C., Wang C., Teer J.K., Toloza E.M., Yao J., Kim S., Landin A.M., Mullinax J.E., Saller J.J., Saltos A.N., et al. Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer: a phase 1 trial. Nat. Med. 2021;27:1410–1418. doi: 10.1038/s41591-021-01462-y. - DOI - PMC - PubMed
    1. Sarnaik A.A., Hamid O., Khushalani N.I., Lewis K.D., Medina T., Kluger H.M., Thomas S.S., Domingo-Musibay E., Pavlick A.C., Whitman E.D., et al. Lifileucel, a tumor-infiltrating lymphocyte therapy, in metastatic melanoma. J. Clin. Oncol. 2021;39:2656–2666. doi: 10.1200/JCO.21.00612. - DOI - PMC - PubMed
    1. Schuster S.J., Bishop M.R., Tam C.S., Waller E.K., Borchmann P., McGuirk J.P., Jäger U., Jaglowski S., Andreadis C., Westin J.R., et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N. Engl. J. Med. 2019;380:45–56. doi: 10.1056/NEJMoa1804980. - DOI - PubMed
    1. Stevanovic S., Draper L.M., Langhan M.M., Campbell T.E., Kwong M.L., Wunderlich J.R., Dudley M.E., Yang J.C., Sherry R.M., Kammula U.S., et al. Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells. J. Clin. Oncol. 2015;33:1543–1550. doi: 10.1200/JCO.2014.58.9093. - DOI - PMC - PubMed
    1. Zacharakis N., Chinnasamy H., Black M., Xu H., Lu Y.C., Zheng Z., Pasetto A., Langhan M., Shelton T., Prickett T., et al. Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer. Nat. Med. 2018;24:724–730. - PMC - PubMed