219P - The landscape and prognostic impact of germline HLA-A subtypes in patients with advanced solid cancers

Background

It is unclear if specific cancers are enriched with specific HLA-A subtypes and whether these subtypes carry a prognostic significance.

Methods

This is a retrospective analysis of patients who underwent CLIA-approved germline HLA status testing as part of advanced immune and cell therapy trials undertaken at the Christie NHS Foundation trust. The HLA-A allele status was evaluated via polymerase sequence-specific primer (PCR-SSP) typing systems employed during pre-screening for the respective clinical trials. An independent healthy cohort composed of 5042 UK residents with HLA genotyping was used for comparison. False discovery rate (FDR) is used to adjust for multiple hypothesis testing.

Results

The HLA-A subtype was available for 285 patients with advanced solid cancers. The median age at diagnosis was 57 years (range of 19 – 82 years). The median follow up was 4.3 years. Eight tumor categories were identified in our cohort with NSCLC (n=93), and melanoma (n=60) being the most frequent. The observed A02:01 frequencies across the 8 cancer categories were significantly different from the expected frequencies (highest in sarcoma (53%), melanoma (46%), and head and neck squamous cell carcinoma (HNSCC) (40%), Goodness-of-Fit p<0.0001). The healthy cohort was more enriched with A02 (49.9% vs 42.2%, FDR p= 0.05) whereas our cancer cohort was more enriched with A32 (11% vs 6.7%, FDR p= 0.05). The median overall survival (OS) ranged from 23 months for HNSCC to 67 months for ovarian cancer and it was 58 and 30 months for melanoma and NSCLC subtypes, respectively. HLA-A01 was associated with better OS in patients with NSCLC (hazard ratio (HR):0.44, 95% confidence intervals (CI): 0.24-0.79, FDR p=0.03) and worse OS in patients with sarcoma (HR: 5.17, 95% CI: 1.45-18.44, FDR p=0.03). In addition, the HLA-A03 was associated with worse OS in patients with urothelial cancer (HR: 5.02, 95% CI: 1.38-18.24, FDR p=0.03).

Conclusions

Our findings suggest a tumor lineage-specific link with HLA-A02:01 status. Specific HLA subtypes are enriched in cancer patients and carry a prognostic value.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The Christie NHS Foundation Trust.

Funding

European School of Oncology (ESO); The Christie NHS Foundation Trust.

Disclosure

K.S. Shohdy: Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Institutional, Research Grant: AstraZeneca, Novartis; Financial Interests, Other, Educational Grant: Adaptimmune. F. Thistlethwaite: Financial Interests, Personal, Advisory Board, Ad board: BMS; Financial Interests, Personal, Advisory Board, Ad boards: GSK; Financial Interests, Personal, Advisory Board, Adboard/consultancy: T-Knife Therapeutics; Financial Interests, Personal, Advisory Board: Immatics, Scenic Biotech, F-Star, Leucid; Financial Interests, Personal, Invited Speaker: Kite Gilead; Financial Interests, Personal, Other, Occasional individual consulting: Guidepoint; Financial Interests, Personal, Advisory Board, Advisory board meeting Feb 2023: CytomX; Financial Interests, Personal, Advisory Board, Advisory board Feb 2024: Grey Wolf Therapeutics; Financial Interests, Institutional, Other, iMATCH is a consortium funded by not for profit Innovate UK (UK government body) partners include clinical and academic institutes. I am director and my salary (0.2WTE) is supported through this work as a grant to my institution (The Christie NHS foundation trust - not for profit NHS hospital) from IUK: iMATCH director; Financial Interests, Institutional, Local PI, NCT02890069: Novartis; Financial Interests, Institutional, Research Grant, Sarcoma pathways project and CAR-T PROMs study: GSK; Financial Interests, Institutional, Local PI, NCT02493751: Pfizer; Financial Interests, Institutional, Local PI, NCT03245736, NCT02988817, NCT02552121, NCT02001623, NCT05180474: GenMab; Financial Interests, Institutional, Local PI, NCT02277717: Synthon; Financial Interests, Institutional, Local PI, NCT03013491: CytomX; Financial Interests, Institutional, Local PI, NCT03314935: Incyte; Financial Interests, Institutional, Local PI, NCT02908906 and CAR-T referrals project: Janssen; Financial Interests, Institutional, Local PI, NCT03132792, NCT04044768,: Adaptimmune; Financial Interests, Institutional, Local PI, NCT03400332: BMS; Financial Interests, Institutional, Local PI, NCT04262466, NCT03973333, NCT03515551: Immunocore; Financial Interests, Institutional, Local PI, EudraCT 2018-001005-85, 2018-003446-16: Achilles ltd; Financial Interests, Institutional, Local PI: Agalimmune Ltd; Financial Interests, Institutional, Local PI, NCT02834247: Millenium Pharmaceuticals/Takeda; Financial Interests, Institutional, Local PI, NCT02690350: Daiichi Sankyo; Financial Interests, Institutional, Local PI, NCT04839991: Crescendo; Financial Interests, Institutional, Local PI, NCT05104515: Oxford Vacmedix Ltd; Financial Interests, Institutional, Local PI, NCT05278975: RS Oncology LLC; Financial Interests, Institutional, Coordinating PI, NCT03697824, NCT03391778: GSK; Financial Interests, Institutional, Coordinating PI, NCT04140500, NCT04857138, NCT04826003: Roche; Financial Interests, Personal, Coordinating PI, NCT05008913, NCT04949425, NCT0331509, NCT03313557: AstraZeneca; Financial Interests, Institutional, Coordinating PI, NCT03829501: Kymab Ltd/Sanofi; Financial Interests, Institutional, Coordinating PI, EudraCT 2019-003329-11: Chugai; Financial Interests, Institutional, Coordinating PI, NCT05430555: T-Knife Therapeutics; Financial Interests, Institutional, Coordinating PI, NCT03621982: ADCT Therapeutics; Financial Interests, Institutional, Research Grant, IRAS Project ID: 227414: Novartis; Financial Interests, Institutional, Coordinating PI, ITIL-306-202: Instil Bio; Financial Interests, Institutional, Funding, CAR-T referrals project: Gilead, Autolus; Financial Interests, Institutional, Local PI, NCT04763083: Novalgen; Financial Interests, Institutional, Local PI, NCT05714553: Nucana; Non-Financial Interests, Other, Panel member for a funding committee (MRC is a UK government NFP organisation) 2020-2024: MRC DPFS panel member; Non-Financial Interests, Advisory Role, Sarcoma UK is a not-for-profit charity. I act as an advisor on their Research Strategy Committee. This role is not compensated: Sarcoma UK; Non-Financial Interests, Leadership Role, Funding is from not-for-profit government bodies. Role is not compensated.: Chair of the Independent Steering Committee for NIHR Blood & Transplant Research Unit, Oxford; Non-Financial Interests, Advisory Role, Funding panel member for CRUK (not-for profit charity). Role is not compensated: CRUK New Agents Committee Member; Non-Financial Interests, Leadership Role, Chair of Cell therapy subgroup. MRC is a not-for-profit organisation. Role is not compensated.: MRC Advanced Therapies Task Group; Non-Financial Interests, Leadership Role: ESMO Congress 2024 Experimental Immunotherapy Track Chair; Non-Financial Interests, Advisory Role: ESMO TAT conference scientific advisory board 2025; Non-Financial Interests, Advisory Role, Target Ovarian Cancer is a not-for-profit charity. I am Chair of their Scientific Advisory board. This role is not compensated: Target Ovarian Cancer. All other authors have declared no conflicts of interest.