Targeting non-mutated MHC-I immunopeptides in head and neck cancers with T-cell adoptive therapy

Primary supervisor: Sergio Quezada, UCL

Secondary supervisor: Tony Ng, King’s College London

Project

The Major Histocompatibility Complex-I (MHC-I) plays a crucial role in the development of the adaptive immune response. Despite the recognised clinical benefit of MHC-I associated peptides, the accurate isolation of these sequences has been termed the ‘Achilles heel’ of immunopeptidomics as recently as 2020 (1).
To date, the field of cancer vaccines has been dominated by an interest in mutated protein sequences, commonly termed neoantigens. The development of vaccines against mutated neoantigens relies on the accurate identification of mutated epitopes. The most used methodology relies on next-generation sequencing and in silico neoantigen prediction algorithms. However, only a very small proportion of neoantigens identified via this methodology were capable of inducing an immune response in preclinical models. Furthermore, like many cancer mutations, the majority of neoantigens are unique to each individual (2). The generation of a cancer vaccine based on a neoantigen will require a personalised, tedious and costly approach.

Advanced head and neck squamous cell carcinoma (HNSCC) is associated with a poor prognosis. While conventionally treated with cytotoxic chemotherapy with modest responses, the success of the KEYNOTE- 048 trial demonstrated the potential of immune checkpoint inhibitors in improving durable responses and survival outcomes in this patient population. However, the survival benefits are marginal, especially in patients with tumours who do not express PD-L1 (Combined Predictive Score, CPS≤1) (3, 4). Moreover, patients with the HLA-A*03 allele have demonstrated poorer responses to immune checkpoint inhibitors (5). Therefore, there is an unmet clinical need for HLA-A*03:01 patients, which encompass up to a quarter of the patient population.

This project has been developed from data generated from previous work that showed patient with HLA- A*03:01 share 40 MHC-I peptide sequences which are tumour exclusive (when compared to matched normal adjacent tissue).

Aims:

1. Identification of antigen reactive clonal TCRs and abundance in patient’s blood throughout tumour evolution
   The student will build a bioinformatic pipeline to identify antigen reactive TCRs from previous reactive hits. The student will also assess the presence of the specific peripheral blood TCRs in the HNSCC patient cohort at the time of surgical resection and throughout cycles of treatment.
2. Development of several engineered TCRs with different modalities to elicit strong immune response
   The student will clone several TCRs that have already shown to have a strong immune response and expanded clonally in vitro in the presence of the target antigen. Moreover, the student will test different generations of TCRs to test specificity to cancer antigens.
3. Test potential engineered TCRs in vitro to observe clonal expansion and tumour penetration and develop combinatory immunotherapies
   Top candidates will be validated with co-culture patient-derived organoids and patient-derived explants to test 1) tissue penetration within the solid tumour; 2) Tumour killing; 3) observe relationship between TCR-T cells and tumour immune microenvironment and 4) observe if combination with anti-PD-1 or anti-PDL1 treatment with cloned TCR elicits strong immune response for tumour killing.

Candidate background

Enthusiastic about cancer immunology and keen to develop and validate engineered TCRs in the setting of HNSCC. The ideal candidate must hold a BSc or MSc in a related field with previous experience in molecular biology and primary cell culturing.

Potential Research Placements

1. Benny Chain, Division of Infection and Immunity, UCL
2. Martin Pule, UCL Cancer Institute
3. Tony Ng, King’s College London

References

1. Vizcaino, J.A., et al., The Human Immunopeptidome Project: A Roadmap to Predict and Treat Immune Diseases. Mol Cell Proteomics, 2020. 19(1): p. 31-49.
2. The problem with neoantigen prediction. Nat Biotechnol, 2017. 35(2): p. 97.
3. Burtness, B., et al., Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet, 2019. 394(10212): p. 1915-1928.
4. Burtness, B., et al., Pembrolizumab Alone or With Chemotherapy for Recurrent/ Metastatic Head and Neck Squamous Cell Carcinoma in KEYNOTE-048: Subgroup Analysis by Programmed Death Ligand-1 Combined Positive Score. J Clin Oncol, 2022: p. JCO2102198.
5. Naranbhai, V., et al., HLA-A*03 and response to immune checkpoint blockade in cancer: an epidemiological biomarker study. Lancet Oncol, 2022. 23(1): p. 172-184.