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TCR T-cell therapies are currently being studied to determine safety and efficacy through clinical trials.

Role of biomarkers in T-cell receptor T-cell therapies

T-cell receptor (TCR) specificity

TCR specificity is responsible for the ability to recognize self and non-self (eg, virus, tumor cells).1,2 Human leukocyte antigens (HLAs) also have a role in regulating the activation or suppression of the immune response.1,3 Most of the TCR T-cell therapies under investigation take advantage of this selectivity to target and kill cancer cells.2

Relevance of HLA typing

Candidates for HLA-dependent TCR T-cell therapy clinical trials are screened via HLA typing through a peripheral blood sample. Therefore, HLA testing can likely occur locally.4-6

Evaluating CTA expression

For TCR T-cell therapies that target CTAs, screening for target tumor antigen expression is also necessary and can be done using immunohistochemistry (IHC).7-9

Because TCR T-cell therapy depends on target expression in the tumor, a biopsy is required for analysis until new technologies allow for assessments via blood samples. Therefore, expression assays for the tumor antigen protein or messenger RNA (mRNA) are used on tumor tissue. The specific amount of tumor tissue needed varies depending on the purpose.4,10-15

Key emerging CTA types and their expression16-22

Key Emerging Cancer Testis Antigens table

CTA=cancer/testis antigen; GP100=glycoprotein 100; MAGE=melanoma-associated antigen; MART-1=melanoma antigen recognized by T cells; NY-ESO-1=New York esophageal squamous cell carcinoma 1; PAGE5=P antigen family member 5; PRAME=preferentially expressed antigen in melanoma; SSX=synovial sarcoma X.

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TCR T-cell therapy treatment process

References

  1. Crux NB, Elahi S. Human leukocyte antigen (HLA) and immune regulation: how do classical and non-classical HLA alleles modulate immune response to human immunodeficiency virus and hepatitis C virus infections? Front Immunol. 2017;8:832.
  2. Zhang J, Wang L. The emerging world of TCR-T cell trials against cancer: a systematic review. Technol Cancer Res Treat. 2019;18:1533033819831068.
  3. Ravindranath MH, Hilali FE, Amato-Menker CJ, Hilali HE, Selvan SR, Filippone EJ. Role of HLA-I structural variants and the polyreactive antibodies they generate in immune homeostasis. Antibodies (Basel). 2022;11(3):58.
  4. Tsimberidou AM, Van Morris K, Vo HH, et al. T-cell receptor-based therapy: an innovative therapeutic approach for solid tumors. J Hematol Oncol. 2021;14(1):102.
  5. Wang T, Navenot JM, Rafail S, et al. Identifying MAGE-A4–positive tumors for SPEAR T-cell therapies in HLA-A*02–eligible patients. Presented at: American Association for Cancer Research (AACR) Annual Meeting; April 8-13, 2022; New Orleans, LA. Poster LB001.
  6. Schinstock CA, Gandhi MJ, Stegall MD. Interpreting anti-HLA antibody testing data: a practical guide for physicians. Transplantation. 2016;100(8):1619-1628.
  7. Doran SL, Stevanović S, Adhikary S, et al. T-cell receptor gene therapy for human papillomavirus-associated epithelial cancers: a first-in-human, phase I/II study. J Clin Oncol. 2019;37(30):2759-2768.
  8. Novosiadly R, Kalos M. High-content molecular profiling of T-cell therapy in oncology. Mol Ther Oncolytics. 2016;3:16009.
  9. Leko V, Rosenberg SA. Identifying and targeting human tumor antigens for T cell-based immunotherapy of solid tumors. Cancer Cell. 2020;38(4):454-472.
  10. Buonaguro L, Tagliamonte M. Selecting target antigens for cancer vaccine development. Vaccines (Basel). 2020;8(4):615.
  11. Yarchoan M, Johnson BA III, Lutz ER, Laheru DA, Jaffee EM. Targeting neoantigens to augment antitumour immunity. Nat Rev Cancer. 2017;17(4):209-222.
  12. D’Angelo SP, Demetri GD, Van Tine BA, et al. Final analysis of the phase 1 trial of NY-ESO-1–specific T-cell receptor (TCR) T-cell therapy (letetresgene autoleucel; GSK3377794) in patients with advanced synovial sarcoma (SS). Presented at: Connective Tissue Oncology Society (CTOS) Annual Meeting [Virtual Format]; November 18-21, 2020. Paper 03.
  13. Duraiyan J, Govindarajan R, Kaliyappan K, Palanisamy M. Applications of immunohistochemistry. J Pharm Bioallied Sci. 2012;4(suppl 2):S307-S309.
  14. Myint KZY, Shimabuku M, Horio R, Kaneda M, Shimizu Y, Taguchi J. Identification of circulating tumour DNA (ctDNA) from the liquid biopsy results: findings from an observational cohort study. Cancer Treat Res Commun. 2023;35:100701.
  15. Kim SW, Jin R, Park CS. Immunohistochemistry for pathologists: protocols, pitfalls, and tips. J Path Transl Med. 2016;50(6):411-418.
  16. Li XF, Ren P, Shen WZ, Jin X, Zhang J. The expression, modulation and use of cancer-testis antigens as potential biomarkers for cancer immunotherapy. Am J Transl Res. 2020;12(11):7002-7019.
  17. Zhang B. Cancer testis antigens and immunotherapy: a new dawn. E3S Web of Conferences. 2021;251:02033.
  18. Hong DS, Van Tine BA, Biswas S, et al. Autologous T cell therapy for MAGE-A4+ solid cancers in HLA-A*02+ patients: a phase 1 trial. Nat Med. 2023;29(1):104-114.
  19. Lezcano C, Jungbluth AA, Nehal KS, Hollmann TJ, Busam KJ. PRAME expression in melanocytic tumors. Am J Surg Pathol. 2018;42(11):1456-1465.
  20. Chen YT, Stockert E, Jungbluth A, et al. Serological analysis of Melan-A(MART-1), a melanocyte-specific protein homogeneously expressed in human melanomas. Proc Natl Acad Sci U S A. 1996;93(12):5915-5919.
  21. Martinez-Perez D, Viñal D, Solares I, Espinosa E, Feliu J. Gp-100 as a novel therapeutic target in uveal melanoma. Cancers (Basel). 2021;13(23):5968.
  22. Clemente O, Ottaiano A, Di Lorenzo G, et al. Is immunotherapy in the future of therapeutic management of sarcomas? J Transl Med. 2021;19(1):173.