Overview of Tumor-Associated Antigens: Key Targets for T Cell Engagers in Cancer Therapy

T cell engagers (TCEs) are a promising class of immunotherapies that facilitate the immune system's attack on cancer cells by bringing T cells, a type of immune cell, into close proximity with the cancer cells. The mechanism involves two binding domains: the first recognizes and attaches to a tumor-associated antigen (TAA) on the surface of cancer cells, while the second binds to the CD3 receptor on T cells, a crucial component of the T-cell receptor (TCR) complex essential for T-cell activation. This review introduces some common TAA targets.

CD19

Applications: CD19 is a B cell surface protein and well-known target, primarily used in treating B cell malignancies such as acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma.

Current Status: Bispecific T cell engagers (BiTEs) targeting CD19 have shown considerable success ^[1], with Blinatumomab (Blincyto) being an FDA-approved example ^[2].

CD20

Applications: CD20 is another B cell surface marker commonly targeted in B cell lymphomas and leukemias, including diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia.

Current Status: CD20-targeting T cell engagers are currently under clinical development and are being explored in clinical trials ^[3].

B-cell Maturation Antigen (BCMA)

Applications: BCMA is expressed on malignant plasma cells and is a key target for multiple myeloma treatment.

Promising Candidates: BCMA-targeting T cell engagers, such as AMG 420 and AMG 701, are under investigation and have shown promising results in clinical trials ^[4].

Human Epidermal growth factor Receptor 2 (HER2) and Epidermal Growth Factor Receptor （EGFR）

Applications: HER2 is overexpressed in certain breast and gastric cancers, making it a common target in solid tumors. Similarly, EGFR is overexpressed in a range of solid tumors, including lung, colorectal, and head and neck cancers.

Development: Precision-activated T cell engagers targeting HER2 or EGFR and CD3 have been engineered to enhance the therapeutic index and minimize off-target effects ^[5]. Bispecific T cell engagers for HER2 are in development, and although HER2 is more commonly known as a target for monoclonal antibodies in breast cancer, it is also being explored as a target for T cell engagers in various cancers ^[6]. Similarly, T cell engagers targeting EGFR are being explored for various solid tumors.

Prostate-specific membrane antigen (PSMA)

Applications: PSMA is highly expressed in prostate cancer cells and is used in therapies to redirect T cells toward PSMA-expressing tumor cells. T cell engagers targeting PSMA are in development and hold promise for treating prostate cancer ^[7].

These TAAs represent significant advancements in cancer immunotherapy, offering new hope for targeted and effective treatments against various malignancies.

References

[1] de Miguel M, Umana P, Gomes de Morais AL, Moreno V, Calvo E. T-cell-engaging Therapy for Solid Tumors. Clin Cancer Res. 2021 Mar 15;27(6):1595-1603. doi: 10.1158/1078-0432.

[2] Topp MS, Gökbuget N, et al.. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015 Jan;16(1):57-66. doi: 10.1016/S1470-2045(14)71170-

[3] American Association for Cancer Research (aacrjournals.org)

[4] Raje N, Berdeja J, Lin Y, et al. Anti-BCMA CAR T-Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma. N Engl J Med. 2019 May 2;380(18):1726-1737. doi: 10.1056/NEJMoa1817226.

[5] Cattaruzza F, Nazeer A, To M, et al.. Precision-activated T-cell engagers targeting HER2 or EGFR and CD3 mitigate on-target, off-tumor toxicity for immunotherapy in solid tumors. Nat Cancer. 2023 Apr;4(4):485-501. doi: 10.1038/s43018-023-00536-9.

[6] Necchi A, Bratslavsky G, Chung J, et al. Genomic Features for Therapeutic Insights of Chemotherapy-Resistant, Primary Mediastinal Nonseminomatous Germ Cell Tumors and Comparison with Gonadal Counterpart. Oncologist. 2019 Apr;24(4):e142-e145. doi: 10.1634/theoncologist.2018-0430.

[7] Trzeciak, A.R., Nyland, S.B., & McCall, J.M. EpCAM as a novel therapeutic target in solid tumors. Current Pharmaceutical Design, 2003 9(22), 1841-1850. doi:10.2174/1381612033453868