Engineered T Cell Receptor-T Cell Therapies

In the past two decades, significant advances in immunology have improved our understanding of immune checkpoint mechanisms and the role of T-cell receptors (TCRs) recognizing tumour antigens and tumour cell eradication (1). This knowledge has led to the development of several immune checkpoint inhibitors (ICIs) such as anti-programmed cell death protein 1 (PD-1) and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) treatments. Although ICIs have cured many cancer patients, some patients fail to respond to ICIs due to the limited presence of tumour-specific effector T cells (2).

Adoptive T-cell therapies

Adoptive T-cell therapies (ACTs), which include chimeric antigen receptor T cells (CAR-T), tumour-infiltrating lymphocytes (TILs), and engineered T-cell receptor-T cells (TCR-Ts), have the potential to overcome these shortfalls. To date, six CAR-T therapies targeting CD19 or B cell maturation antigen have been approved by the regulators and have shown encouraging results in haematological cancers; however, their clinical impact on solid tumours has been modest due to antigen scarcity, tumour heterogeneity, and immunosuppression within the tumour microenvironment (TME) (3–4). Thus, companies have been exploring other ACT approaches to overcome these issues (5–6).

Engineered T-cell receptor-T cell therapies

TCR-T increases the flexibility for targeting solid tumours, particularly those with a high mutational burden (HMB). Unlike TILs, one does not need access to the primary tumour, which allows the use of upstream sources of material, for example, peripheral blood. Importantly, TCR-T cells can target inside the cell surface and recognize a broader range of epitopes than CAR-T cells and up to 90% of cellular proteins, including:

• tumour-associated antigens (TAAs) that are over-expressed in cancer cells compared with normal tissues. For example, tissue differentiation antigens (TDAs) such as melanoma antigen recognized by T 1 (MART-1) and gp100, and cancer germline antigens (CGAs) such as melanoma-associated antigen A (MAGE-A) protein family, New York oesophageal squamous cell carcinoma-1 (NY-ESO-1), and preferentially expressed antigen in melanoma (PRAME)
• tumour-specific antigens (TSAs) or neoantigens (NAs) that are exclusively expressed in tumour cells. For example, TP53 and Kirsten rat sarcoma virus (KRAS)
• viral antigens, for instance, antigens stemming from viral-induced cancers such as Epstein-Barr virus (EBV), human papillomavirus (HPV), hepatitis B virus (HBV), and Merkel cell polyomavirus (MCPyV).

Importantly, TCR-T cells exhibit high antigen sensitivity that could result in improved tumour cell detection and removal, and they are associated with a high level of T cell persistence (7). More than 30 clinical trials are underway exploring the potential of TCR-T cells in haematological and solid tumours (Table I).

Allogeneic “off-the-shelf” solutions are emerging

The use of gene editing in autologous (patient-derived) CAR-T and TCR-T cell therapies is dictated by the compatibility of the highly polymorphic HLA molecules between donors and recipients, which can lead to graft-versus-host disease (GVHD) and rejection. Academic researchers and biotechs are looking at ways to generate “off-the-shelf” or allogeneic (universal) solutions using virus-specific T cells, lipid-restricted (CD1) T cells, MR1-restricted T cells, and γδ-TCR T cells (8). This approach could enable TCR-T therapies to be produced more cost-effectively and be made available to a broader patient population. For instance, researchers at Princess Máxima Center for Paediatric Oncology, Utrecht, The Netherlands, have engineered allogeneic cord blood-derived CD8+ T cells with a specific TCR targeting the tumour-associated antigen WT1 to achieve high efficiency and potent cytotoxicity against AML cells (9).

European biotech investing in TCR-T therapies

Several European biotechs are leading the way in TCR-T therapies, including the following.

Anocca AB, Sweden. The biopharma company was co-founded by CEO Reagan Jarvis in 2014 to develop TCR-T therapies to treat solid tumours and other difficult-to-treat diseases, including infectious and autoimmune diseases. Its proprietary TCR discovery platform systematically maps cancer targets to build TCR libraries and generate personalized TCR-T treatments. To date, the company has raised US$120 million (€111 million) in three funding rounds, attracting investment from AMF, Danske Bank, European Investment Bank, Melby Gard, and others (10). In May 2024, Anocca teamed up with Shinobi Therapeutics to co-develop “off-the-shelf” allogeneic TCR-induced pluripotent stem cell (iPS)-T-cell therapies for the treatment of solid tumours (11). In March 2025, Anocca received authorization for its Clinical Trial Application (CTA) to initiate a Phase I/II, VIDAR-1 trial with ANOC-001, a non-viral gene-edited TCR-T therapy targeting mutant KRAS G12V in advanced pancreatic cancer. Anocca aims to initiate the study in the second quarter of 2025 and enrol 20 patients with HLA and KRAS mutations at leading medical centres in Sweden, Denmark, Germany, and the Netherlands (12).

Immunocore, UK. Immunocore was founded by Bent Jakobsen and James Noble in 2008 as a spinout of MediGene AG. The core TCR technology was developed at Oxford University in 1999. The company has raised more than US$574 million (€531 million) and undertook an IPO in February 2021. Immunocore’s proprietary TCR technology generates a novel class of bispecific biologics called ImmTAC (Immune mobilizing monoclonal TCRs Against Cancer) that enable the immune system to recognize and eliminate virally infected cells. ImmTACs recognize intracellular cancer antigens and selectively kill haematological and solid tumour cells via an anti-CD3 immune-activating effector function. In January 2022, the US Food and Drug Administration (FDA) approved Kimmtrak (tebentafusp), a bispecific gp100 peptide-HLA-directed CD3 T cell engager, for the treatment of metastatic uveal melanoma (13). Kimmtrak generated global sales of US $310 million (€280 million) in 2024. Tebentafusp is currently being evaluated in two Phase III trials (TEBE-AM and ATOM) in additional melanoma indications. Immunocore is evaluating brenetafusp (IMC-F106C) targeting PRAME-A02 in the Phase III PRISM-MEL-301 in first-line advanced cutaneous melanoma and a Phase I/II trial of brenetafusp combinations in ovarian cancer and NSCLC. In addition, the company is evaluating an IMC-P115C targeting PRAME-A02-HLE in a Phase I trial for colorectal and other gastrointestinal cancers (14). The company is also evaluating the ImmTAC technology in infectious diseases (HIV and HBV) and autoimmune diseases (type 1 diabetes and dermatology) (15).

Medigene, Germany. Medigene is an immuno-oncology platform company developing TCR-T therapies. Its End-to-End Platform aims to generate and optimize TCRs for multiple therapeutic modalities, including TCR-guided T cell engager therapies (TCR-TCEs), TCR-natural killer (TCR-NK) cell therapies, and TCR-T cell therapies. The company has codeveloped an allogeneic TCR-TCE therapy, MDG3010, with WuXi Biologics that targets KRAS G12V in solid tumours. It is also developing autologous TCR-T therapies, including MDG1015 (NY-ESO01/LAGE-1a), MDG2011 (KRAS G12V), MGD2021 (KRAS G12D), and MDG2012 (KRAS G12V) (16). Medigene has forged partnerships with BioNTech and Regeneron where it is codeveloping a PRAME TCR-T and MAGE-A4 TCR-T therapy, respectively (17). In February 2025, the company partnered with EpimAb Biotherapeutics to develop MCD3020, an allogeneic TCR-TCE for the treatment of solid tumours and immune-related disorders (18).

Biotechs in the US and the Asian Pacific are active in the TCR-T space

In the United States, Adaptimmune Therapeutics and Iovance Biotherapeutics have received regulatory approval for ACTs. In March 2024, FDA approved Iovance’s Amtagvi (lifileucel), the first TIL therapy for advanced melanoma following anti-PD1 and targeted therapy (19). In clinical studies, the overall response rate for pooled data in 153 patients was 31.4%, the median duration of response (mDOR) was 21.5 months, and the four-year pooled analysis mDOR was not reached at 48.1 months. In August 2024, FDA approved Adaptimmune’s Tecelra (afamitresgene autoleucel), the first MAGE-A4-targeted TCR-T therapy for unresectable or metastatic synovial sarcoma (20). Among the 44 patients in the trial who received Tecelra, the overall response rate was 43.2%, and the median duration of response was six months.

Several other US biotech companies are evaluating TCR-T therapies in the clinic, including BioNTech, Cartesian Therapeutics, Immatics, and Regeneron. Immatics has developed three proprietary platforms: an autologous ACTengine, an allogeneic ACTallo platform, and an antibody-like TCR bispecific platform or T cell engaging receptors (TCER). Its lead programme, IMA203, uses ACTengine technology and is currently being evaluated in the Phase III SUPRAME targeting PRAME in heavily pretreated metastatic melanoma patients (21).

In January 2025, BioNTech published proof-of-concept data from Phase I trials with BNT221, a personalised, neoantigen-specific autologous T-cell product derived from peripheral blood (22). The infused T cells were highly specific, polyfunctional, and cytotoxic and expressed TCRs with a wide range of avidities in patients with advanced melanoma. The treatment was well-tolerated, and the vast majority of adverse events observed were attributed to the lymphodepletion chemotherapy preceding BNT221 infusion.

Other US biotechs working in this field include Alaunos Therapeutics, Affini-T Therapeutics, BlueSphere Bio, and TScan Therapeutics.

In the Asian-Pacific region, HRYZ Biotech, Neowise Biotechnology, Precision Biotech, and TCRCure Biological Technology in China; Lion TCR and SCG Cell Therapy in Singapore; and Takara Bio in Japan all have products in early clinical development.

Future directions

Advances in TCR-T applications and the clinical approval of novel ACTs have paved the way for a new generation of T-cell therapies targeting solid tumours (23). Despite the promising clinical results, the total time to manufacture the cell product still limits the broader use of ACT therapies. Like CAR-T therapies, TCR-T cell therapy requires cellular expansion; however, the CAR-T field is moving towards in-vivo approaches. Further work is needed to enhance the potency, expansion, and persistence of T-cells; this may be achieved by combining products such as PD-1 inhibitors/TCR-T or cancer vaccine/TCR-T therapy (24).

Alternatively, the development of allogeneic TCR-T therapies could provide a cost-effective “off-the-shelf” solution, enabling patients broader access to these innovative therapies. Several large pharma companies, AstraZeneca, Galapagos, GlaxoSmithKline, and Shionogi, have TCR-T programmes in clinical development, and this field is likely to attract further investment from biopharma and private investors as proof-of-concept studies report out.

References

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About the author

Cheryl Barton is founder and director of PharmaVision, Pharmavision.co.uk.

Article details

Pharmaceutical Technology Europe
Vol. 37, No. 3
April 2025
Pages: 8–12

Citation

When referring to this article, please cite it as Barton, C. Engineered T Cell Receptor-T Cell Therapies. Pharmaceutical Technology Europe 2025 37 (3).