T cell engagers or TCEs represent a revolutionary class of immunotherapeutic proteins that function as molecular bridges between the immune system’s T cells and harmful cells in the body. These engineered molecules act like biological matchmakers, specifically binding to T cells with one arm while using their other arm to grab onto cancer cells or infected cells. This precise linking triggers T cells to launch a powerful, targeted attack against these harmful cells. [1]
Think of TCEs as sophisticated guidance systems that help T cells, our body’s natural defense force, find and eliminate threats they might otherwise miss. By creating this artificial connection, TCEs essentially force an interaction that results in the T cell releasing its arsenal of cell-killing compounds directly at the target cell. [1]
The remarkable success of TCE therapy, particularly in hematological cancers, has, over the last decade, led to several FDA-approved treatments. Their effectiveness has sparked ongoing intense research into their potential use against solid tumors, marking them as one of the most promising advances in modern cancer immunotherapy.[1][2] And this promises is seen in global expansion of the immuno-oncology (IO) market, which expanded at an impressive 24.3% compound annual growth rate from $10.4 billion in 2014 to $74 billion in 2024.
This initial market growth was fueled by the success of immune checkpoint inhibitors (ICIs) and CAR-T cell therapies. As many of the ICIs approach the patent cliff, the spotlight has shifted toward next-generation therapies.
According to GlobalData, a global date and analytics company, among these, bispecific T-cell engagers (TCEs) have gained traction, with multiple recent approvals in both hematologic and solid tumor indications.
In 2024, TCEs accounted for 10% of the IO market; this share will rise to 35% by 2031, while ICIs will decline from 77% to 43% of the projected $186 billion market over the same period. [3]
Start of a revolution
The approval of the CD19/CD3-targeting TCE blinatumomab (Blincyto®; Amgen), a recombinant murine protein that acts as a bispecific CD19-directed CD3 T-cell engager, on December 3, 2014, for the treatment of Philadelphia chromosome-negative relapsed or refractory (R/R) precursor B-cell acute lymphoblastic leukemia (ALL), not only demonstrated the clinical potential of this technology, but also set off a wave of new research to extend TCE therapies beyond hematologic malignancies and into solid tumors. [4][5]
But the ‘revolution’ did not stop here. TCEs are not just changing the treatment for adult patients, they are also significantly improving disease-free survival (DFS) in pediatric patients. For example, B-cell acute lymphoblastic leukemia (B-cell ALL) is the most common childhood cancer. And despite a high overall cure rate, relapsed B-cell ALL remains a leading cause of cancer-related death among children. However, results from a recent study demonstrated that adding blinatumomab to combination chemotherapy in patients with newly diagnosed childhood standard-risk B-cell ALL of average or higher risk of relapse significantly improved disease-free survival. [6]
Landmark approvals
In 2024, two landmark approvals underscored the continued evolution of the IO space. Afamitresgene autoleucel (Tecelra®; Adaptimmune), a treatment for of adult patients diagnosed with unresectable or metastatic synovial sarcoma who have received prior chemotherapy, are HLA-A*02:01P, -A*02:02P, -A*02:03P, or -A*02:06P positive, and whose tumor expresses melanoma-associated antigen A4 (MAGE-A4) as determined by FDA-approved or cleared Companion Diagnostic devices, became the first FDA-approved T-cell receptor (TCR) therapy, while lifileucel (Amtagvi®; Iovance Biotherapeutics) became the first tumor-infiltrating lymphocyte (TIL) therapy approved for the treatment of adult patients with unresectable or metastatic melanoma previously treated with a PD-1 blocking antibody, and if BRAF V600 mutation positive, a BRAF inhibitor with or without a MEK inhibitor.
With the approval ofafamitresgene autoleucel, Adaptimmune is positioned to make a significant impact on the synovial sarcoma community. And while synovial sarcoma is rare and aggressive type of soft tissue sarcoma, it is a serious condition that can be challenging to treat, especially when diagnosed in later stages.
“For decades, therapeutic options for people diagnosed with synovial sarcoma have been limited. With a current five-year survival rate as low as 36%, and for those with metastatic disease at diagnosis, as low as 20%, it is long past time that synovial sarcoma patients have expanded treatment options” explained Brandi Felser, Chief Executive Officer, Sarcoma Foundation of America.
“Since one third of patients are diagnosed under age 30, improved outcomes can have a tremendous impact. Today, there is a renewed sense of hope for this patient community,” Felser added.
Hope
“These therapies offer new hope for patients, with the potential for long-term remissions and even curative outcomes,” noted Israel Stern, MSc, Oncology & Hematology Analyst at GlobalData.
“Continued investment in IO research and development—both in academia and the biopharmaceutical industry—will be key to further improving clinical outcomes for oncology patients,” Stem added.
Pipeline
The current IO pipeline is extensive and diverse, with over 900 agents in clinical development across the eight major markets, including the USA, Germany, France, Italy, Spain, UK, Japan and China.
Cell therapies represent the most advanced segment, with more than 300 agents in development, the majority of which are CAR-T cell therapies. Checkpoint modulators follow with around 160 agents currently in clinical development.
“The greatest investment is concentrated in therapeutic classes with proven efficacy, namely cell therapies and TCEs. The ICI landscape, while still growing, is becoming increasingly saturated. New entrants need to target novel immune checkpoints that either improve response rates or offer treatment options for patients previously exposed to checkpoint inhibitors,” Stern continued.
“There is intense competition facing pipeline cell therapies entering the blood cancer space, especially in B-cell malignancies, with several CAR-T therapies on the market. To gain an edge, next-generation therapies such as CTX-112, an allogeneic off-the-shelf CAR-T with shortened manufacturing time being developed by CRISPR Therapeutics, may present a more scalable and accessible solution.”
Multispecific antibodies
Another IO class showing strong potential is multispecific antibodies, the majority of which are bispecific TCEs. Currently, eight out of ten globally approved bispecific TCEs target hematologic cancers.
There is growing enthusiasm among physicians for wider adoption of TCEs.These off-the-shelf therapies link the patient’s T-cells to tumor-expressed antigens, promoting a direct and targeted immune response. Four TCEs are FDA-approved in relapsed/refractory multiple myeloma, three of which bind BCMA.
Linvoseltamab (Lynozyfic™; Regeneron) a treatment for adult patients with relapsed or refractory (R/R) multiple myeloma (MM) who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti‑CD38 monoclonal antibody, is the most recent entrant. Linvoseltamab offers a key advantage: monthly dosing after a partial response, compared to biweekly dosing required by competitors following a complete response.
Challenges
The development of TCEs is not without challenges. Among these challenges is the transient nature of the efficacy of these novel agents, the need for continuous infusion, and the risk of cytokine release syndrome (CRS) which initially manifests with fever and can progress to life-threatening capillary leak with hypoxia and hypotension. However, these challenges are also observed in other cellular therapy modalities. For example, CRC is the most common side effect of CAR-T therapy. [7]
Beyond clinical challenges, there are also challenges related to insurance and reimbursement. Reimbursement challenges represent the most significant access barrier, particularly for cell therapies, and in some cases for checkpoint inhibitors and bispecific antibodies. Furthermore,the need for the development of a supportive infrastructure with specialized treatment centers and trained healthcare professionals creates additional limitations, particularly for advanced modalities like CAR-T and TIL therapies, which require complex administration protocols.
“Other unmet clinical need experts highlight include predictive biomarkers to identify patients who are likely to respond, given the high cost and potential toxicities associated with these agents. Additionally, limited efficacy in so-called ‘cold’ tumors that are not immunogenic, as well as resistance to IO therapies in immunogenic tumors is common. Next-generation IO therapies with novel mechanisms of action may help address these persistent gaps,” Stem concluded.
Clinical trials
A Study to Investigate Blinatumomab in Combination With Chemotherapy in Patients With Newly Diagnosed B-Lymphoblastic Leukemia – ClinicalTrials.gov ID NCT03914625
Highlights of prescribing information
Blinatumomab (Blincyto®; Amgen)[Prescribing Information]
Afamitresgene autoleucel (Tecelra®; Adaptimmune)[Prescribing Information]
Lifileucel (Amtagvi®; Iovance Biotherapeutics)[Prescribing Information]
Linvoseltamab (Lynozyfic™; Regeneron)[Prescribing Information]
Reference
[1] Albayrak G, Wan PK, Fisher K, Seymour LW. T cell engagers: expanding horizons in oncology and beyond. Br J Cancer. 2025 Jul 23. doi: 10.1038/s41416-025-03125-y. Epub ahead of print. PMID: 40702106.
[2] Cech P, Skórka K, Dziki L, Giannopoulos K. T-Cell Engagers-The Structure and Functional Principle and Application in Hematological Malignancies. Cancers (Basel). 2024 Apr 20;16(8):1580. doi: 10.3390/cancers16081580. PMID: 38672662; PMCID: PMC11048836.
[3] Strategic Intelligence: Immuno-oncology (2025). GlobalData. Online. Last accessed August 9, 2025.
[4] Przepiorka D, Ko CW, Deisseroth A, Yancey CL, Candau-Chacon R, Chiu HJ, Gehrke BJ, Gomez-Broughton C, Kane RC, Kirshner S, Mehrotra N, Ricks TK, Schmiel D, Song P, Zhao P, Zhou Q, Farrell AT, Pazdur R. FDA Approval: Blinatumomab. Clin Cancer Res. 2015 Sep 15;21(18):4035-9. doi: 10.1158/1078-0432.CCR-15-0612. PMID: 26374073.
[5] Zhu M, Wu B, Brandl C, Johnson J, Wolf A, Chow A, Doshi S. Blinatumomab, a Bispecific T-cell Engager (BiTE(®)) for CD-19 Targeted Cancer Immunotherapy: Clinical Pharmacology and Its Implications. Clin Pharmacokinet. 2016 Oct;55(10):1271-1288. doi: 10.1007/s40262-016-0405-4. PMID: 27209293.
[6] Gupta S, Rau RE, Kairalla JA, Rabin KR, Wang C, Angiolillo AL, Alexander S, Carroll AJ, Conway S, Gore L, Kirsch I, Kubaney HR, Li AM, McNeer JL, Militano O, Miller TP, Moyer Y, O’Brien MM, Okada M, Reshmi SC, Shago M, Wagner E, Winick N, Wood BL, Haworth-Wright T, Zaman F, Zugmaier G, Zupanec S, Devidas M, Hunger SP, Teachey DT, Raetz EA, Loh ML. Blinatumomab in Standard-Risk B-Cell Acute Lymphoblastic Leukemia in Children. N Engl J Med. 2025 Feb 27;392(9):875-891. doi: 10.1056/NEJMoa2411680. Epub 2024 Dec 7. PMID: 39651791; PMCID: PMC11864901.
[7] Frey N, Porter D. Cytokine Release Syndrome with Chimeric Antigen Receptor T Cell Therapy. Biol Blood Marrow Transplant. 2019 Apr;25(4):e123-e127. doi: 10.1016/j.bbmt.2018.12.756. Epub 2018 Dec 23. PMID: 30586620.
Featured image: Doctor explaining diagnosis to her female patient, Photo Courtesy: © 2017 – 2015 Fotolia/Adobe. Used with permission.
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