For what indications are T cell engagers (TCE) being investigated?

Introduction to T Cell Engagers (TCE)
T cell engagers (TCEs) represent an innovative class of immunotherapeutic agents that are designed to physically bridge cytotoxic T cells and tumor cells, thereby enabling the immune system to selectively recognize and eliminate malignant cells. These engineered molecules embody the promise of harnessing natural immune mechanisms in a more controlled and targeted fashion than conventional therapies. Over the past decades, remarkable progress in antibody engineering and cellular immunology has led to a proliferation of T cell–redirecting agents that are now being extensively evaluated for various indications, primarily in oncology. The increasing body of preclinical and clinical evidence has spurred further development and refinement of TCE platforms to address both safety and efficacy concerns while expanding their utility across a spectrum of diseases. This review explores the indications for which TCEs are being investigated from a general perspective, delves into details regarding hematological and solid tumor applications, summarizes research and development efforts including emerging indications, and discusses current challenges with future prospects.

Definition and Mechanism of Action
T cell engagers are a type of bispecific antibody or multispecific molecule that simultaneously binds to CD3 on T cells and a specific tumor-associated antigen (TAA) on cancer cells. This dual binding creates an artificial immune synapse that activates and redirects T cells to kill the target tumor cell in a non-MHC restricted manner. The mechanism of TCEs involves the clustering of CD3 molecules, which triggers T cell activation, cytokine release, and cytolytic granule exocytosis. The ensuing T cell–mediated cytotoxicity is highly potent and independent of the conventional T cell receptor (TCR) specificity, enabling the targeting of tumors that might otherwise evade immune detection. Importantly, the fine balance between binding affinity for CD3 and the tumor antigen is crucial; overly strong CD3 engagement may result in systemic cytokine release or off-target toxicity, whereas suboptimal binding can reduce efficacy. This elegant mechanism translates into a rapid and targeted immune response that can overcome many of the limitations seen in traditional antibody therapies.

Overview of TCEs in Immunotherapy
TCEs have emerged as a cornerstone technology within the broader field of cancer immunotherapy. Their “off-the-shelf” nature gives them an advantage over cellular therapies such as chimeric antigen receptor (CAR) T cells, which require individualized manufacturing processes. Early clinical successes, such as the approval of blinatumomab for B cell acute lymphoblastic leukemia (ALL), have validated the concept and spurred further innovation in this domain. The range of TCE constructs now extends from traditional bispecific formats to more complex designs that can incorporate multiple binding domains or even costimulatory signals to enhance T cell activation while mitigating adverse effects. Accordingly, TCEs continue to be refined and optimized to improve their structural stability, pharmacokinetic profiles, and therapeutic windows, thereby broadening the spectrum of cancer types and possibly non-oncological diseases that may benefit from this therapy.

Current Indications for TCE Investigation
TCEs are being investigated across a broad range of indications, primarily focused on cancer, where their unique mechanism of action has the potential to improve outcomes in diseases that are either resistant to conventional therapies or suffer from limited treatment options. The indications under investigation can broadly be divided into two primary categories: hematological malignancies and solid tumors. This division also reflects the evolution of immunotherapy research; while initial success was predominantly seen in blood cancers, subsequent advancements have led to a concerted effort to adapt TCE technology to the far more challenging landscape of solid tumors.

Hematological Malignancies
In the realm of hematological malignancies, T cell engagers have generated significant enthusiasm owing to the relative accessibility and homogeneous antigen expression on blood cancers.
- B-Cell Malignancies:
The strongest evidence for TCE efficacy comes from B cell malignancies, where antigens such as CD19, CD20, and BCMA are predominantly and specifically expressed on malignant cells. Early clinical trials with the CD19/CD3 bispecific blinatumomab demonstrated potent activity in patients with relapsed and refractory ALL. Moreover, recent approvals and clinical trials involving mosunetuzumab, teclistamab, and epcoritamab further underscore the feasibility of TCE strategies against B-cell non-Hodgkin lymphomas and other B-cell malignancies.
- Multiple Myeloma:
TCEs targeting BCMA have also shown promising results in the treatment of multiple myeloma. Clinical studies indicate response rates of approximately 60% in phase 1 trials, making this an attractive target for ongoing investigation. The development of trispecific TCEs that can engage additional costimulatory receptors or simultaneously target two different antigens on plasma cells holds promise for improved specificity and efficacy, while potentially reducing adverse events.
- Other Hematologic Cancers:
Beyond B-cell malignancies, TCEs are being explored in other hematologic conditions where distinct TAAs are identifiable. The ongoing clinical research programs often utilize advanced modeling and adaptive dosing strategies to maximize efficacy while mitigating the risks associated with on-target, off-tumor activity. The promising results in hematological indications provide a strong foundation for extending TCE applications to more complex tumor ecosystems.

Solid Tumors
The translation of TCE technology to the treatment of solid tumors has been more challenging due to the complexity of tumor microenvironments, heterogeneous antigen expression, and issues with drug penetration. Nonetheless, significant progress has been made:
- Uveal Melanoma and Melanoma Subtypes:
Among the initial breakthroughs in solid tumor indications was the approval of tebentafusp (targeting gp100 peptide/MHC complexes), which demonstrated significant efficacy in metastatic uveal melanoma. This success illustrated that even tumors with low immunogenicity, often classified as “cold” tumors, can be effectively targeted by TCEs when using innovative antigen recognition strategies.
- Small Cell Lung Cancer (SCLC):
Early clinical data on TCEs targeting DLL3 in SCLC have shown promising antitumor activity, offering an alternative approach to conventional therapies that have struggled to make a significant impact on this aggressive tumor type. This has prompted further evaluation of TCEs as a modality for SCLC treatment, with attention being paid to the optimization of dosing regimens to balance efficacy and safety.
- Prostate and Breast Cancers:
Other solid tumor indications include prostate cancer and breast cancer. AbCellera’s recent poster presentations have detailed their work on TCE programs targeting prostate-specific membrane antigen (PSMA) in prostate cancer and dual-antigen targeted TCEs for breast cancers that co-express antigens such as B7-H4 and Ly6E. These studies underscore the necessity of exploiting logic-gated, dual targeting approaches to improve tumor selectivity, particularly when the target antigens are expressed at low levels on solid tumors.
- CLDN6-Positive Tumors:
Claudin 6 (CLDN6), a tight junction protein expressed in certain epithelial cancers, is another promising target. News reports have highlighted the development of TCEs that specifically target CLDN6-positive solid tumors in order to harness a more precise immune response while mitigating collateral damage to normal tissues.
- Intracellular Targets via Peptide-MHC Complexes:
The expansion of TCE technology to include TCR mimetic antibodies introduces a novel paradigm for targeting intracellular tumor-associated antigens. This approach broadens the scope of therapy beyond cell surface proteins by redirecting T cell activity to peptide-MHC complexes, thus potentially targeting a wider array of tumor types.
- Other Solid Tumor Indications:
Additional indications under investigation include gastrointestinal cancers, head and neck cancers, and other epithelial malignancies where TAAs such as EGFR, HER2, and CEA are overexpressed. The challenges of tumor heterogeneity and physical barriers that hinder T cell infiltration have driven developers to design multivalent or conditionally activated TCEs that aim to improve tumor penetration and reduce systemic toxicity.

Research and Development
Advances in research and clinical development have been critical in expanding the indications for TCEs. Continuous innovation in molecular design, dosing strategies, and biomarker-driven patient selection has facilitated the translation of TCEs from hematological malignancies into a promising therapeutic modality for solid tumors as well.

Clinical Trials and Studies
A wealth of clinical trial evidence has contributed to our evolving understanding of TCE pharmacology, dosing, and therapeutic efficacy.
- Dose Optimization and Modeling:
Given the immunological potency of TCEs and the risk of cytokine release syndrome (CRS), model-informed drug development (MIDD) has become instrumental in defining safe starting doses and adaptive dosing regimens. Quantitative systems pharmacology (QSP) models have been used to predict patient-specific responses and inform dose escalation strategies to minimize adverse events while ensuring robust tumor engagement.
- Clinical Outcomes in Hematologic Cancers:
In hematologic malignancies, robust clinical trials using TCEs such as blinatumomab have demonstrated significant survival benefits in refractory and relapsed patients. Comparative studies that evaluate TCEs against conventional chemotherapy or CAR-T therapies have provided insights into their mechanism of action and potential combinatorial benefits.
- Innovative Study Designs in Solid Tumors:
In the context of solid tumors, clinical trials are increasingly incorporating novel endpoints and adaptive designs to account for the complex pharmacokinetics and tumor microenvironment. Early-phase studies with TCEs targeting gp100 in uveal melanoma and DLL3 in SCLC have been accompanied by sophisticated biomarker analyses, enhancing our understanding of target engagement and safety profiles.
- Biomarker Integration:
The identification and validation of appropriate biomarkers are crucial for the ongoing clinical development of TCEs. Biomarkers not only facilitate patient selection by confirming the expression of target antigens on tumor cells, but also allow for the monitoring of immune activation and prediction of adverse events. This information is vital for guiding clinical trial designs and ensuring that therapeutic windows are maximized.

Emerging Indications
Beyond the established applications in hematological malignancies and a growing list of solid tumors, emerging indications for TCEs are beginning to surface:
- Autoimmune Diseases:
Although the vast majority of TCE research is focused on oncology, there is growing interest in exploring TCEs for autoimmune diseases. TCEs that can finely tune T cell activation might be adapted to modulate aberrant immune responses, thereby offering potential for treating conditions such as rheumatoid arthritis or systemic lupus erythematosus.
- Infectious Diseases and Chronic Infections:
In select preclinical studies, TCEs have been investigated as a means of directing T cells to clear chronic infections or to target pathogen-infected cells. Such applications require a careful balance between immune activation and the risk of collateral tissue damage, but they underscore the versatility of T cell redirection strategies.
- Personalized Therapeutic Platforms:
Emerging research is also focused on integrating TCE technology into personalized medicine platforms. Studies involving patient-specific tumor models and high-throughput screening are being used to tailor TCE therapies to the unique antigenic profile of an individual’s tumor, thereby optimizing efficacy and minimizing toxicity.
- Combination Therapies:
Combining TCEs with other agents—such as checkpoint inhibitors, costimulatory antibodies, or even other cell therapies—is an area of active investigation in order to enhance their therapeutic effect. These combination strategies are particularly appealing in solid tumors, where overcoming an immunosuppressive microenvironment remains a significant barrier.
- Rare and Refractory Diseases:
Finally, TCE technology is also being considered for rare malignancies or refractory cancers that have failed conventional therapies. The adaptability of the TCE platform allows it to be engineered to target tumor-specific neoantigens or antigens that are uniquely expressed on rare tumor types, thereby expanding its potential clinical utility.

Challenges and Future Directions
Notwithstanding the promising clinical outcomes and broad indications for TCE investigation, several challenges persist that need to be addressed to fully realize their therapeutic potential.

Current Challenges in TCE Development
There are multiple layers of challenges in the development of T cell engagers, spanning from molecular design issues to clinical management:
- Safety and Toxicity:
One of the most critical concerns is the potential for severe adverse events, such as cytokine release syndrome (CRS) and neurotoxicity. These toxicities are often associated with the potent activity of TCEs and require innovative dosing strategies and molecular modifications to minimize risk. The design of TCEs with fine-tuned CD3 affinity is crucial to prevent overstimulation of T cells without compromising tumor killing efficacy.
- Tumor Selectivity and On-target/Off-tumor Toxicity:
TCEs must discriminate between tumor cells and healthy cells that may express low levels of the target antigen. This is particularly challenging in solid tumors, where TAAs are often shared between malignant and normal cell populations. Logic-gated dual targeting strategies are under investigation as a means to increase specificity.
- Tumor Microenvironment (TME):
Solid tumors present a formidable barrier due to their immunosuppressive microenvironment, heterogeneity, and physical barriers that restrict T cell infiltration. Strategies to remodel the TME—such as combination therapies or engineered TCEs that are conditionally activated within the tumor milieu—are being actively developed, but these approaches add another layer of complexity to clinical development.
- Pharmacokinetics and Dosing:
The short half-life and rapid clearance of some early TCE formats have necessitated continuous infusion or complex dosing regimens, which can hamper widespread clinical adoption. Advances in half-life extension, such as Fc-based modifications or peptide conjugation, are being pursued to address these limitations.
- Manufacturing and Scalability:
The biopharmaceutical production of complex multispecific molecules poses unique challenges in terms of yield, purity, and consistency. Establishing robust manufacturing processes that comply with regulatory standards is a critical aspect of bringing these therapies to market.

Future Prospects and Research Directions
Looking forward, several research avenues promise to overcome current limitations and further expand the applications of TCEs:
- Next-Generation Molecular Designs:
Innovative designs that incorporate conditional activation, dual-antigen targeting, or costimulatory modalities offer the promise of enhancing both efficacy and safety. These next-generation TCEs may incorporate engineered binding affinities, modular platforms, and innovative architectures to precisely modulate T cell responses, thereby widening the therapeutic index and reducing toxicity.
- Integration with Advanced Biomarker Strategies:
As the field advances, the integration of cutting-edge biomarker analyses—including genomic, proteomic, and immune profiling—will be essential for patient selection, dose optimization, and real-time monitoring of T cell activity. These robust biomarker strategies will enable more personalized therapeutic approaches and allow clinicians to predict responses and adverse events more accurately.
- Combination and Sequential Therapies:
Future clinical strategies are likely to explore the synergistic potential of combining TCEs with checkpoint inhibitors, adoptive cell therapies, oncolytic viruses, or traditional chemotherapies. Such combinations could address the limitations inherent in monotherapy approaches and overcome the immunosuppressive barriers encountered in solid tumors.
- Expanding Indications Beyond Oncology:
Although cancer remains the primary target, emerging research is also considering the applicability of TCEs in non-oncological settings such as autoimmune diseases and chronic infections. By adjusting the design and controlling the activation thresholds, TCEs may be tailored to modulate immune responses in a manner that is therapeutically beneficial for such conditions.
- Adaptive Clinical Trial Designs and Digital Health Integration:
The future of TCE clinical development lies in the adoption of adaptive trial designs that allow rapid modification of dosing regimens based on real-time pharmacokinetic and pharmacodynamic data. Furthermore, the integration of digital health tools, including wearable devices and remote monitoring, could enhance the collection of robust clinical data, enabling more informed decisions during clinical trials.
- Overcoming Manufacturing Complexities:
Advances in bioprocessing and synthetic biology could lead to more efficient production techniques, ensuring scalability and cost-effectiveness for complex TCE molecules. This will be crucial for making these therapies accessible on a broader scale.

Conclusion
In summary, T cell engagers (TCEs) are being investigated for a broad range of indications, particularly within oncology. Their mechanism of creating an artificial immune synapse enables potent T cell–mediated killing of tumor cells—a property that has been harnessed with impressive results in hematological malignancies, such as B-cell cancers and multiple myeloma. Equally, the application of TCEs to solid tumors, despite inherent challenges related to tumor accessibility, immune suppression, and target specificity, is showing promise with indications that include uveal melanoma, small cell lung cancer, prostate cancer, breast cancer, CLDN6-positive malignancies, and others.

Ongoing research has refined dosing strategies using quantitative systems pharmacology models to optimize administration and reduce toxicities while pushing the envelope on antigen targeting through dual or logic-gated mechanisms. Emerging research directions are now exploring the use of TCEs for non-oncological indications such as autoimmune diseases and chronic infections, expanding the potential clinical horizons of this modality. The integration of comprehensive biomarker strategies, innovative molecular designs, and adaptive clinical trial paradigms further enhances the prospect of translating these therapies into routine clinical practice with an improved therapeutic index.

While current challenges persist—ranging from safety concerns like cytokine release syndrome and on-target/off-tumor toxicity to manufacturing scale-up and tumor microenvironment barriers—the future prospects are bright. Addressing these challenges through next-generation engineering and combinatorial approaches will likely expand the clinical applications of TCEs and ultimately improve patient outcomes.

Overall, T cell engagers represent a dynamic and rapidly evolving field within immunotherapy. Their ability to bridge T cells and tumor antigens, along with the continuously improving safety and efficacy profiles, makes them a pivotal therapeutic strategy for treating hematological malignancies and solid tumors. The innovations in TCE technology, driven by rigorous clinical research and adaptive design strategies, are poised to overcome current limitations and pave the way for broader clinical applications. With ongoing advancements in molecular engineering, biomarker integration, and adaptive clinical paradigms, TCEs are projected to play an increasingly central role in the future of cancer immunotherapy and potentially beyond.