T-Cell Engager Toxicities in Solid Tumors: Recognition and Management

Because they harness the immune system to target malignant cells, T-cell engagers have emerged as a promising new class of molecules in the treatment of patients with solid tumors.¹ These compounds are designed to bridge T cells with tumor-associated antigens, thereby redirecting cytotoxic activity toward cancer cells even in an otherwise immunosuppressive microenvironment.² One of the most common strategies to achieve this effect involves bispecific antibodies—immunoglobulins engineered to bind 2 distinct epitopes on the same or different antigens.³ When one of those antigens is a tumor-associated antigen and the other is CD3, those molecules are referred to as bispecific T-cell engagers (BiTEs). First approved in hematological malignancies, BiTEs have been successfully tested in solid tumors over the past few years.

Some of the most successful molecules are those targeting DLL3, a protein overexpressed in a high proportion of neuroendocrine carcinomas, including small cell lung cancer (SCLC).⁴ A leading agent in clinical development is tarlatamab-dlle (Imdelltra). The results of a phase 2 clinical trial demonstrated an overall response rate (ORR) of 40% (95% CI, 30%-50%) in a pretreated population.⁵ Recently, the results of a phase 3 clinical trial comparing second-line tarlatamab vs standard-of-care chemotherapy in patients diagnosed with extensive-stage SCLC demonstrated a prolonged overall survival (13.6 vs 8.3 months; stratified HR, 0.60; 95% CI, 0.47-0.77; P < .001).⁶ Despite their promising efficacy results, tarlatamab and other BiTEs come with challenging toxicities that must be managed appropriately so that these compounds can reach optimal potential.

Navigating the Storm: Understanding and Managing Cytokine Release Syndrome

The most frequent and well-described toxicity of BiTEs is cytokine release syndrome (CRS). When the drug physically links T cells with tumor cells, it triggers a major histocompatibility complex–independent T-cell activation, proliferation, and subsequent overproduction of proinflammatory cytokines.⁷ This powerful, intended, on-target effect results in a systemic inflammatory response that can affect at least half the patients who receive these BiTEs, with severity ranging from mild to life-threatening.⁸ Prompt recognition and treatment of this syndrome are paramount to avoid serious complications and improve patient outcomes.⁹

One of the most salient characteristics of CRS is that it tends to occur with the earliest administrations of the drug, often during the initial step-up dosing phase, which is specifically designed to minimize this risk. In the tarlatamab trials, the median time from infusion to onset was approximately 15 hours, with most events occurring after the first or second dose.⁵ The clinical manifestations are broad and can mimic a severe infection. The most common initial sign is fever, which may be accompanied by tachycardia, hypotension, hypoxia, chills, myalgias, and/or fatigue.⁹ In more severe cases, this can progress to vasopressor-dependent shock, respiratory failure requiring mechanical ventilation, and multiorgan dysfunction, including renal and hepatic impairment.⁹

Management begins with supportive care, including antipyretics, intravenous fluids, and supplemental oxygen. For grade 1 CRS, this is often sufficient. However, for grades 2 and higher, targeted intervention is required. The cornerstone of CRS management is the inhibition of IL-6, a key cytokine implicated in its pathophysiology. Tocilizumab (Actemra), a monoclonal antibody that targets and blocks the IL-6 receptor, is the standard of care. For grade 2 CRS, a single dose of tocilizumab (8 mg/kg; maximum, 800 mg) is typically administered. If there is no clinical improvement, the dose can be repeated. For grade 3 or 4 CRS, tocilizumab should be administered promptly in conjunction with more aggressive supportive measures. Corticosteroids (eg, dexamethasone 10 mg every 6 hours) are also given for CRS, usually concurrently with tocilizumab.¹⁰

Neurotoxicity: A Complex Complication

Following CRS, the second most significant toxicity is immune effector cell-associated neurotoxicity syndrome (ICANS). Believed to be driven by endothelial activation and blood-brain barrier disruption from systemic inflammation, ICANS can present with subtle signs such as word-finding difficulty (anomia) or confusion and can progress to seizures or coma in severe cases.¹⁰ Importantly, ICANS may occur alongside CRS, follow its resolution, or present in isolation, which argues for routine neurologic surveillance across the step-up period and early cycles.

Bedside tools help standardize detection and grading. The Immune Effector Cell–Associated Encephalopathy (ICE) score is a simple 10-point screening that captures orientation, naming, command following, writing, and attention.¹¹ In parallel, the ASTCT (American Society for Transplantation and Cellular Therapy) ICANS grading framework adds to the ICE score by recording the level of consciousness, motor findings, seizures, and signs of increased intracranial pressure.

Management is driven by grade. For grade 1 ICANS, supportive care is key. For grades 2 and higher, corticosteroids (eg, dexamethasone) are the mainstay of treatment.¹¹ Because anti–IL-6 agents have limited central nervous system penetration, tocilizumab is reserved for patients with concurrent CRS rather than used as monotherapy for isolated ICANS.¹² Seizure prophylaxis should be considered for patients with grade 2 or higher ICANS.¹² Most ICANS episodes emerge in cycle 1, resolve within 48 to 72 hours, and do not preclude rechallenge once symptoms have returned to grade 1 or less and corticosteroids have been tapered.

Other On-Target, Off-Tumor Toxicities

Beyond CRS and ICANS, the expression of the target antigen on healthy tissues can lead to on-target, off-tumor toxicities. The ideal target antigen for a BiTE would be exclusively expressed on tumor cells, but such antigens are rare. For instance, DLL3 is also expressed in normal neuroendocrine cells, including in the brain and pituitary gland. This may contribute to some of the neurological and endocrine toxicities observed, although a direct causal link is still under investigation. Management is typically supportive and depends on on the organ system affected.

Structured Toxicity Management

The successful use of T-cell engagers such as BiTEs depends on proactive, structured toxicity management. In practice, this means step-up dosing to modulate T-cell activation, premedication with corticosteroids and antihistamines, and monitored starts during the initial doses. Institutional readiness is essential, including multidisciplinary teams trained in these toxicities, clear protocols, and rapid access to tocilizumab.

Clinically, DLL3-targeted therapy in SCLC delivers meaningful antitumor activity with predictable, mechanism-based adverse events. The task is to convert that predictability into safety: Expect CRS and ICANS early; monitor vigilantly using standard grading; manage CRS promptly with IL-6 blockade and add corticosteroids when needed; treat ICANS with corticosteroids; and operationalize care with stocked rescue agents, standardized order sets, and clear escalation rules shared across the oncology and emergency departments. With this disciplined approach, most patients navigate the high-risk early period and transition to outpatient dosing, enabling teams to realize the therapeutic potential of T-cell engagement without compromising patient safety.

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