Review Article: Immune Effector Cell-Mediated Enterocolitis Following CAR-T Cell Therapy-Clinical Features, Pathophysiology and Management.

Introduction

Immune‐based therapies have long been used to treat various immune‐mediated inflammatory disorders and more recently have been leveraged to target solid tissue and hematologic malignancies. The application of such therapies in Oncology has transformed the field, leading to unprecedented improvement in outcomes including mortality, best exemplified by survival outcomes in metastatic melanoma [ 1 , 2 ]. Since the intestinal epithelium harbours a rich network of immune tissue, therapies which target the immune system often come with a high gastrointestinal side effect burden, sometimes even leading to inflammation and tissue destruction. Mycophenolate, for example, has long been known to cause colitis which can mimic inflammatory bowel disease (IBD) [ 3 ]. Treatments targeting CD20 such as rituximab and ocrelizumab have been shown to cause an IBD‐like phenotype [ 4 , 5 ]. Interleukin (IL)‐17 inhibitors such as secukinumab are associated with de novo IBD [ 6 ]. Even TNF inhibitors, which are used to treat IBD, have been associated with de novo IBD, particularly in the case of etanercept [ 7 ]. Whereas all of these immunotherapy‐associated enterocolitides are relatively rare, some immunotherapies portend a much higher risk. Immune checkpoint inhibitors, including cytotoxic T lymphocyte associated antigen 4 (CTLA‐4) inhibitors, programmed death‐1 (PD1) inhibitors, and PD‐ligand 1 (PDL‐1) inhibitors have been associated with colitis (with or without enteritis) in up to 54% of patients treated with these agents, particularly with CTLA‐4 inhibitors and combination therapy [ 8 , 9 ]. T cell redirecting therapies represent a novel strategy being used primarily to treat certain haematological malignancies such as lymphomas, myeloma and B‐acute lymphoid leukaemia (now with FDA approved therapies). These are also now being trialled in solid organ tumours and various immune‐mediated inflammatory diseases. Specific therapy classes include bispecific antibodies and chimeric antigen receptor T cell (CAR‐T) therapy.

CAR‐T cell therapy, in which a patient's own T cells are engineered to target and kill specific disease‐causing cells, represents another type of immunotherapy associated with gastrointestinal side effects, including rare instances of enterocolitis, termed immune effector cell‐mediated enterocolitis (IEC‐EC). Use of CAR‐T therapy has steadily risen each year, with only 61 done in 2016 to 4721 in 2023, and projected to near 10,000 annually, particularly with the high likelihood of expanding indications [ 10 ]. In the following sections, we describe the clinical, endoscopic, and histopathologic manifestations of IEC‐EC and conclude with a comprehensive diagnostic and treatment protocol.

CAR‐T Mechanism

CAR‐T therapy describes genetic engineering of a patient's own T lymphocytes to express a synthetic receptor which recognizes specific cells (most commonly cancer cells) independent of MHC‐mediated antigen presentation and induces cell death (Figure 1 ). The chimeric antigen receptor (CAR) protein is a synthetic fusion protein with four key domains: an extracellular antigen‐binding domain (ectodomain) which binds directly to a tumour‐associated surface antigen, a hinge/spacer domain to facilitate antigen binding, a transmembrane domain to anchor the receptor within the T cell membrane, and an intracellular signalling domain (endodomain) featuring one or more costimulatory domains (commonly CD28 or CD137/4‐1BB) to provide the second signal to allow for full T cell activation [ 11 ]. Currently approved CAR‐T therapies target either CD19 or B‐cell maturation antigen (BCMA). CD19 is a transmembrane glycoprotein expressed broadly on B cells from early development through differentiation, making it an ideal target in B cell malignancies such as acute lymphoblastic leukaemia and diffuse large B‐cell lymphoma. CAR‐T cells directed against CD19 selectively eliminate both malignant and normal B cells, effectively resetting the patient's B‐cell compartment [ 12 ]. BCMA, on the other hand, is a member of the TNF receptor superfamily expressed primarily on plasma cells whose function is to activate pathways to promote plasma cell survival, and is therefore a key target in multiple myeloma. BCMA‐targeted CAR‐T cells can recognize and destroy malignant plasma cells while sparing most other tissues, offering a highly specific approach to treating refractory myeloma [ 13 , 14 ]. Both select for antigens that are highly expressed on disease‐driving cells but minimally present on essential normal tissues. In the case of BCMA‐targeted therapies, BCMA‐positive B cells and normal plasma cells get depleted, causing profound hypogammaglobulinemia. A typical process for CAR‐T therapy begins with leukapheresis to obtain and isolate autologous T lymphocytes, genetic manufacturing of the CAR introduced to the T cells via a viral vector, administering lymphodepleting chemotherapy (commonly cyclophosphamide and fludarabine), and then infusing the engineered T cells into the patient.

At the time of this writing there are seven FDA‐approved CAR‐T products with 18 indications, including five CD19‐targeted products for various types of leukaemia and lymphoma and two BCMA‐targeted products for multiple myeloma [ 15 ]. While CAR‐T is currently approved only for hematologic malignancies, there is rapidly growing interest in leveraging the CAR‐T mechanism for other diseases, particularly immune‐mediated inflammatory disorders such as systemic lupus erythematosus, systemic sclerosis, inflammatory myopathies, and multiple sclerosis [ 16 , 17 , 18 ]. Relevant to gastroenterology, there has been enthusiasm about the potential for CAR‐T and other T cell directed therapies as a potential therapeutic modality to treat inflammatory bowel diseases [ 19 ] particularly after reports of a 21‐year‐old with medically refractory ulcerative colitis ultimately successfully treated with the CD19‐directed bispecific T‐cell engager blinatumomab [ 20 ].

Adverse Effects

While CAR‐T is designed to target cells expressing antigens which are present mainly on malignant cells and limited or absent in healthy tissue, there are several well described and common side effects of CAR‐T therapy, termed CAR‐T cell therapy‐associated immune‐related adverse events (CirAEs), which are summarized in Figure 2 [ 21 ]. The most common adverse effects are cytokine release syndrome (CRS) and immune effector cell‐associated neurotoxicity syndrome (ICANS). CRS is the most common acute toxicity, seen in up to 35%–93% of patients, occurring typically within the first week after CAR‐T infusion and lasting about 1–2 days. Manifestations include fever, hypotension, tachycardia, hypoxia, and chills, with serious events including cardiac dysfunction, renal insufficiency, and capillary leak syndrome, and treatments may include corticosteroids, IL‐6 receptor antagonist tocilizumab, or sometimes IL‐1 receptor antagonist anakinra [ 21 , 22 ]. ICANS occurs in 10%–70% of cases, and presents 4–10 days following CAR‐T infusion with encephalopathy, aphasia, tremor, headache, and in severe cases seizures or cerebral oedema. Corticosteroids are the standard treatment, and anakinra is used in refractory cases [ 21 , 22 ]. Other potential consequences of CAR‐T therapy include immune effector cell‐associated hemophagocytic lymphohistiocytosis‐like syndrome, prolonged cytopenias, and infections [ 21 , 22 ].

Immune Effector Cell‐Associated Enterocolitis

With increased usage of CAR‐T therapy, it has become apparent that rare gastrointestinal toxicities can also occur. Transient mild gastrointestinal symptoms including nausea, vomiting and diarrhoea occur in 28%–40% of patients in the acute setting following infusion of the CAR‐T cells [ 23 , 24 ]. These are commonly mild and not associated with hospital length of stay or in‐hospital mortality [ 24 ]. However, a minority of patients treated with anti‐BCMA CAR‐T therapy develop a chronic immune‐mediated inflammatory response in the small intestine and/or colon presenting as persistent diarrhoea, which has been termed immune‐effector cell‐mediated enterocolitis (IEC‐EC) [ 21 ]. In the following sections, we review in detail the clinicopathologic features and management of IEC‐EC.

Pathogenesis

The pathophysiology of IEC‐EC is not completely elucidated. Mucosal injury begins with lymphodepleting chemotherapy which can injure the epithelium, deplete the mucosal immune cells, and disrupt the gut microbiome even prior to CAR‐T infusion. Once the CAR‐T cells are administered and begin to expand, the ensuing cytokine release syndrome floods the systemic circulation with pro‐inflammatory mediators like IL‐6, TNF‐α and IF‐γ which increase intestinal permeability and promote apoptosis. The CAR‐T cells can traffic to the intestinal mucosa and exert cytotoxic activity by on‐target/off‐tumour recognition of antigen expressing cells (such as BCMA on plasma cells and CD‐19 on B cells present in the gut).

A likely major driver is direct CAR‐T cell infiltration into the gastrointestinal mucosa, resulting in immune‐mediated epithelial injury [ 25 ]. Immunohistochemistry has shown CAR‐T cells in association with residual BCMA‐positive B cells in the lamina propria, supporting an on‐target/off‐tumour mechanism of injury [ 25 ]. Additionally, the plasma cell depletion, profound mucosal IgA deficiency, interferon‐driven immune dysregulation, T cell imbalance (particularly Th1/Th17 imbalance), and chronic infections all contribute to the characteristic histopathologic features of absent plasma cells, villous atrophy, and intraepithelial lymphocytosis. This physiology is akin to common variable immunodeficiency‐associated enteropathy. The depletion of mucosal IgA may explain the high co‐occurrence of gastrointestinal infections in IEC‐EC which has been demonstrated [ 26 , 27 ]. Bile acid malabsorption has also been documented; [ 26 ] however, this may arise as a secondary phenomenon from intestinal inflammation and rapid transit.

There is also profound gut microbiome disruption caused by lymphodepletion and antibiotic use. In particular, loss of short‐chain fatty acid (SCFA) producing bacteria causes reduced butyrate impairing the intestinal barrier function [ 28 ]. Small intestinal microbial dysbiosis (SIMD) has been consistently documented in inflammatory states of the gastrointestinal tract including coeliac disease, CVID enteropathy, and autoimmune atrophic gastritis [ 29 , 30 , 31 ] so it is very likely that SIMD is a prominent feature of IEC‐EC, although this has not been evaluated.

Histopathological features include increased villous atrophy, absence of plasma cells, intraepithelial lymphocytes, crypt apoptosis and crypt architecture distortion. Next generation sequencing has also shown both CD‐4 and CD‐8 dominant T cell clonal populations. The significance of T cell lymphoproliferative disorders is not well understood at present, and there has been one case of a small bowel lymphoma [ 32 ].

Clinical Features

The main findings from case series documenting IEC‐EC are displayed in Table 1 .

In the original study of 1287 CAR‐T infusions, 14 cases of IEC‐EC were identified (13 after ciltacabtagene autoleucel and one after idecabtagene vicleucel), corresponding to a 1.2% incidence of IEC‐EC and specific incidences 0.2% for idecabtagene vicleucel and 2.2% for ciltacabtagene autoleucel [ 33 ]. In this report, patients most commonly experienced non‐bloody diarrhoea a median of 92.5 days after CAR‐T infusion. Gastrointestinal mucosal biopsies demonstrated inflammation, including small bowel features of villous blunting and intraepithelial lymphocytosis. Immunofluorescence confirmed CAR‐T presence within the lamina propria in one case. Patients were treated with a variety of agents including corticosteroids, infliximab, or vedolizumab and five patients (36%) died from complications of IEC‐EC including bowel perforation and septic shock [ 33 ]. In another series of 125 patients who were treated with ciltacabtagene autoleucel, 5.6% developed IEC‐EC, with similar clinical, endoscopic, and histopathologic features [ 25 ]. In one patient, CAR‐T cells were identified in the colon 9 months after symptom onset, despite various treatments for IEC‐EC. Notably, while IEC‐EC has mainly been described in association with anti‐BCMA CAR‐T therapy, it has also been reported in patients receiving anti‐CD19 CAR‐T therapy [ 34 ]. Our institutional experience identified IEC‐EC in 3.9% of patients treated with ciltacabtagene autoleucel over a 2 year period [ 26 ]. Gastrointestinal infections were seen in 56%, including norovirus and Clostridioides difficile . Bile acid malabsorption was seen in 100% of patients tested. Risk factors for IEC‐EC include alkylator‐based bridging therapy, higher CAR‐HEMATOTOX scores (determined by haemoglobin, absolute neutrophil count, platelets, ferritin and CRP, and where a higher score reflects patients with cytopenias or a high inflammatory profile at baseline), antecedent delayed neurotoxicity, and the presence of gastrointestinal infections [ 26 ]. In the largest series to date spanning six academic centres, IEC‐EC was identified in 19 patients (4.3% of patients treated with ciltacabtagene autoleucel) [ 27 ]. Further prospective studies are needed to better define predisposing factors across immune‐mediated enterocolitides.

Presentation

Diarrhoea is a common occurrence among immunocompromised patients and among those receiving immunotherapies. When diarrhoea is deemed to result as a consequence of immunotherapy, the severity is characterized by the Common Terminology Criteria for Adverse Events as outlined by the National Cancer Institute and summarized in Table 2 [ 35 ]. Patients typically present 1–3 months after CAR‐T infusion with persistent watery, non‐bloody diarrhoea, often Grade 3 or higher [ 33 ]. Diarrhoea is often severe and persistent, frequently accompanied by malnutrition and significant weight loss, and may necessitate prolonged parenteral nutritional support [ 25 ]. Diagnosis is often delayed due to the rarity and novelty of this condition, and the fact that patients receiving CAR‐T have numerous other potential reasons to experience diarrhoea.

Laboratory Evaluation

Blood and stool testing are reported heterogeneously in the literature. Findings from a cohort at our institution identified elevated ferritin in 100%, elevated faecal fat in 100%, evidence of bile acid malabsorption in 100%, and elevated C‐reactive protein in 80% of the subset of patients tested for these [ 26 ]. Gastrointestinal infections have been consistently identified across patient cohorts. While the seminal series of IEC‐EC did not identify enteric infection [ 33 ] and another study of five patients evaluated for infections after CAR‐T found Escherichia coli infection in only one patient, [ 36 ] analysis of the U.S. Food and Drug Administration Adverse Event Reporting System found enteric infections to be relatively common after CAR‐T therapy, including Clostridioides difficile (odds ratio 5.55), enterovirus infection (OR 20.02), and mucormycosis (OR 3.09), with the latter portending 60% fatality rate [ 37 ]. We have previously reported enteric infection in 56% of patients, including two with norovirus, one with sapovirus, one with C. difficile , and one with both norovirus and C. difficile . In some of these patients there was chronic infection after treatment [ 26 ]. From a more recent cohort, 37% had a preceding infection, including four patients with C. difficile [ 27 ].

Imaging Features

Cross‐sectional imaging can show variable findings, ranging from normal to inflammation to frank bowel perforation. In one series, 43% of cases showed imaging evidence of inflammation in the small intestine and/or colon, and two cases had diffuse colonic pneumatosis [ 33 ]. Our cohort also had an abnormal CT in 43%; features suggestive of enterocolitis were seen in two patients, and two patients had pneumatosis intestinalis. Pneumatosis was seen in four cases from another series, and two patients had bowel perforation [ 27 ]. Bowel perforation has been reported as a cause of death in patients with IEC‐EC [ 27 , 33 ].

Endoscopic Findings

Endoscopic findings are variable and nonspecific, and can range from grossly normal mucosa to subtle changes in mucosal pattern and vascularity to frank inflammation and ulceration [ 36 ]. In our cohort, 78% had gross mucosal changes in the duodenum, most commonly nodularity. Fifty percent of patients had abnormal mucosa on colonoscopy [ 26 ]. In another cohort, 64% had an abnormal oesophagogastroduodenoscopy, most commonly mucosal changes in the duodenum such as scalloping, granularity, congestion, erythema and ulceration. Colonoscopy was abnormal in 47%, including features of erythema, congestion, granularity, and ulceration. Terminal ileal involvement was seen in two patients [ 27 ]. Characteristic endoscopic findings are demonstrated in Figure 3 .

Histopathologic Findings

While IEC‐EC can affect the small intestine and/or colon, it has a predilection for the small intestine, particularly the duodenum (unlike immune checkpoint inhibitor enterocolitis which most commonly affects the colon) [ 38 ]. All patients treated with BCMA‐targeted CAR‐T therapy have depletion of plasma cells and CD20+ B cells. Other features include villous atrophy, intraepithelial lymphocytosis, and crypt apoptosis with graft‐versus‐host disease (GvHD)‐like changes [ 25 , 26 , 27 , 33 , 38 ]. IHC testing displays a prominent CD8+ cytotoxic T cell infiltrate which can be found both intraepithelial and in the lamina propria, [ 26 ] although previous series have also demonstrated a mixture of CD4 and CD8+ T cells. Fortuna et al. demonstrated direct CAR‐T cell identification within intestinal tissue, with anti‐camelid V H H immunohistochemical staining, however, this specialized technique remains available only at a limited number of academic centres in the United States [ 33 ]. In a subset of cases, clonal CD4+ or CD8+ T‐cell expansion consistent with enteropathic T cell lymphoproliferative disorders or even lymphoma has been identified (Figure 4 ) [ 26 , 39 ]. This latter point is crucial since IEC‐EC and CAR‐T lymphoproliferative disorders present almost identically and may even represent an overlap or progression of disease [ 32 , 40 , 41 ]. Future diagnostics will require identification of a monoclonal CAR‐T cell infiltrate. Future diagnostic approaches will require identification and characterization of monoclonal CAR‐T infiltrates.

Representative histopathologic samples from a patient with IEC‐EC are displayed in Figure 5 (Figure 2A IEC‐duodenitis, Figure 2B IEC‐colitis). Histopathology evaluation is an evolving area, and close collaboration between the haematologist/oncologist, pathologist, and molecular diagnostics laboratory is essential for accurate interpretation.

Management

Management of IEC‐EC is extrapolated from experience with IBD, graft‐versus‐host disease, and other immunotherapy toxicities such as immune checkpoint inhibitor enterocolitis. Infectious complications are common, warranting heightened clinical suspicion for early recognition and treatment. And persistent symptoms despite adequate antimicrobial treatment should heighten the suspicion for IEC‐EC. Once enteric infections are excluded or adequately treated, corticosteroids are the most commonly used first line agents [ 21 , 25 , 26 , 27 , 33 ]. However, systemic corticosteroids may provide limited or non‐durable benefit, and expose patients to the adverse effects of corticosteroids. Indeed, in one series, systemic corticosteroids were used in 71% of cases, but there was a symptomatic response in only 40% [ 33 ]. In our cohort, 67% were refractory to steroids, [ 26 ] and in another, only one out of 11 patients (9%) saw benefit from steroids [ 27 ]. No patients treated with steroids had a durable treatment response [ 26 ]. Budesonide is another corticosteroid option which has the benefit of topical administration, thereby reducing systemic corticosteroid absorption. Open‐capsule dosing (as has been described to treat enteropathies such as refractory coeliac disease) [ 42 ] may be useful to treat disease affecting the small bowel. However, in our experience, most patients with severe enterocolitis do not respond to budesonide [ 26 ]. Indeed, while budesonide is more commonly used in mild to moderate enterocolitis, severe hospitalized cases generally warrant escalation to systemic therapy. Patients uniformly receive intravenous immunoglobulins (IVIG) to replace the depleted mucosal immunoglobulins with a goal to restore IgG levels above 500 mg/dL. Other first‐line supportive measures to reduce diarrhoea include octreotide, opioids (such as loperamide and diphenoxylate‐atropine), and bile acid sequestrants, although these are frequently ineffective. Indeed, in our cohort, a durable response was seen in 0% of patients treated with bile acid sequestrants or octreotide [ 26 ]. Second line agents are drawn from the pharmacotherapeutic armamentarium for IBD, most commonly agents which have demonstrated efficacy in ICI enterocolitis, specifically anti‐TNF agent infliximab and anti‐α4β7 integrin agent vedolizumab [ 21 ]. In two series, infliximab led to improvement in 50% among patients who did not respond to steroids [ 27 , 33 ]. Vedolizumab presents a mechanistically appealing option since its effects are restricted to the gastrointestinal mucosa. However, its onset of action is longer and it may be less effective for small intestinal than colonic disease, as has been consistently demonstrated in trials of patients with Crohn disease [ 43 , 44 ]. Infliximab is faster acting and likely has greater efficacy for small bowel disease than vedolizumab. In one cohort of steroid‐refractory IEC‐EC, vedolizumab led to improvement in one of three patients (33%); however that patient then went on to contract C. difficile and required faecal microbiota transplantation [ 33 ]. Conversely, in our cohort, 100% of two patients with steroid‐refractory IEC‐EC had a durable response to vedolizumab. Other therapies approved for IBD including IL‐23 receptor inhibitors (e.g., guselkumab, risankizumab, mirikizumab) have not been reported to treat IEC‐EC, however these agents have been used successfully to treat ICI toxicities [ 45 , 46 , 47 ]. The JAK 1/2 inhibitor ruxolitinib may be considered for steroid‐refractory cases of IEC‐EC, based on a series where three out of five patients with steroid‐refractory IEC‐EC experienced rapid clinical improvement and improvement in histopathology following treatment with ruxolitinib [ 48 ]. However, other studies have not shown the same benefit. In one study, a prior responder to infliximab was able to see a response after ruxolitinib and photopheresis, while a second treated with ruxolitinib alone had no response [ 27 ]. Our one multiply refractory patient had no response to ruxolitinib [ 26 ] The JAK‐1 inhibitor upadacitinib had no response in the same patient [ 26 ].

In cases unresponsive to second line therapies, other T cell directed therapy like cyclophosphamide or cyclosporin may be considered. High‐dose cyclophosphamide effectively ablates CAR‐T cells, and this approach is used in other IEC‐mediated toxicities including non‐ICANS neurotoxicities (such as IEC‐mediated parkinsonism) and refractory CRS [ 21 , 49 , 50 ]. However, their efficacy in IEC‐EC is questionable. In our cohort, of two patients treated with cyclosporine or cyclophosphamide, none had durable response [ 26 ].

In light of evidence that gut microbiota are altered in chronic inflammatory conditions of the intestines and among patients who are treated with CAR‐T therapy, there is growing interest in the possibility of faecal microbiota transplantation (FMT) in CAR‐T recipients for both preventive and treatment indications, including potentially to augment the effect of CAR‐T [ 51 , 52 ]. Similarly, FMT has demonstrated efficacy in treating ICI colitis, and is a recommended salvage therapy for steroid‐ and biologic‐refractory disease [ 21 ]. For example, among 15 patients with refractory ICI colitis, 75% of cases resolved with FMT [ 9 ]. Since there are shared pathophysiological contributors to the development of immune mediated enterocolitides, future studies should evaluate the utility of FMT in IEC‐EC specifically.

Prognosis

In contrast to ICI‐related toxicities which are often associated with enhanced anti‐tumour efficacy and improved survival, [ 53 ]. IEC‐EC demonstrates poor therapeutic responsiveness and is associated with an unfavourable prognosis. Durable resolution of symptoms occurs in only a minority of patients, ranging from 29%–37% [ 25 , 26 , 27 , 33 ]. In one patient, CAR‐T cells were found to persist in the colonic mucosa 9 months after the onset of IEC‐EC and despite prolonged treatment [ 25 ]. Mortality in IEC‐EC is substantial, ranging from 33%–37% [ 26 , 27 , 33 ]. Death can occur directly from IEC‐EC or from complications including infections and sepsis or bowel perforation.

Conclusions and Future Directions

IEC‐EC represents a rare but increasingly recognized, serious, and potentially fatal delayed complication of CAR‐T cell therapy that demands heightened clinical vigilance among clinicians caring for patients treated with the CAR‐T mechanism. A suggested diagnostic and treatment algorithm is displayed in Figure 6 .

The delayed onset of IEC‐EC is a defining feature of this condition. This temporal dissociation from the infusion itself means that patients may have already transitioned out of the intensive post‐infusion monitoring period and back to the care of community physicians who may be unfamiliar with this entity. The result is a significant risk of diagnostic delay, empirical treatment with corticosteroids that are frequently ineffective, and progression to a potentially fatal outcome. Clinicians must therefore maintain a high index of suspicion for IEC‐EC in any patient presenting with new or worsening gastrointestinal symptoms within the first several months following CAR‐T infusion and obtain specialist consultation early.

Infections have been noted in one‐third to half of cases adding a further layer of diagnostic complexity. Thorough microbiological evaluation including stool cultures, PCR‐based enteric pathogen panels, CMV immunohistochemistry on mucosal biopsy tissue, and Clostridioides difficile testing should be pursued in parallel with endoscopic and histopathologic evaluation. The predilection for proximal small bowel involvement means that colonoscopy alone is insufficient, and oesophagogastroduodenoscopy with duodenal biopsies should be prioritized as part of the initial evaluation in any patient in whom IEC‐EC is suspected. Histopathologic findings, while variable, include villous atrophy, intraepithelial lymphocytosis, and crypt apoptosis, a constellation that overlaps with several other conditions including coeliac disease, graft‐versus‐host disease, common variable immunodeficiency, medication‐induced enteropathy, and infectious enteritis. The absence of plasma cells is a unique feature which is a direct consequence of the anti‐BCMA mechanism. Adequate biopsies with submission of sufficient tissue for both routine histopathology and immunohistochemical analysis are essential to maximize diagnostic yield. Review by expert gastrointestinal pathologists and hematopathologists is required, especially to exclude post‐CAR‐T lymphoproliferative disorders.

The therapeutic landscape of IEC‐EC is currently limited by the absence of prospective trial data and the consequent reliance on case series, registry data, and expert opinion to guide management decisions. The frequent ineffectiveness of corticosteroids as the standard first‐line intervention for most immune‐related gastrointestinal toxicities is a clinically important characteristic of IEC‐EC and has direct implications for management. Indeed, because of the frequent lack of response to steroids, steroids should only be used for short courses and rapid escalation to advanced therapies should be entertained. Biologic agents including infliximab and vedolizumab have demonstrated some utility in a subset of patients and therefore are reasonable second line options, though the optimal sequencing of these agents (and whether other biologics and small molecules have a role) remains to be clarified. For patients with refractory disease, T cell‐directed salvage therapies including cyclophosphamide, cyclosporine, and the JAK1/2 inhibitors have been employed with variable success. The mechanistic rationale for JAK inhibition in this context is particularly compelling given the central role of cytokine signalling in CAR‐T mediated immune activation, and ruxolitinib in particular warrants further prospective evaluation. The variability in treatment response across reported cases reflects the clinical and immunopathological heterogeneity of IEC‐EC itself, and future therapeutic trials must incorporate robust tissue‐based correlative endpoints to identify the biological features that predict response to individual treatment strategies. Management in the interim should feature a multi‐disciplinary approach.

Several important questions regarding the pathogenesis and epidemiology of IEC‐EC remain unanswered. The identification of clinical, biological, and treatment‐related risk factors that predispose individual patients to develop IEC‐EC would enable risk stratification and potentially prophylactic intervention in high‐risk groups. The putative relationship between IEC‐EC and ICANS deserves systematic exploration, as shared inflammatory mechanisms may link these two serious delayed complications, and their co‐occurrence may reflect a particularly high‐risk clinical phenotype. The gut microbiome represents an additional and largely unexplored dimension of post‐CAR‐T biology; pre‐infusion microbiota composition, antibiotic‐mediated dysbiosis in the peri‐infusion period, and microbiome‐immune interactions in the post‐infusion recovery phase may all affect susceptibility to and severity of IEC‐EC, drawing parallels with established microbiome associations in GVHD and immune checkpoint inhibitor‐associated colitis.

In conclusion, IEC‐EC is a rare but serious and potentially fatal delayed complication of CAR‐T cell therapy that requires a high index of suspicion, early and comprehensive endoscopic evaluation to obtain biopsies for systematic histopathologic and immunohistochemical analyses, and prompt initiation of IEC‐EC directed therapy within a multispecialty framework. As the indications for CAR‐T therapy continue to expand and the number of treated patients grows, IEC‐EC will inevitably be encountered with greater frequency. Raising awareness of this entity is an immediate priority, and investment in prospective studies to define the risk factors, pathogenesis, and optimal treatment of IEC‐EC is paramount.

Author Contributions

Yi Lin: investigation, methodology, validation, writing – review and editing, formal analysis, project administration, data curation, supervision, resources. John A. Damianos: conceptualization, investigation, writing – original draft, methodology, validation, visualization, writing – review and editing, formal analysis, data curation. Navreet M. Chowla: conceptualization, investigation, methodology, writing – original draft, validation, writing – review and editing, formal analysis, project administration, supervision, data curation, resources. Kenneth J. C. Lim: investigation, methodology, validation, writing – review and editing, formal analysis, project administration, data curation, supervision, resources. Zongming Eric Chen: investigation, methodology, validation, writing – review and editing, formal analysis, project administration, data curation, supervision, resources.

Funding

The authors have nothing to report.

Disclosure

Yi Lin: advisory board role for Janssen, Sanofi, BMS, Regeneron, Genentech, Tesserae, Legend, NexT Therapeutics, steering committee for Janssen, Kite/Gilead, research funding from Janssen, BMS, scientific advisory board for Nonimmune, Caribou and sata safety monitor board for Pfizer. Kenneth JC Lim: Research funding from Sanofi; R.P.: advisory board role for Sanofi Aventis and Astra Zeneca, research funding from Bristol Myers Squibb Foundation and GlaxoSmithKline; S.C. reports honoraria from Sanofi, Ascentage Pharma, Sobi, Legend Biotech, BMS, Pfizer and institutional research funding from Johnson & Johnson, Takeda, C4 Therapeutics, Abbvie, Ascentage Pharma, AstraZeneca. The remaining authors report no relevant disclosures.

Acknowledgements

We are grateful to Dr. Harmeet Malhi for her assistance with image files.

Damianos J. A., Lin Y., Chen Z. E., Lim K. J. C., and Chowla N. M., “Review Article: Immune Effector Cell‐Mediated Enterocolitis Following CAR‐T Cell Therapy—Clinical Features, Pathophysiology and Management,” Alimentary Pharmacology & Therapeutics 64, no. 8 (2026): 1046–1057, 10.1111/apt.70920.

Handling Editor: Colin Howden

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Associated Data

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.