Immune effector cell-associated enterocolitis following chimeric antigen receptor T-cell therapy in multiple myeloma

Abstract

We report 14 cases of immune effector cell (IEC)-associated enterocolitis following chimeric antigen receptor T-cell (CAR-T) therapy in multiple myeloma, with a 1.2% incidence overall (0.2% for idecabtagene vicleucel and 2.2% for ciltacabtagene autoleucel). Patients developed acute-onset symptoms (typically non-bloody Grade 3+ diarrhea) with negative infectious workup beginning a median of 92.5 days (range: 22-210 days) after CAR-T therapy and a median of 85 days after cytokine release syndrome resolution. Gut biopsies uniformly demonstrated inflammation, including intra-epithelial lymphocytosis and villous blunting. In one case where CAR-specific immunofluorescence stains were available, CAR T-cell presence was confirmed within the lamina propria. Systemic corticosteroids were initiated in 10 patients (71%) a median of 25.5 days following symptom onset, with symptom improvement in 40%. Subsequent infliximab or vedolizumab led to improvement in 50% and 33% of corticosteroid-refractory patients, respectively. Five patients (36%) have died from bowel perforation or treatment-emergent sepsis. In conclusion, IEC-associated enterocolitis is a distinct but rare complication of CAR-T therapy typically beginning 1-3 months after infusion. Thorough diagnostic workup is essential, including evaluation for potential T-cell malignancies. The early use of infliximab or vedolizumab may potentially hasten symptom resolution and lower reliance on high-dose corticosteroids during the post-CAR-T period.

Fig. 1. Representative images of IEC-associated enterocolitis.

Top panel: Representative colitis-related images from different patients. Panel A: diffuse bowel wall pneumatosis and pneumoperitoneum on computed tomography imaging consistent with toxic megacolon, which subsequently required subtotal colectomy. Panel B: ulcerations noted on endoscopic evaluation of the transverse colon. Panel C: 10× magnification of colonic mucosa showing focal crypt dropout and increased apoptotic activity; minimal expansion by scattered eosinophils and focal intraepithelial lymphocytes are also seen. Bottom panel: Representative enteritis-related images from one patient. Marked infiltration of the lamina propria by T lymphocytes at low power (2×, panel D) and high power (10×, panel E). Immunohistochemical stain for CD3 (20×, panel F) demonstrates that the majority of the lamina propria cells and intraepithelial lymphocytes are T cells.

Fig. 2. Evidence of CAR T-cell infiltration into gut lamina.

Multiplex immunofluorescence (mIF) images from a duodenal FFPE biopsy of a patient who developed IEC-associated enterocolitis after ciltacabtagene autoleucel therapy for multiple myeloma. Panel A shows a representative merged image demonstrating presence of CAR+ (Camelid VHH+, red) T cells (CD3+, green) infiltrating the affected tissue. CD8 staining (yellow) determines CD8+ and CD8− T cell subsets among the T cells. Single channel images of the field of view are shown on the right. Panel B shows (1) Camelid V_HH detection by mIF (left), (2) co-expression of CD3 and VHH (center) demonstrating that infiltrating CAR+ (red) cells are CAR-transduced CD3+ T cells (green), and (3) differential expression of CD8 and V_HH (right) indicating that some but not all CAR-T cells are CD8+ (yellow) cells. Panel C shows representative images of different areas of the biopsy identifying CD3+ T cells (green) by mIF infiltrating the tissue (top). Those same regions from the IHC-stained slide are shown (bottom), demonstrating similar pattern of infiltration of CAR+ cells (V_HH+), indicating that great majority of the infiltrating T cells are CAR-T cells. CAR chimeric antigen receptor, FFPE formalin-fixed paraffin-embedded, IEC immune effector cell, IHC Immunohistochemistry, V_HH variable heavy chain of a heavy-chain antibody.