TPS9600 Background: Immune checkpoint inhibitors (ICIs) are approved for multiple malignancies, however, durable remission rates with ICI monotherapy remains low. Combined treatment with anti-CTLA-4 and anti-PD1 has shown higher response rates in several cancers but is associated with up to 60% grade 3/4 immune-related adverse events (irAEs) leading to frequent treatment discontinuation. The need for corticosteroids to control irAEs may further diminish anti-tumor activity. A multi-disciplinary approach using clinical, preclinical, and translational analyses implicated the IL-6/Th17 axis in both ICI-related autoimmunity and resistance. Further, preliminary data showed that targeting interleukin 6 (IL-6) could be an effective approach to reduce irAEs while maintaining and possibly boosting the antitumor immune response. Methods: We are conducting a phase II, open-label, single center study to evaluate the use of combination treatment with tocilizumab (toci; anti-IL6), ipilimumab (ipi; anti-CTLA4) and nivolumab (nivo; anti-PD1) as a front-line therapy for patients (pts) with treatment-naïve advanced cutaneous melanoma (cohort 1), urothelial carcinoma (cohort 2), and EGFR mutant non-small cell lung cancer after tyrosine kinase inhibitors failure (cohort 3) (NCT04940299). Ten pts per disease site will be enrolled, plus an additional 25 melanoma pts in an expansion cohort. Key inclusion criteria are age ≥18 years (yrs) and histologically confirmed locally advanced or metastatic disease, with specific eligibility criteria defined for each cohort. Patients with interstitial lung diseases, autoimmune diseases, infection, or conditions requiring immunosuppressive therapies are not eligible, but stable asymptomatic brain mets are allowed. Ipi/Nivo dosing is as per approved disease indications: in cohort 1 &2, ipi 3 mg/kg + nivo 1 mg/kg is administered intravenously (IV) every 3 weeks (wks) for 4 doses then nivo 480 mg/4 wks up to 2 yrs. In cohort 3, IV ipi 1 mg/kg/6 wks + nivo 3 mg/kg/2 wks is administered up to 2 yrs. In all 3 cohorts, subcutaneous (SQ) toci 162 mg/2wks is administered up to 12 wks. Imaging is every 12 wks up to 2 yrs or until dose-limiting toxicities or progression. The primary outcome is safety/tolerability of the triple therapy. The secondary outcomes are antitumor efficacy and overall survival. Additionally, tumor and blood samples are being collected for longitudinal immune analysis, including gene expression and multiplex histochemistry to identify predictive biomarkers of response, resistance, and toxicity. The trial opened in October 2021 and has enrolled 14 patients to date. Clinical trial information: NCT04940299.
Although immune checkpoint inhibitors (ICIs) have provided practice-changing outcomes in treating many cancers, ICI-related gastrointestinal toxicity can limit their use. Upper gastrointestinal toxicity is not common nor as well described as lower gastrointestinal toxicity. We aimed to characterize the clinical presentation, endoscopic and histologic features, treatment response, and outcomes of ICI-related esophagitis.We retrospectively studied patients at The University of Texas MD Anderson Cancer Center in whom esophagitis developed after receiving ICIs from June 2011 through January 2020. We included patients with endoscopic evidence of esophagitis and excluded those with other obvious causes of esophagitis. A chi-square test was used to assess associations between categorical variables. The Mann-Whitney U test was used to compare differences between continuous variables.Of 657 consecutive patients who underwent esophagogastroduodenoscopy (EGD) during or within 6 months of completing ICI-based therapy, 21 (3%) had esophagitis deemed to be from ICIs. Of these patients, 1 (5%) received an inhibitor of CTLA-4 alone, 15 (71%) received anti-PD-1 or PD-L1 monotherapy, and 5 (24%) received a combination of these. Median time from ICI initiation to onset of esophagitis was 4 months. Upon evaluation with EGD, only 3 patients (14%) had isolated esophageal involvement; 18 (86%) had concurrent involvement of the stomach, duodenum, or both. Most patients (67%) were treated with proton pump inhibitors, and 4 (19%) received steroids (prednisone or budesonide). The mortality rate was 38% (median follow-up, 15 months).Esophagitis associated with ICI use is rare. The diagnosis is one of exclusion because its clinical presentation appears similar to that of inflammation resulting from other causes. It often occurs in conjunction with other upper gastrointestinal toxicity. Symptoms are mild and respond well to nonimmunosuppressive treatment, with few severe complications.
B7-H4 (VTCN1) is a member of the CD28/B7 family of immune co-inhibitory molecules. The relationship of tumor and stromal B7-H4 protein expression with PD-L1, tumor infiltrating lymphocytes (TILs) and its association with clinico-pathological variables are not well defined. Herein, we explore the expression level of B7-H4 protein in breast cancer and evaluate its association with TILs, levels of PD-L1 expression, and clinico-pathological characteristics in two independent populations. In this study, we used multiplexed automated quantitative immunofluorescence (QIF) to measure the levels of B7-H4 and PD-L1 protein and determined TILs through pathologist assessment of H&E-stained preparations in over a thousand breast cancer cases from two institutions represented in tissue microarray format. Associations between the marker levels, major clinico-pathological variables, and survival were analyzed. We detected B7-H4 protein was highly expressed in both breast cancer and stromal cells. Its expression was independent of breast cancer intrinsic subtypes. PD-L1 expression was higher in triple negative breast cancers. Neither B7-H4 nor PD-L1 were associated with survival in breast cancer. Our study shows there is a mutually exclusive pattern of B7-H4 with both tumor PD-L1 expression and TILs in all breast cancers, independent of breast cancer intrinsic subtype. This exclusive pattern suggests that some breast tumors may preferentially use one B7-related immune evasion mechanism/pathway. This could explain the clinical benefit that is seen only in a fraction of patients with immune checkpoint inhibitors directed exclusively towards PD-L1 in breast cancer.
Links between the tumor mutational signature, myeloid and tumor-infiltrating lymphocytes (TIL) phenotype and functional states are lacking in malignant pleural mesothelioma (MPM). We performed multi-omic profiling of the tumor immune microenvironment (TIME) of epithelioid MPM cases to provide insights that could drive novel therapeutic avenues in future studies. MPM tumor tissue from patients who underwent surgical resection was confirmed by a pathologist as epithelioid histological type. Flow cytometry, cytokine profiing and TIL expansion was performed ex vivo. Twenty-two tumor samples were processed for bulk RNA-seq with 15 matched cases profiled for WES. Single cell(sc) RNA-seq with matched scTCR-seq was performed on 9 tumor cases. Analysis was performed using in-house set open-source pipelines with downstream analysis in R. Statistical significance was determined using BH adjusted p-value and +/-1 log2FC with Wilcoxon Sum Ranking test for differentially expressed genes (adjusted p-value significance: 0 ≤ *** < 0.001 ≤ ** < 0.01). BAP1 was the dominant mutation identified in the analyzed cohort (SNV (6/22, 27.3%), CNV (3/15, 20%)). Median tumor mutation burden was low (0.80) and no HLA loss of heterozygosity was identified. scRNA-seq profiling identified clusters of highly proliferative, effector memory CD8+ TIL that contained hyper and highly expanded clones. TIL expressed a high degree of checkpoint receptors (PD-1***, LAG3***, TIM3***) which was confirmed by flow cytometry, and the transcription factor, TOX***. Treg clusters and suppressive myeloid cell types were identified which could limit immune responses against the tumor. CCL22, IP-10 and sCD25 were detected in the tumor tissue. Expanded TIL showed a loss of polyfunctional cytokine secretion but retained production of IFNγ. Hyper and highly expanded TCRs were identified suggesting potential anti-tumor response despite having a dysfunctional, highly proliferative phenotype and a highly suppressive TIME. Our ongoing efforts are focused on receptor-ligand interaction predictions as well as identifying predicted neo-antigens.
BACKGROUND: Patients undergoing chemotherapy are at risk for mucosal injury and neutropenia, which facilitate colonic mucosal invasion by the bowel flora and subsequent neutropenic enterocolitis, which has a poor prognosis. OBJECTIVE: This study aimed to assess the clinical features and outcomes of neutropenic enterocolitis in patients at a comprehensive cancer center. DESIGN: This is a retrospective cohort study. SETTING: The study was conducted at the University of Texas MD Anderson Cancer Center. PATIENTS: Neutropenic enterocolitis was defined by the presence of an absolute neutrophil count <1000/mm 3 , compatible abdominal symptoms, and either mucosal thickening on abdominal imaging or mucosal injury on colon biopsy. Patients who had been diagnosed between 2010 and 2018 were included. MAIN OUTCOMES: Complication and survival rates were analyzed using logistic regression and Cox regression analyses, respectively. RESULTS: Of the 49,244 patients who had neutropenia during the study period, 134 (2.7%) were included. The median time from neutropenia onset to neutropenic enterocolitis was 2 days (interquartile range, 1–10 days). Neutropenic enterocolitis symptoms lasted for a median of 11 days (interquartile range, 6–22 days). Most patients received antibiotics (88%) and granulocyte colony-stimulating factor (68%). Complications included sepsis (11%), colonic perforation (2%), pneumatosis intestinalis (2%), and abscess formation (2%). The risks associated with complications included immunosuppressive therapy use within 1 month before neutropenic enterocolitis onset (OR, 3.92; 95% CI, 1.04–14.76) and delayed imaging (OR, 1.10; 95% CI, 1.03–1.17). Older age, severe neutropenia, prolonged neutropenia before and after neutropenic enterocolitis diagnosis, and other concomitant systemic infections were associated with lower survival rates. LIMITATIONS: The performance of this study at a single center and its retrospective nature are limitations of the study. CONCLUSION: The prompt diagnosis and management of neutropenic enterocolitis are critical to prevent complications. The use of granulocyte colony-stimulating factor can be beneficial to shorten the duration of neutropenia. See Video Abstract at http://links.lww.com/DCR/B116. ENTEROCOLITIS NEUTROPÉNICA: CARACTERÍSTICAS CLÍNICAS Y RESULTADOS ANTECEDENTES: Los pacientes sometidos a quimioterapia, están en riesgo de lesión de la mucosa y neutropenia, lo que facilita la invasión de la mucosa colónica por la flora intestinal y la subsecuente enterocolitis neutropénica, con un mal pronóstico. OBJETIVO: Evaluar las características clínicas y los resultados de la enterocolitis neutropénica de pacientes en un centro integral de cáncer. DISEÑO: Estudio de cohorte retrospectivo. AJUSTES: El estudio se realizó en el MD Anderson Cancer Center de la Universidad de Texas. PACIENTES: Se definió la enterocolitis neutropénica, como la presencia de un recuento absoluto de neutrófilos <1000 / mm3, con síntomas compatibles abdominales y engrosamiento de la mucosa en imagen abdominal o lesión de la mucosa en biopsia de colon. Se incluyeron pacientes diagnosticados entre 2010 y 2018. PRINCIPALES MEDIDAS DE RESULTADO: Se analizaron las tasas de complicaciones y supervivencia mediante análisis de regresión logística y regresión de Cox. RESULTADOS: De 49,244 pacientes que tuvieron neutropenia durante el período de estudio, 134 (2.7%) fueron incluidos. La media del tiempo desde el inicio de la neutropenia hasta la enterocolitis neutropénica, fue de 2 días (RIC, 1-10 días). Los síntomas de enterocolitis neutropénica duraron una media de 11 días (RIC, 6-22 días). La mayoría de los pacientes recibieron antibióticos (88%) y factor estimulante de colonias de granulocitos (68%). Las complicaciones incluyeron sepsis (11%), perforación colónica (2%), neumatosis intestinal (2%) y formación de abscesos (2%). Los riesgos asociados con las complicaciones incluyeron, uso de terapia inmunosupresora dentro de 1 mes antes del inicio de la enterocolitis neutropénica (razón de probabilidades 3.92; intervalo de confianza del 95% 1.04-14.76) y demora en la obtención de imágenes (razón de probabilidades 1.10; intervalo de confianza del 95% 1.03-1.17), edad avanzada, neutropenia grave, neutropenia prolongada antes y después del diagnóstico de enterocolitis neutropénica y de otras infecciones sistémicas concomitantes, se asociaron con bajas tasas de supervivencia. LIMITACIONES: Centro único y estudio retrospectivo. CONCLUSIONES: El rápidodiagnóstico y manejo de la enterocolitis neutropénica, es crítico para prevenir complicaciones. El uso del factor estimulante de colonias de granulocitos puede ser beneficioso para acortar la duración de la neutropenia. Consulte Video Resumen en http://links.lww.com/DCR/B116.
Background/Aims Locally advanced (T4 per American Joint Committee on Cancer (AJCC) 8th edition) periocular basal cell carcinoma (BCC) can lead to loss of the eye. We report the neoadjuvant use of vismodegib followed by surgery in patients with such lesions with eye preservation as primary goal. Methods This retrospective interventional study includes all patients with a T4 periocular BCC (per 8th edition AJCC for eyelid carcinoma) treated by the senior author between 2013 and 2017 with neoadjuvant vismodegib prior to definitive surgery. Results Eight patients had a T4 tumour. Six patients presented with recurrent disease. Indications for neoadjuvant treatment were an unresectable tumour in one patient, an attempt to avoid an orbital exenteration in six patients and an attempt to avoid disfiguring facial surgery in one patient. Patients were treated for a median of 14 months (range: 4–36 months). All patients underwent an eye-sparing surgery following neoadjuvant vismodegib and all final surgical margins were negative for tumour. Five patients had a complete response to vismodegib with no microscopic residual BCC found during surgery; three patients had a significant partial response with residual tumour found on pathology. At last follow-up, a mean of 18 (range: 6–43) months after surgery, all patients were off-vismodegib and alive without evidence of disease. Conclusions Neoadjuvant vismodegib for locally advanced (T4) periocular BCC enabled an eye-sparing surgery in all patients in our cohort. Prolonged treatment was well tolerated by most patients. Over half of patients achieved a complete response with no residual microscopic disease. Careful long-term follow-up is needed to confirm long-term disease-free survival.
Introduction: A variety of tyrosine kinase inhibitors (TKIs) are currently approved for the treatment of solid tumor and hematologic malignancies. However, TKIs are often associated with GI toxicities, especially diarrhea. We aimed to describe the clinical features and outcomes of TKI associated lower GI toxicities. Methods: This is a retrospective single-center cohort study of patients with cancer treated with a TKI between 3/2016-9/2020 who developed diarrhea without other identifiable causes. Baseline demographic and clinical data were obtained through chart review. Differences in the proportions of patients with categorical clinical outcomes were examined by χ2 testing and comparisons between continuous variables were examined by Mann-Whitney U testing. Results: Among 2,172 patients who received TKI over the study period, 228 patients were included for final analysis, of which 166 (72.8%) had hematologic malignancy. Other than diarrhea, GI toxicity symptoms also included nausea (36.4%), vomiting (21.9%), abdominal pain (15.4%), and bleeding (3.1%); symptoms were typically mild, with 209 patients (91.7%) presenting with diarrhea severity grade 1-2. Immunosuppressants were used for treatment in 5 patients (2.2%), 83 patients (36.4%) received no treatment, 29 patients (12.7%) received antibiotics, 101 patients (44.3%) received loperamide, and 17 patients (7.5%) required dose reduction or cessation of TKI. Colonoscopy was performed in only 15 patients (6.6%), with normal endoscopic findings in 8 patients (53.3%) and non-ulcer inflammation in 5 patients (33.3%); distribution of inflammation universally involved the left colon. When compared to patients with hematologic malignancies, patients with solid tumor malignancies treated with TKI had higher rates of hospitalization (29% vs 12%, P < 0.001) and increased mortality (75.8% vs 43.4%, P < 0.001), but lower rates of recurrent TKI related GI toxicity (21% vs 42.8%, P = 0.002). Within the hematologic malignancy group, AML patients had lower rates of recurrent TKI related GI toxicity compared to other hematologic malignancies (7.2% vs 30.1%, P = 0.001). Conclusion: 10% of patients receiving TKI developed lower GI toxicities, which are usually mild in severity. Symptoms are nonspecific, often overlapping with other cancer therapy related GI toxicities. Treatment is largely supportive, antibiotic therapy is not warranted, and immunosuppressants are rarely required.
