RESUMEN
Immune checkpoint blockade enhances antitumor responses, but can also lead to severe immune-related adverse events (IRAE). To avoid unnecessary exposure to these potentially hazardous agents, it is important to identify biomarkers that correlate with clinical activity and can be used to select patients that will benefit from immune checkpoint blockade. To understand the consequences of CTLA-4 blockade and identify biomarkers for clinical efficacy and/or survival, an exploratory T cell monitoring study was performed in a phase I/II dose escalation/expansion trial (n = 28) of combined Prostate GVAX/ipilimumab immunotherapy. Phenotypic T cell monitoring in peripheral blood before and after Prostate GVAX/ipilimumab treatment revealed striking differences between patients who benefited from therapy and patients that did not. Treatment-induced rises in absolute lymphocyte counts, CD4(+) T cell differentiation, and CD4(+) and CD8(+) T cell activation were all associated with clinical benefit. Moreover, significantly prolonged overall survival (OS) was observed for patients with high pre-treatment frequencies of CD4(+)CTLA-4(+), CD4(+)PD-1(+), or differentiated (i.e., non-naive) CD8(+) T cells or low pre-treatment frequencies of differentiated CD4(+) or regulatory T cells. Unsupervised clustering of these immune biomarkers revealed cancer-related expression of CTLA-4(+) in CD4(+) T cells to be a dominant predictor for survival after Prostate GVAX/ipilimumab therapy and to thus provide a putative and much-needed biomarker for patient selection prior to therapeutic CTLA4 blockade.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Linfocitos T CD4-Positivos/efectos de los fármacos , Antígeno CTLA-4/inmunología , Vacunas contra el Cáncer/uso terapéutico , Neoplasias de la Próstata/terapia , Anciano , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Antígeno CTLA-4/análisis , Vacunas contra el Cáncer/inmunología , Línea Celular Tumoral , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Humanos , Ipilimumab , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Masculino , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/mortalidadRESUMEN
BACKGROUND: In refractory celiac disease (RCD) type II, a phenotypically aberrant (CD7+ CD3- CD4/8-cytoplasmicCD3+) intraepithelial lymphocyte (IEL) population is present, and 50-60% of these patients develop enteropathy-associated T-cell lymphoma (EATL). TCRgammadelta+ IELs play an important role in mucosal repair, homeostasis, and tumor surveillance. Recently, human small intestinal TCRgammadelta+ IELs were shown to have regulatory potential in uncomplicated celiac disease (CD). AIM: In the present study, we investigated whether TCRgammadelta+ IELs are decreased in RCD II, providing a possible explanation for persisting mucosal damage and inflammation, and the emergence of aberrant T cells with clonal expansion to EATL. DESIGN AND METHODS: Multiparameter flow cytometric immunophenotyping was performed on IELs isolated from fresh small bowel biopsy specimens of relatively large distinct CD patient and control groups (N = 87). RESULTS: A significantly lower percentage of TCRgammadelta+ IELs was found in RCD II as compared to all other CD groups. In contrast, in uncomplicated CD patients significantly more TCRgammadelta+ IELs were found than in controls. Overall, there is a clear negative relation between TCRgammadelta+ IELs and aberrant IELs. Interestingly, TCRgammadelta+ IELs increase again in RCD II after effective therapy. CONCLUSIONS: The observed negative relation between TCRgammadelta+ and aberrant IELs, along with their known regulatory capacity in uncomplicated CD, implies that TCRgammadelta+ IELs may play a crucial role in mucosal repair, regaining homeostasis and possibly even tumor surveillance. These cells may be important markers, in addition to the aberrant T cells, to differentiate between disease categories and to evaluate the effectiveness of therapeutic strategies.
Asunto(s)
Enfermedad Celíaca/inmunología , Intestino Delgado/inmunología , Linfoma/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Linfocitos T/inmunología , Anciano , Enfermedad Celíaca/complicaciones , Femenino , Citometría de Flujo , Humanos , Mucosa Intestinal/inmunología , Linfoma/etiología , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Refractory celiac disease (RCD) patients with aberrant, often clonal, intraepithelial T-cells are at high risk for development of enteropathy associated T-cell lymphoma (EATL). Early detection of those patients that actually develop EATL is of utmost importance for curative intervention. AIM: First, to establish an optimal cut-off value for the percentage of aberrant lymphocytes, previously determined based on clinical observations, via reference ranges for aberrant T-cells in the duodenal mucosa of celiac disease patient and control groups. Secondly, to compare aberrancy with intestinal T-cell clonality as a prognostic parameter for EATL development in RCD. METHODS: Immunophenotyping using flow cytometry was performed on small intestinal biopsy-derived lymphocytes, obtained from distinct celiac disease (CD) patient and control groups (N=167 in total). T-cell clonality in duodenal biopsy specimens was assessed by PCR in RCD, ulcerative jejunitis and EATL patients (N=31 in total). RESULTS: In 95% of non-refractory CD patients, the highest percentage aberrant T-cells was 20%. Using this cut-off value, EATL development was exclusively seen in RCD with more than 20% aberrant T-cells (median 52% aberrant T-cells, range 27-94%). When compared with T-cell clonality analysis, >20% aberrancy showed a much higher negative predictive value and sensitivity (both 100%) for EATL development in RCD patients than T-cell clonality analysis (respectively 75% and 78%). CONCLUSIONS: Quantification of aberrant T-cells by flow cytometry is preferable to T-cell clonality analysis for identification of RCD patients at risk for EATL development. A cut-off value of 20% is of use in risk stratification, therapeutic options and subsequent follow-up of RCD patients.
Asunto(s)
Enfermedad Celíaca/complicaciones , Enfermedad Celíaca/inmunología , Duodeno/inmunología , Citometría de Flujo , Reordenamiento Génico de la Cadena gamma de los Receptores de Antígenos de los Linfocitos T , Mucosa Intestinal/inmunología , Linfoma de Células T/diagnóstico , Linfocitos T/inmunología , Adolescente , Adulto , Anciano , Enfermedad Celíaca/patología , Duodeno/patología , Femenino , Humanos , Inmunofenotipificación , Mucosa Intestinal/patología , Linfoma de Células T/etiología , Masculino , Persona de Mediana Edad , Valor Predictivo de las PruebasRESUMEN
Autologous hematopoietic stem cell transplantation (ASCT) is an increasingly accepted treatment for refractory autoimmune diseases. Refractory celiac disease with aberrant T cells (RCD type II) is unresponsive to available therapies and carries a high risk of transition into enteropathy associated T-cell lymphoma (EATL). This study reports on the feasibility, safety, and efficacy of ASCT in patients with RCD type II. Thirteen patients with RCD type II were evaluated. Seven patients (4 men, 3 women, mean age 61.5 years [range, 51-69 years]) underwent transplantation. After conditioning with fludarabine and melphalan, ASCT was performed. Patients were monitored for response, adverse effects, and hematopoietic reconstitution. All 7 patients completed the mobilization and leukapheresis procedures successfully and subsequently underwent conditioning and transplantation. Engraftment occurred in all patients. No major nonhematologic toxicity or transplantation-related mortality was observed. There was a significant reduction in the aberrant T cells in duodenal biopsies associated with improvement in clinical well-being and normalization of hematologic and biochemical markers (mean follow-up, 15.5 months; range, 7-30 months). One patient died 8 months after transplantation from progressive neuroceliac disease. These preliminary results showed that high-dose chemotherapy followed by ASCT seems feasible and safe and might result in long-term improvement of patients with RCD type II whose condition did not respond promptly to available drugs.