Petra E. T. Scholten

Differences in immune status between well-nourished andmalnourished head and neck cancer patients

Malnutrition is reported to occur in approximately 30% of head and neck cancer patients. Also, impaired immunocompetence is described as a common phenomenon in this patient group. The purpose of this study was to assess the possible relationship between malnutrition and some prognostically important immune parameters in head and neck cancer patients. Thirty-two malnourished (recent weight loss >/= 10%) and 34 well-nourished patients undergoing curative treatment for advanced head and neck cancer were studied prospectively, and six parameters of their immune status (leucocytes, lymphocytes, lymphocyte phenotyping, monocytes, HLA-DR expression on monocytes and serum interleukin-10) were determined on the day of panendoscopy. Reference values for monocytes, HLA-DR expression and interleukin-10 were obtained from 43 healthy controls. Although the number of monocytes was elevated in both patient groups, the HLA-DR expression on these monocytes was significantly lower in the malnourished than in the well-nourished and control groups. Tumor stage, tumor localization, recurrence after initial radiotherapy, age and gender were not correlated to HLA-DR expression. No relationships emerged between nutritional status and lymphocyte subsets. Malnourished head and neck cancer patients show a significantly lower HLA-DR expression on monocytes than well-nourished ones and healthy controls. According to the literature this would imply an increased risk for postoperative complications. Indeed, postoperative complications occur more frequently in malnourished than in well-nourished patients.

The Presence of Small Intestinal Intraepithelial Gamma/Delta T-Lymphocytes Is Inversely Correlated With Lymphoma Development in Refractory Celiac Disease

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). TCRγδ+ IELs play an important role in mucosal repair, homeostasis, and tumor surveillance. Recently, human small intestinal TCRγδ+ IELs were shown to have regulatory potential in uncomplicated celiac disease (CD).AIM:In the present study, we investigated whether TCRγδ+ 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 TCRγδ+ IELs was found in RCD II as compared to all other CD groups. In contrast, in uncomplicated CD patients significantly more TCRγδ+ IELs were found than in controls. Overall, there is a clear negative relation between TCRγδ+ IELs and aberrant IELs. Interestingly, TCRγδ+ IELs increase again in RCD II after effective therapy.CONCLUSIONS:The observed negative relation between TCRγδ+ and aberrant IELs, along with their known regulatory capacity in uncomplicated CD, implies that TCRγδ+ 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.

Survival of malnourished head and neck cancer Patients can be predicted by human leukocyte antigen-DR expression and interleukin-6/tumor necrosis factor-α response of the monocyte

BACKGROUND Patients with advanced stages of head and neck cancer are often characterized by malnutrition and by an impaired immune system. Because some of the suppressed immune parameters were shown to be of prognostic importance in trauma and sepsis, we investigated whether these would also correlate with survival in head and neck cancer. METHODS Severely malnourished head and neck cancer patients undergoing ablative and reconstructive surgery were followed prospectively and their perioperative immune parameters were related to long-term survival. RESULTS Forty-nine patients with a preoperative weight loss of more than 10% were followed up for a period of at least 16 months after surgery. Analyses of variance revealed that preoperative human leukocyte antigen-DR (HLA-DR) expression on monocytes and endotoxin-induced production of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were different between patients who survived and patients who died. Proportional hazards identified a weight loss of more than 12%, the presence of coexistent disease, and an HLA-DR expression on monocytes below the cutoff points (mean fluorescence index < 15, peak channel index < 9) to be of significant influence on survival. CONCLUSIONS In addition to known prognostic parameters such as tumor stage, coexistent disease, and weight loss, the immune parameters HLA-DR expression on monocytes and endotoxin-induced cytokine production may carry prognostic value in cancer patients. Immunomodulating therapies leading to improvement of these parameters might in the future lead to increased options for treatment.

A pilot study investigating the effects of orally administered pentoxifylline on selected immune variables in patients with multiple sclerosis

Multiple sclerosis is probably mainly mediated by T-helper 1 (TH1)-lymphocytes. TH1-function can be down-regulated in vitro and in animal experiments by pentoxifylline. Therefore, we included 20 multiple sclerosis patients in an open label pilot trial of pentoxifylline. Outcome parameter was the effect of treatment on levels of various cytokines and adhesion molecules in cerebrospinal fluid and serum, on production of TH1- and TH2-cytokines using cell stimulation assays, as well as on measures of T-cell activation and proliferation. Kurtzkes EDSS was a secondary efficacy parameter. A convincing and consistent effect of pentoxifylline could not be demonstrated.

Abstract B20: Immune vs. clinical response monitoring in patients with metastatic hormone-refractory prostate cancer receiving combined prostate GVAX and anti-CTLA4 immunotherapy

The effects of a GM-CSF-secreting allogeneic prostate cancer vaccine (Prostate GVAX) and the anti-CTLA4 antibody Ipilimumab were investigated in a Phase I dose escalation/expansion trial of patients with metastatic, hormone-refractory prostate cancer (mHRPC). Patients received a 500 million cell GVAX priming dose on day 1 followed by 12 bi-weekly intradermal administrations of 300 million cells, while Ipilimumab was administered every 4 wks from day 1 for a total of 6 times. Initially, 12 patients were enrolled in cohorts of 3 and each cohort was assigned an escalating dose of Ipilimumab at 0.3, 1, 3 or 5 mg/kg. 16 additional patients were enrolled in the expansion cohort of 3 mg/kg Ipilimumab. Results showed that the GVAX and Ipilimumab combination was clinically active in mHRPC patients. PSA declines of more than 50% (Partial Response, PR) were observed in 5 of 22 patients in the 3–5 mg/kg Ipilimumab dose cohorts, and were associated with Autoimmune Breakthrough Events (ABE), including Grade 2 or 3 hypophysitis and Grade 3 alveolitis. PSA stabilizations (Stable Disease, SD) were observed in 1/3 patients in lower (0.3 and 1 mg/kg), and in 7 of 22 in the higher (3–5 mg/kg) dose levels. Moreover, regressing bone and lymph node metastases were observed in 2/5 PR patients. Immune response monitoring was performed to identify changes that might predict or correlate with clinical efficacy. Most notably, pronounced and significant increases in frequencies of activated and effector CD4+ and CD8+ T cells were observed by HLA-DR and ICOS expression upon administration of high (3 and 5 mg/kg) Ipilimumab doses; a relation to clinical behaviour was only observed for HLA-DR with earlier and more pronounced increases in patients with PR or SD. As an indication of tumor-specific responsiveness HLA-Tetramer (Tm) and seroreactivity to NY-ESO and PSMA were tested. For NY-ESO, therapy-induced increased seroreactivity (by Western Blot or ELISA) was observed in 6/28 patients. Of these 6 patients, three could be tested for Tm reactivity and in two (1SD, 1 Progressive Disease, PD) increased NY-ESO157 rates were found concomitant with increasing serum Ab levels, whereas no Tm reactivity was detected in 8 patients without seroconversions. PSMA seroconversions were observed in a total of 12/28 patients (and, of note, in 4/5 PR), but no Tm positivity at any time was found in a total of 15 patients tested. In the 3–5 mg/kg dose levels (n=22), PSMA seroconversion was associated with increased overall survival (P=0.062). In addition, combined GVAX/Ipilimumab administration was found to induce Type-2/Th17 profiles, as determined ex vivo by intracellular staining of peripheral T cells. Significantly increased levels of IL-4 in both CD4+ and CD8+ T cells were observed in patients with PR or SD (P In summary, our analyses so far reveal a relationship between clinical efficacy, PSMA seroconversion, and generalized T cell activation accompanied by Th2 and Th17 skewing. Together these data point to a mechanism of action whereby combined Prostate GVAX and anti-CTLA4 immunotherapy can induce both Th2/humoral and Th17/cell-mediated immune responses, resulting in tumor destruction and collateral autoimmunity. Supported by the Prostate Cancer Foundation and the Dutch Cancer Society (KWF-VU 2006-3697) Citation Information: Clin Cancer Res 2010;16(7 Suppl):B20

Abstract 5588: T cell activation in relation to clinical responsiveness in patients with metastatic hormone-refractory prostate cancer receiving combined Prostate GVAX and anti-CTLA4 immunotherapy

The effects of a GM-CSF-secreting allogeneic prostate cancer vaccine (Prostate GVAX) and the anti-CTLA4 antibody Ipilimumab were investigated in a Phase I dose escalation/expansion trial of patients with metastatic, hormone-refractory prostate cancer (mHRPC). Patients received a 500 million cell GVAX priming dose on day 1 followed by 12 bi-weekly intradermal administrations of 300 million cells, while Ipilimumab was administered every 4 wks from day 1 for a total of 6 times. Initially, 12 patients were enrolled in cohorts of 3 and each cohort was assigned an escalating dose of Ipilimumab at 0.3, 1, 3 or 5 mg/kg. 16 additional patients were enrolled in the expansion cohort of 3 mg/kg Ipilimumab. Results showed that the GVAX and Ipilimumab combination was clinically active in mHRPC patients. PSA declines of more than 50% (Partial Response, PR) were observed in 5 of 22 patients in the 3-5 mg/kg Ipilimumab doses and PSA stabilizations (Stable Disease, SD) were observed in 1/3 pts in lower (0.3 and 1 mg/kg), and in 7/22 in the higher (3-5 mg/kg) dose levels. Phenotypic and functional (anti-tumor) effector T cell activation was monitored to identify changes that might predict or correlate with clinical efficacy. Most notably, pronounced and significant increases in frequencies of activated and effector CD4 + and CD8 + T cells were observed by HLA-DR and ICOS expression upon administration of high (3 and 5 mg/kg) but not of low (0.3 and 1 mg/kg) Ipilimumab doses. We also observed a significant increase of CTLA4 and PD-1 expression on CD4 + T cells compared to pre-treatment values in the 3 mg/kg Ipilimumab-administered patients. The latter might be indicative of the induction of concomitant negative feedback signaling. As an indiciation of Tumor-Associated Antigen (TAA) specific responsiveness we tested HLA-Tetramer (Tm) reactivity to NY-ESO and PSMA in HLA-A2 or -A3 positive patients. For NY-ESO, GVAX/Ipi-induced increased seroreactivity (by Western Blot or ELISA) was observed in 6/28 patients. Of these 6 patients, three could be tested for Tm reactivity and in two (1SD, 1 Progressive Disease, PD) increased NY-ESO 157 rates were found concomitant with increasing serum Ab levels, whereas no Tm reactivity was detected in 8 patients without seroconversions. Whereas PSMA seroconversions were observed in a total of 12/28 patients (and of note, in 4/5 PR), no Tm positivity at any time was found in a total of 15 patients tested. Further functional Treg and CTL analyses are ongoing. So far, only early HLA-DR upregulation on CD4+ or CD8+ T cells (visit 1 versus visit 3) showed any value for response prediction, since it was observed to significant levels in patients with PR or SD, but not in patients with PD. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5588.