Antitumor Responses in the Absence of Toxicity in Solid Tumors by Targeting B7-H3 via Chimeric Antigen Receptor T Cells

The high expression across multiple tumor types and restricted expression in normal tissues make B7-H3 an attractive target for immunotherapy. We generated chimeric antigen receptor (CAR) T cells targeting B7-H3 (B7-H3.CAR-Ts) and found that B7-H3.CAR-Ts controlled the growth of pancreatic ductal adenocarcinoma, ovarian cancer and neuroblastoma in vitro and in orthotopic and metastatic xenograft mouse models, which included patient-derived xenograft. We also found that 4-1BB co-stimulation promotes lower PD-1 expression in B7-H3.CAR-Ts, and superior antitumor activity when targeting tumor cells that constitutively expressed PD-L1. We took advantage of the cross-reactivity of the B7-H3.CAR with murine B7-H3, and found that B7-H3.CAR-Ts significantly controlled tumor growth in a syngeneic tumor model without evident toxicity. These findings support the clinical development of B7-H3.CAR-Ts

Differential role of HLA-A and HLA-B, C expression levels as prognostic markers in colon and rectal cancer

Purpose The association of human leucocyte antigen (HLA) class I expression levels with the clinical course of many malignancies reflects their crucial role in the recognition and elimination of malignant cells by cognate T cells and NK cells. In colorectal cancer, results regarding this association are conflicting. The potential pathogenetic and therapeutic implications of this association prompted us to perform a large patient-level pooled analysis assessing the role of the expression level of HLA class I loci gene products in colon and rectal cancer. Experimental design Included studies provided patient-level data on HLA class I expression levels determined by immunohistochemistry on surgical specimens. Expression levels of the HLA class I loci gene products (HLA-A, HLA-B/C) were correlated with common genetic events and survival. Results Data from 5 studies including 2863 patients were used. In the 1620 colon cancer patients, lower HLA-A, HLA-B/C and total HLA class I expression levels were associated with microsatellite instability (p=0.044, p=0.008 and p=0.022, respectively), higher frequency of BRAF mutations (p<0.001, p=0.021 and p<0.001, respectively) and lower frequency of KRAS mutations (p=0.001, ns and p=0.002, respectively). In the 1243 rectal cancer patients, HLA-A expression was higher in tumors treated with neoadjuvant radiation (p=0.024). High HLA-B/C, but not HLA-A, expression level was an independent predictor of favorable overall survival in colon (p=0.006) and rectal (p<0.001) cancer. Conclusions T-cells and HLA-B/C antigens, rather than NK cells and HLA-A antigens, likely play an important role in controlling colon/rectal cancer growth. Colon/rectal cancer patients may benefit from strategies that upregulate HLA-B/C and trigger or enhance T cell immunity.Surgical oncolog

Differential role of HLA-A and HLA-B, C expression levels as prognostic markers in colon and rectal cancer

Purpose The association of human leucocyte antigen (HLA) class I expression levels with the clinical course of many malignancies reflects their crucial role in the recognition and elimination of malignant cells by cognate T cells and NK cells. In colorectal cancer, results regarding this association are conflicting. The potential pathogenetic and therapeutic implications of this association prompted us to perform a large patient-level pooled analysis assessing the role of the expression level of HLA class I loci gene products in colon and rectal cancer. Experimental design Included studies provided patient-level data on HLA class I expression levels determined by immunohistochemistry on surgical specimens. Expression levels of the HLA class I loci gene products (HLA-A, HLA-B/C) were correlated with common genetic events and survival. Results Data from 5 studies including 2863 patients were used. In the 1620 colon cancer patients, lower HLA-A, HLA-B/C and total HLA class I expression levels were associated with microsatellite instability (p=0.044, p=0.008 and p=0.022, respectively), higher frequency of BRAF mutations (p<0.001, p=0.021 and p<0.001, respectively) and lower frequency of KRAS mutations (p=0.001, ns and p=0.002, respectively). In the 1243 rectal cancer patients, HLA-A expression was higher in tumors treated with neoadjuvant radiation (p=0.024). High HLA-B/C, but not HLA-A, expression level was an independent predictor of favorable overall survival in colon (p=0.006) and rectal (p<0.001) cancer. Conclusions T-cells and HLA-B/C antigens, rather than NK cells and HLA-A antigens, likely play an important role in controlling colon/rectal cancer growth. Colon/rectal cancer patients may benefit from strategies that upregulate HLA-B/C and trigger or enhance T cell immunity

Laparoscopic subtotal colectomy with antiperistaltic ceco-rectal anastomosis: a new step in the treatment of slow-transit constipation

Background: Subtotal colectomy with antiperistaltic ceco-rectal anastomosis (SCCRA) has proved to be an effective alternative to total colectomy for the treatment of severe slow-transit constipation. The laparoscopic approach has made this procedure even more attractive. This is the first controlled trial on laparoscopic SCCRA: the study compares the laparoscopic and the open approach. Methods: Since 2001 all SCCRAs have been performed laparoscopically at our institution. Only severely symptomatic patients are offered surgery, after stringent patient selection. Laparoscopic SCCRA was carried out following the same steps we first described for the open approach, by utilizing a 5-trocar technique. Outcome parameters were prospectively collected every 3 and 6 months. Wexner constipation and incontinence scales (WCS, WI) and gastrointestinal quality of life index (GIQLI) were adopted for functional results. We conducted a case-control study of 15 consecutive patients who underwent laparoscopic SCCRA (VL) and 15 patients previously operated on by the open approach (Op) to compare post-operative and functional outcomes. Results: Complication rates were similar. The VL group had better postoperative outcomes (pain, ileus) resulting in a significantly shorter hospital stay. Resolution of constipation was impressive in both groups, with no significant difference at follow-up. The VL group presented with a higher number of bowel movements at 3 months (3.8 vs 2.8, p=0.039), resulting in a significantly higher incontinence rate at 3 months (WI 6.4 vs 2.73, p= 0.004), although the difference was no longer significant at 1-year follow-up. The quality of life was good for both groups; the VL group showed a significant improvement at 1-year follow-up (64.18 vs 114.79, p< 0.01). Conclusions: Laparoscopic SCCRA confirmed the good functional results of the open approach, with no increase in morbidity rate and a faster postoperative recovery. An early higher incontinence rate did not affect quality of life

Invasive intraductal papillary mucinous carcinomas of the pancreas: predictors of survival and the role of lymph node ratio

Introduction: Intraductal papillary mucinous neoplasms (IPMNs) are being increasingly recognized, and often harbor cancer. Lymph node metastases are an important prognostic factor for patients with invasive intraductal papillary carcinoma (I-IPMC), but the role of lymph node ratio (LNR) in predicting survival after surgery for I-IPMC is unknown. Methods: The combined databases from the Surgical Department of Massachusetts General Hospital of Boston and the University of Verona were queried. We retrospectively reviewed clinical and pathologic data of all patients with resected, pathologically confirmed, I-IPMC between 1990 and 2007. Univariate and multivariate analysis were performed. Results: I-IPMCs were diagnosed in 104 patients (55 males and 49 females), median age was 69 years. Recurrent disease was identified in 49 patients (47.1%) and the median 5-year disease specific survival (DSS) was 60.1%. The median number of resected/ evaluated nodes was 15 (range, 5-60). There were 60 (57.7%) patients who had negative lymph nodes (N0), whereas 44 (42.3%) had lymph node metastases (N1). Patients with lymph node metastases had a shorter 5-year DSS (28.9%) compared with patients with negative lymph nodes (80.3%; P 0 to 0.2, 34.4%; LNR >0.2, 11.1%; P 37 U/L were significant predictors of survival (P < 0.05). Conclusions: Lymph node ratio is a strong predictor of survival after resection for invasive intraductal papillary mucinous carcinoma