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

Stressed target cancer cells drive nongenetic reprogramming of CAR T cells and solid tumor microenvironment

The poor efficacy of chimeric antigen receptor T-cell therapy (CAR T) for solid tumors is due to insufficient CAR T cell tumor infiltration, in vivo expansion, persistence, and effector function, as well as exhaustion, intrinsic target antigen heterogeneity or antigen loss of target cancer cells, and immunosuppressive tumor microenvironment (TME). Here we describe a broadly applicable nongenetic approach that simultaneously addresses the multiple challenges of CAR T as a therapy for solid tumors. The approach reprograms CAR T cells by exposing them to stressed target cancer cells which have been exposed to the cell stress inducer disulfiram (DSF) and copper (Cu)(DSF/Cu) plus ionizing irradiation (IR). The reprogrammed CAR T cells acquire early memory-like characteristics, potent cytotoxicity, enhanced in vivo expansion, persistence, and decreased exhaustion. Tumors stressed by DSF/Cu and IR also reprogram and reverse the immunosuppressive TME in humanized mice. The reprogrammed CAR T cells, derived from peripheral blood mononuclear cells of healthy donors or metastatic female breast cancer patients, induce robust, sustained memory and curative anti-solid tumor responses in multiple xenograft mouse models, establishing proof of concept for empowering CAR T by stressing tumor as a promising therapy for solid tumors

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

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

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