Biology subjects

Cenciarelli, C.

Publications and source records attributed to Cenciarelli, C..

3 recordsLinked to original sources

bioRxiv2019

CD16-158-VALINE CHIMERIC RECEPTOR T CELLS OVERCOME THE RESISTANCE OF KRAS-MUTATED COLORECTAL CARCINOMA CELLS TO CETUXIMAB

KRAS mutation hinders the therapeutic efficacy of epidermal-growth-factor-receptor (EGFR) mAb (cetuximab and panitumumab)-based immunotherapy of EGFR+ cancers. Although, cetuximab controls KRAS-mutated cancer cell growth in vitro utilizing a NK cell-mediated antibody-dependent-cellular-cytotoxicity-(ADCC) mechanism, KRAS-mutated colorectal carcinoma (CRC) cells can still escape NK cell immunosurveillance. To overcome this limitation, we used cetuximab and panitumumab to redirect Fc{gamma} chimeric receptor (CR) T cells against KRAS-mutated HCT116 CRC cells. We compared 4 polymorphic Fc{gamma}-CR constructs including CD16158F-CR, CD16158V-CR, CD32131H-CR, and CD32131R-CR which were transduced into T cells utilizing retroviral transduction. Percentages of transduced T cells expressing CD32131H-CR (83.5{+/-}9.5) and CD32131R-CR (77.7.{+/-}13.2) were significantly higher than those expressing with CD16158F-CR (30.3{+/-}10.2) and CD16158V-CR (51.7{+/-}13.7) (p<0.003). CD32131R-CR T cells specifically bound soluble cetuximab and panitumumab. However, only CD16158V-CR T cells released significantly higher levels of interferon gamma (IFN{gamma}=1145.5 pg/ml {+/-}16.5 pg/ml, p<0.001) and tumor necrosis factor alpha (TNF=614 pg/ml {+/-} 21 pg/ml, p<0.001) than non-transduced T cells when incubated with KRAS-mutated HCT116 cells opsonized with cetuximab. Only CD16158V-CR T cells combined with cetuximab controlled the growth of HCT116 cells subcutaneously engrafted in CB17-SCID mice. These results suggest that CD16158V-CR T cells combined with cetuximab represent useful reagents to develop an effective immunotherapy of EGFR+KRAS-mutated cancer.

immunology↗

bioRxiv2019

ELIMINATION OF EGFR-OVEREXPRESSING CANCER CELLS BY CD32 CHIMERIC RECEPTOR T CELLS IN COMBINATION WITH CETUXIMAB OR PANITUMUMAB

Cetuximab and panitumumab bind the human epidermal growth factor receptor (EGFR). While the chimeric cetuximab (IgG1) triggers antibody-dependent-cellular-cytotoxicity (ADCC) of EGFR positive target cells, panitumumab (a human IgG2) does not. The inability of panitumumab to trigger ADCC reflects a poor binding affinity of human IgG2 Fc for the Fc{gamma}RIII (CD16) on NK cells. However, both human IgG1 and IgG2 bind the Fc{gamma}RII (CD32) to a similar extent. Here, we have compared the ability of T cells, engineered with a novel low-affinity CD32131R -chimeric receptor (CR), and those engineered with the low-affinity CD16158F-CR T cells in eliminating EGFR positive epithelial cancer cells (ECCs) in combination with cetuximab or panitumumab. Following T cell transduction, the percentage of CD32131R-CR T cells was (74{+/-}10) significantly higher than that of CD16158F-CR T cells (46{+/-}15). Only CD32131R-CR T cells bound panitumumab. CD32131R-CR T cells combined with the mAb 8.26 (anti-CD32) and CD16158F-CR T cells combined with the mAb 3g8 (anti-CD16) eliminated colorectal carcinoma (CRC), HCT116Fc{gamma}R+ cells, in a reverse ADCC assay in vitro. Cross-linking of CD32131R-CR on T cells by cetuximab or panitumumab and CD16158F-CR T cells by cetuximab induced elimination of triple negative breast cancer (TNBC) MDA-MB-468 cells, and secretion of IFN gamma (IFN{gamma}) and tumor necrosis factor alpha (TNF). Neither cetuximab nor panitumumab induced Fc{gamma}-CR T anti-tumor activity against KRAS-mutated HCT116, non-small-cell-lung-cancer, A549 and TNBC, MDA-MB-231 cells. ADCC of Fc{gamma}-CR T cells was significantly associated with the over-expression of EGFR on ECCs. In conclusion, CD32131R-CR T cells are efficiently redirected by cetuximab or panitumumab against BC cells overexpressing EGFR.\n\nArticle categoryTumor Immunology and Microenvironment\n\nNovelty and ImpactMonoclonal antibody-redirected Fc{gamma}-CR T cell immunotherapy represents a promising approach in the fight against cancer. Here, we expand the application of this methodology to TNBC overexpressing the EGFR utilizing a novel CD32A131R-CR in combination with anti-EGFR mAbs. Our study supports the use of CD32A131R-CR T cells combined with panitumumab or cetuximab for targeting TNBC cells overexpressing the EGFR. Our results may be utilized as a platform for the rational design of therapies targeting TNBC overexpressing EGFR.

immunology↗

bioRxiv2019

Effects of estrogen on Survival and Neuronal Differentiation of adult human olfactory bulb neural stem Cells Transplanted into Spinal Cord Injured Rats

In the present study we developed an excitotoxic spinal cord injury (SCI) model using kainic acid (KA) to evaluate of the therapeutic potential of human olfactory bulb neural stem cells (h-OBNSCs) for spinal cord injury (SCI). In a previous study, we assessed the therapeutic potential of these cells for SCI; all transplanted animals showed successful engraftment. These cells differentiated predominantly as astrocytes, not motor neurons, so no improvement in motor functions was detected. In the current study we used estrogen as neuroprotective therapy before transplantation of OBNSCs to preserve some of endogenous neurons and enhance the differentiation of these cells towards neurons. The present work demonstrated that the h-GFP-OBNSCs were able to survive for more than eight weeks after sub-acute transplantation into injured spinal cord. Stereological quantification of OBNSCs showed approximately a 2.38-fold increase in the initial cell population transplanted. 40.91% of OBNSCs showed differentiation along the neuronal lineages, which was the predominant fate of these cells. 36.36% of the cells differentiated into mature astrocytes; meanwhile 22.73% of the cells differentiated into oligodendrocytes. Improvement in motor functions was also detected after cell transplantation.

neuroscience↗