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Mesothelin Chimeric Antigen Receptor (CAR)-Mediated Therapy for Ovarian Cancer
Vol. 225, No. 4S2, October 2017
with Rag1tm1Mom mutation (RAG1 KO mice), with non-functional adaptive immune system. RESULTS: In both melanoma and pancreatic cancer models, tumors were significantly smaller in antibiotic-treated mice compared to that in saline-treated mice. Tumors from Abx mice also showed significantly lower Ki-67 immunofluorescence and splenocytes from these mice showed higher anti-cancer cytotoxicity. However, ability of gut microbiome depletion to reduce cancer growth was lost in RAG1 KO mice suggesting an immune mediated mechanism. CONCLUSIONS: Gut sterilization decreases cancer burden through a possible immune-mediated mechanism. Influence of Body Composition Profile on Surgical Outcomes after Esophageal Cancer Surgery Yasuhiko Mohri, MD, PhD, FACS, Takashi Ichikawa, MD, Masaki Ohi, PhD, Hiromi Yasuda, MD, Shigeyuki Yoshiyama, Hiroki Imaoka, MD, PhD, Yuji Toiyama, MD, PhD, Toshimitsu Araki, MD, PhD, Masato Kusunoki, MD, PhD Mie University, Tsu, Japan INTRODUCTION: Muscle depletion is characterized by reduced muscle mass (myopenia), and increased intermuscular and intramuscular fat (myosteatosis). This study examined the role of particular body composition profiles as postoperative and prognostic markers for patients with esophageal cancer undergoing curative resection. METHODS: Patients with esophageal cancer undergoing elective surgical resection between 2002 and 2015 were included. Using preoperative plain CT at the umbilical level, we measured the cross-sectional areas of the bilateral psoas muscles by manual tracing for calculating psoas muscle index (PMI). Intramuscular adipose tissue content (IMAC) was calculated by the ratio of multifidus muscle and subcutaneous fat CT values. Logistic and Cox regression models were used to determine the role of different profiles on postoperative and long-term outcomes, respectively. RESULTS: A total of 110 patients were identified. The incidence of postoperative complication was 54.5%. Median follow-up period was 32.6 (interquartile range 19.1e56.0) months. Multivariate analysis identified myopenia as an independent prognostic factor for overall survival (hazard ratio 2.69, 95% CI 1.39 to 5.20, p ¼ 0.003). The presence of myosteatosis was related to higher incidence of postoperative complication rate and was an independent predictor of developing postoperative complication (odds ratio 6.07, 95% CI 2.37 to 15.54, p <0.001). CONCLUSIONS: Myopenia may have an independent prognostic effect on cancer survival for patients with esophageal cancer. Myosteatosis may have an independent predictor for postoperative complication after surgery for esophageal cancer. Muscle depletion may represent a modifiable risk factor in patients with esophageal cancer and needs to be targeted as a relevant endpoint of health recommendations.
Scientific Forum: 2017 Clinical Congress
e47
Mesothelin Chimeric Antigen Receptor (CAR)-Mediated Therapy for Ovarian Cancer Oksana V Gruzdyn, Scott A Gruber, MD, FACS, Ramesh B Batchu, Ebrahem M Mahmud, Fatme K Chukr, Rajesh Dachepalli, Santosh K Manmari, MD, Advaitha Tiruvaipati, MD, Gamal Mostafa, MD, Donald W Weaver, MD, FACS John D Dingell VA Medical Center, Wayne State University, Detroit, MI INTRODUCTION: CAR T-cell therapy improves upon earlier cellbased cancer immunotherapies in that it avoids the negative effects of the immunosuppressive tumor microenvironment. CARs are comprised of an extracellular single-chain fragment variable (scFv) derived from antibody against tumor-specific antigen (TSA) and connected to intracellular co-stimulatory and activation domains. Using mesothelin, a differentiating TSA that is overexpressed in ovarian cancer, we explored CAR T-cell-based immunotherapy. METHODS: The mesothelin scFv sequence was synthesized and incorporated into a lentiviral CAR vector. Effector (E) human T-cells were isolated from PBMC and cultured with OKT3 antibody. Tcells were transduced with lentiviruses encoding mesothelin-CAR at a multiplicity of infection of 50 followed by selection with puromycin. In co-cultures with mesothelin-CAR T-cells, the mesothelin-positive human ovarian cancer cell line SKOV-3 was used as a target (T). RESULTS: When compared with mock-transduced controls, ELISA assays of co-culture supernatants displayed significantly increased secretion of IFN-g (p <0.05) and granzyme B (p< 0.05), both of which are crucial for rapid initiation and induction of target cell cytotoxicity. Further, in line with our ELISA assays, we observed substantial activation of mesothelin-CAR T-cell-induced cytotoxicity of SKOV-3 cells at an E:T ratio of 10:1 (40.2% increase in target cell lysis) and even a more pronounced effect at 20:1 (61.8% increase). CONCLUSIONS: Upon contact with ovarian cancer cells, mesothelin-engrafted CAR T-cells can induce secretion of granzyme B and IFN-g with efficient target cell lysis, providing a basis for potential clinical application. Modeling Breast Cancer Metastasis in a Novel 3-Dimensional Biomimetic Platform Julia L Jin, Matthew R Zanotelli, Jaime L Bernstein, Yoshiko Toyoda, Andrew I Abadeer, Sarah J Karinja, Omer Kaymakcalan, MD, Peter Torzilli, PhD, Jason A Spector, MD, FACS Weill Cornell Medical College, New York, NY; Cornell University, Ithaca, NY; Hospital for Special Surgery, New York, NY INTRODUCTION: A crucial step in the progression of cancer involves the transendothelial migration of tumor cells into vessels, a process that is facilitated by the interactions of malignant cells within their microenvironment. Traditional 2D culture systems employed to study metastatic breast cancer behavior have been limited by nonanatomic arrangement of cells. We have fabricated a novel biomimetic vascularized platform with proper in vivo vascular anatomy and adjustable elastic modulus to study factors that influence tumor progression and vascular remodeling. METHODS: Type-I collagen was enzymatically stiffened with ribose. Pluronic fibers were sacrificed in the collagen, creating a
with Rag1tm1Mom mutation (RAG1 KO mice), with non-functional adaptive immune system. RESULTS: In both melanoma and pancreatic cancer models, tumors were significantly smaller in antibiotic-treated mice compared to that in saline-treated mice. Tumors from Abx mice also showed significantly lower Ki-67 immunofluorescence and splenocytes from these mice showed higher anti-cancer cytotoxicity. However, ability of gut microbiome depletion to reduce cancer growth was lost in RAG1 KO mice suggesting an immune mediated mechanism. CONCLUSIONS: Gut sterilization decreases cancer burden through a possible immune-mediated mechanism. Influence of Body Composition Profile on Surgical Outcomes after Esophageal Cancer Surgery Yasuhiko Mohri, MD, PhD, FACS, Takashi Ichikawa, MD, Masaki Ohi, PhD, Hiromi Yasuda, MD, Shigeyuki Yoshiyama, Hiroki Imaoka, MD, PhD, Yuji Toiyama, MD, PhD, Toshimitsu Araki, MD, PhD, Masato Kusunoki, MD, PhD Mie University, Tsu, Japan INTRODUCTION: Muscle depletion is characterized by reduced muscle mass (myopenia), and increased intermuscular and intramuscular fat (myosteatosis). This study examined the role of particular body composition profiles as postoperative and prognostic markers for patients with esophageal cancer undergoing curative resection. METHODS: Patients with esophageal cancer undergoing elective surgical resection between 2002 and 2015 were included. Using preoperative plain CT at the umbilical level, we measured the cross-sectional areas of the bilateral psoas muscles by manual tracing for calculating psoas muscle index (PMI). Intramuscular adipose tissue content (IMAC) was calculated by the ratio of multifidus muscle and subcutaneous fat CT values. Logistic and Cox regression models were used to determine the role of different profiles on postoperative and long-term outcomes, respectively. RESULTS: A total of 110 patients were identified. The incidence of postoperative complication was 54.5%. Median follow-up period was 32.6 (interquartile range 19.1e56.0) months. Multivariate analysis identified myopenia as an independent prognostic factor for overall survival (hazard ratio 2.69, 95% CI 1.39 to 5.20, p ¼ 0.003). The presence of myosteatosis was related to higher incidence of postoperative complication rate and was an independent predictor of developing postoperative complication (odds ratio 6.07, 95% CI 2.37 to 15.54, p <0.001). CONCLUSIONS: Myopenia may have an independent prognostic effect on cancer survival for patients with esophageal cancer. Myosteatosis may have an independent predictor for postoperative complication after surgery for esophageal cancer. Muscle depletion may represent a modifiable risk factor in patients with esophageal cancer and needs to be targeted as a relevant endpoint of health recommendations.
Scientific Forum: 2017 Clinical Congress
e47
Mesothelin Chimeric Antigen Receptor (CAR)-Mediated Therapy for Ovarian Cancer Oksana V Gruzdyn, Scott A Gruber, MD, FACS, Ramesh B Batchu, Ebrahem M Mahmud, Fatme K Chukr, Rajesh Dachepalli, Santosh K Manmari, MD, Advaitha Tiruvaipati, MD, Gamal Mostafa, MD, Donald W Weaver, MD, FACS John D Dingell VA Medical Center, Wayne State University, Detroit, MI INTRODUCTION: CAR T-cell therapy improves upon earlier cellbased cancer immunotherapies in that it avoids the negative effects of the immunosuppressive tumor microenvironment. CARs are comprised of an extracellular single-chain fragment variable (scFv) derived from antibody against tumor-specific antigen (TSA) and connected to intracellular co-stimulatory and activation domains. Using mesothelin, a differentiating TSA that is overexpressed in ovarian cancer, we explored CAR T-cell-based immunotherapy. METHODS: The mesothelin scFv sequence was synthesized and incorporated into a lentiviral CAR vector. Effector (E) human T-cells were isolated from PBMC and cultured with OKT3 antibody. Tcells were transduced with lentiviruses encoding mesothelin-CAR at a multiplicity of infection of 50 followed by selection with puromycin. In co-cultures with mesothelin-CAR T-cells, the mesothelin-positive human ovarian cancer cell line SKOV-3 was used as a target (T). RESULTS: When compared with mock-transduced controls, ELISA assays of co-culture supernatants displayed significantly increased secretion of IFN-g (p <0.05) and granzyme B (p< 0.05), both of which are crucial for rapid initiation and induction of target cell cytotoxicity. Further, in line with our ELISA assays, we observed substantial activation of mesothelin-CAR T-cell-induced cytotoxicity of SKOV-3 cells at an E:T ratio of 10:1 (40.2% increase in target cell lysis) and even a more pronounced effect at 20:1 (61.8% increase). CONCLUSIONS: Upon contact with ovarian cancer cells, mesothelin-engrafted CAR T-cells can induce secretion of granzyme B and IFN-g with efficient target cell lysis, providing a basis for potential clinical application. Modeling Breast Cancer Metastasis in a Novel 3-Dimensional Biomimetic Platform Julia L Jin, Matthew R Zanotelli, Jaime L Bernstein, Yoshiko Toyoda, Andrew I Abadeer, Sarah J Karinja, Omer Kaymakcalan, MD, Peter Torzilli, PhD, Jason A Spector, MD, FACS Weill Cornell Medical College, New York, NY; Cornell University, Ithaca, NY; Hospital for Special Surgery, New York, NY INTRODUCTION: A crucial step in the progression of cancer involves the transendothelial migration of tumor cells into vessels, a process that is facilitated by the interactions of malignant cells within their microenvironment. Traditional 2D culture systems employed to study metastatic breast cancer behavior have been limited by nonanatomic arrangement of cells. We have fabricated a novel biomimetic vascularized platform with proper in vivo vascular anatomy and adjustable elastic modulus to study factors that influence tumor progression and vascular remodeling. METHODS: Type-I collagen was enzymatically stiffened with ribose. Pluronic fibers were sacrificed in the collagen, creating a