Mesothelin CAR memory-like NK cells secreting fusion IL12-A3 cytokine demonstrate enhanced anti-tumor responses in multiple malignancies — ASN Events
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  3. Mesothelin CAR memory-like NK cells secreting fusion IL12-A3 cytokine demonstrate enhanced anti-tumor responses in multiple malignancies

Mesothelin CAR memory-like NK cells secreting fusion IL12-A3 cytokine demonstrate enhanced anti-tumor responses in multiple malignancies (#257)

Mubin Tarannum 1 , KhanhLinh Dinh 1 , Mila Stanojevic 1 , Grace Birch 1 , Fuguo Liu 1 , Andreia Maia 1 , Maily Nguyen 1 , Eden Bobilev 1 , Marco Campisi 1 , Michal Sheffer 1 , Junning Wang 1 , Seema Chugh 1 , David A Barbie 1 , Andrew J Aguirre 1 , Rebecca Porter 1 , Ursula A Matulonis 1 , Robert J Soiffer 1 , Jerome Ritz 1 , Jianzhu Chen 2 , Rizwan Romee 1
  1. Division of Transplantation and Cellular Therapies, Dana Farber Cancer Institute, Boston, MA, United States
  2. Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, United states

Immune suppressive tumor microenvironment (TME) remains one of the major challenges for the successful application of cellular therapies including chimeric antigen receptor (CAR)-NK cells. Use of standalone cytokines and/or their combination with CAR-based approaches aimed at enhancing effector function of immune cells while modulating the immune-suppressive TME has been extensively studied. We engineered cytokine-induced memory-like (CIML) NK cells armed with novel CAR construct that include secretory IL12 or IL12-A3 fusion cytokine based on the hypothesis that relatively benign secretome of NK cells will make this approach safer (vs CAR T cells) while significantly enhancing their efficacy and mediating robust TME modulation. Furthermore, the incorporation of a single collagen-binding A3-domain fused to the secretory IL12 would trap it in the collagen I/III rich TME in solid tumors like pancreatic and ovarian cancer and thus minimize systemic exposure and toxicity of IL12. IL12-engineered mesothelin (MSLN)-CAR CIML NK cells demonstrated superior metabolic fitness and increased expression of key genes enriched in the following pathways: inflammatory response, MTORC1 signaling, IFNa/g response, TNFa response, MYC and E2F targets. Increased expression of multiple genes including IFNg, GZMA/B, PRF1 and FASLG involved in mediating anti-tumor responses while decreased CISH expression suggested enhanced responsiveness to the physiological levels of IL15/IL2 were also observed. IL12 and IL12-A3 engineered MSLN-CAR CIML NK cells had significantly enhanced anti-tumor responses (cytotoxicity, IFNg and TNFa) against multiple resistant ovarian and pancreatic cell lines as well as patient-derived xenograft (PDX) cells or organoids (PDO). We also observed significantly improved tumor control (BLI and survival) in xenograft mice bearing Luc+OVCAR8 (ovarian cancer) or Luc+ASPC1 (pancreatic cancer) tumors when injected with a single dose (1x106) of IL12-A3 MSLN-CAR CIML NK cells and minimal systemic IL12 exposure (<1ng/mL). These results make a compelling argument for the evaluation of this approach in patients with ovarian and pancreatic cancer.