Anti-Mullerian inhibiting substance type II receptor (MISRII) specific CAR T cell therapy for the targeted, safe treatment of ovarian cancer.
Ovarian cancer is the 5th leading cause of cancer-related deaths in women and is the most lethal of all gynecologic malignancies with an overall 5-year survival rate of 46%. The Müllerian Inhibiting Substance Type 2 Receptor (MISIIR),a member of the TGF-β receptor family, overexpressed in the majority of ovarian tumors and other gynecologic tumors, makes it an appealing target for cell immunotherapy.
Dr. Powell and colleagues have developed MISIIR-specific CAR T cells with distinct single-chain antibody variable fragments of MISIIR, coupled to CD27 and CD3z intracellular signaling domains. The select GM7-27Z CAR variant exhibits antigen-specific reactivity, cytokine secretion and tumor cell lysis in vitro against a broad range of human tumor cell lines including ovarian and endometrial cancer expressing variable levels of endogenous MISIIR. GM7-27Z does not exhibit cytotoxicity when co-cultured with a broad panel of normal primary human cells, suggesting a safe profile of targeting. Additionally, in vivo GM7 CAR T cells showed potent antitumor effect in immunocompromised mice bearing large established subcutaneous C30.
MISIIR tumors, completely clearing 60% of the tumors and significantly prolonging mice survival. Overall, the GM7-27Z variant supports the potential of MISIIR as a novel target for the efficacious and safe treatment of ovarian cancer and other gynecologic malignancies using CAR T cell therapy.
(A)Schematic representation of MISIIR CAR constructs based on 4 different scFv and containing CD27 and CD3z I trace lunar domains. CD19 CAR was used as a control. (B) GM7-27Z CAR shows specific activation and response in vivo.
CAR T therapy for the treatment of ovarian cancer and other gynecologic malignancies
- Enhances capability of CAR T therapy use for the treatment of solid tumors, particularly those related to ovarian cancer
- Improved safety, specificity, and targeting of CAR T cells to tumor cells given very low expression levels of MISIIR in healthy tissue tissue but overexpression in gynecologic cancers
Stage of Development:
- In Vivo anti-tumor effect of MISIIR-CAR T cells demonstrated in several subcutaneous tumor models in mice
- In vitro efficacy using patient-derived ovarian cancer cell: upregulation of T cell activation markers and cytokine secretion
Provisional patent filed
Rodriguez-Garcia et. al. Molecular Biology 2020 Feb; 28(2): 548
Docket # 15-7298