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Abstract
Background Epithelial OVCA remains a highly fatal disease. FSHR is a tissue specific antigen expressed in >55% of high-grade epithelial OVCAs of different histological types. No significant FSHR expression is found in non-ovarian healthy tissues in women (figure 1). The treatment of OVCA patient derived xenografts with FSHCER T (FSH-Chimeric Endocrine Receptor + T-Cell (CER T)) cells (figure 2) in controlled, paired, mice was shown to effectively redirect the cytotoxic activity of T cells against patient-derived FSHR+ ovarian carcinomas (figure 3).1 We hypothesize targeting FSHR in women with FSHR+ OVCA will result in improved response rates due to engraftment, expansion, and survival of these adoptively transferred FSHCER T cells and will have acceptable toxicity.
Methods This is an open phase 1 dose-escalation study (NCT05316129) in high-grade epithelial OVCA to assess the safety of autologous T cells genetically modified to express CER targeting FSHR. Primary objective is to assess the safety of the intraperitoneal (IP) and intravenous (IV) infusions of FSHCER T cells with or without prior cyclophosphamide plus fludarabine. Secondary objectives include antitumor efficacy, persistence of transferred FSHR T cells, expansion of endogenous tumor-targeted cells, and to compare IP and IV routes of administration.,
A screening part of the study will examine archived tissue from patients with recurrent platinum resistant or refractory OVCA following 2-8 prior lines of chemotherapy. Those who demonstrate positive or indeterminate FSHR Expression by an RNA Salah Targeted Expression Panel (STEP) will be eligible to screen for the treatment dose-escalation portion. Additional criteria include measurable or evaluable disease; performance status 0-2; adequate bone marrow, renal, and hepatic function; and eligibility for IP catheter placement.
If a patient is unable to be treated in the IP arm, the patient may be treated in the IV arm in the lowest unfilled cohort for that arm. Cohorts of 3 to 6 patients will be infused with escalating doses of FSHCER T cells to establish the maximum tolerated dose (MTD) with 6 planned dose levels: 1 × 105, 3 × 105, 1 × 106, 3 × 106, and 1 x 107 FSHCER T cells/kg. If the MTD is not established after 3 × 106, then next cohorts will receive conditioning cytoxan/fludarabine 5 days before starting T-cell infusion at dose levels 1 × 106, 3 × 106 and 1 × 107 FSHCER T cells/kg. Following determination of MTD, an expansion phase will be initiated.
Acknowledgements We wish to acknowledge Carrie Thomas, Keri Erb, Tam Jackson, Allison Murphy, Van Barnes, Kumar Karyampudi, Samantha Demmi, Denise Dorman, Cheryl Cox, Tanner Pearson, Brook Olmo, and many others on the teams at both Moffitt Cancer Center and Anixa Biosciences involved in cell therapies and clinical trial development and execution who have helped to enable this study.
Trial Registration NCT05316129
Reference
Perales-Puchalt A, Svoronos N, Rutkowski MR, Allegrezza MJ, Tesone AJ, Payne KK, Conejo-Garcia JR. Follicle-Stimulating Hormone Receptor Is Expressed by Most Ovarian Cancer Subtypes and Is a Safe and Effective Immunotherapeutic Target. Clin Cancer Res. 2017;23(2):441–453. doi:10.1158/1078-0432.CCR-16-0492
Ethics Approval This study was approved by Moffitt Scientific Review #21113 and Advarra Institutional Review Board #00000971. Patients give informed consent before participation.
Normalized real-time quantitative-PCR of FSHR exprNormalized real-time quantitative-PCR of FSHR expression in human healthy tissues.
FSHCER construct for expression in T cells.
Patient-derived ovarian cancer xenografts could be effectively targeted with FSH-expressing chimeric receptors. Hematoxilin-Eosin staining of ovarian PDX tumor grown in NOD-SCID mice ovary treated with either FSHCER (”case” mouse) or mock (”control” mouse) transduced autologous HUMAN FSHCER T cells (106 total; >70%GFP+).