New FSHR-mediated CAR T approach being explored in recurrent ovarian cancer
An experimental follicle-stimulating hormone receptor-mediated CAR T cell technology is being explored in patients with recurrent ovarian cancer.
Investigative follicle-stimulating hormone receptor (FSHR)-mediated CAR T cell (CER-T) technology is being explored in patients with recurrent ovarian cancer as part of from a phase 1 trial (NCT05316129) conducted at the Moffitt Cancer Center.1
“All the evidence we have indicates that [this CER-T approach] behaves exactly like CAR T-cell [therapy], with the only difference that the reason referred to is different. We are selecting 4-1BB as the stimulation domain,” said Jose Conejo-Garcia, MD, PhD, chair of the Department of Immunology at Moffitt Cancer Center, in an interview with Live®. “Other CAR T-cell [therapies] use CD28 [as a stimulatory domain, which] may be more sensitive. However, what we have [learned] of patients who received CAR T lymphocytes is that the CAR based on 4-1BB [T-cell therapies] seem more persistent. We decided to opt for persistence to prevent further recurrences, as opposed to enhancement of short-term cytotoxic activity, which the basis of CD28 [therapies] seem to provide.
Several CAR T-cell therapies have been shown to be effective in hematological cancers; However, developing a safe and effective CAR T cell approach for solid tumors remains a challenge. Autologous cell therapy consists of modified T cells that target FSHR, which is detected at immunological levels exclusively on ovarian granulosa cells.
Conejo-Garcia noted that FSH is overexpressed in approximately 60% of patients with ovarian cancer, and that preclinical research has demonstrated that FSHR becomes upregulated upon resistance to chemotherapy.
The phase 1 trial is recruiting patients with a pathologically confirmed diagnosis of high-grade epithelial ovarian cancer, primary peritoneal cancer or fallopian tube carcinoma expressing the FSHR antigen.2 To be eligible for enrollment, patients must have an ECOG performance status of 2 or better, a life expectancy of at least 3 months, and acceptable bone marrow, kidney, and liver function. Patients must also have received 1 platinum-based chemotherapy regimen and be considered treatment refractory. Patients must also have measurable disease.
Those with a known or somatic germline BRCA pathogenic mutation must have previously received a PARP inhibitor and subsequently experienced disease progression. Patients can, but do not have to, receive 6 additional prior chemotherapy treatment regimens. Conejo-Garcia added that the trial aims to include a patient population with no available treatment options.
The estimated enrollment for the trial is 48 participants, who will receive intraperitoneally or intravenously 1 infusion of FSHR T cells at the following dose levels (DL): 1 x 105 (DL1), 3×105 (DL2), 1×106 (DL3), 3×106 (DL4), and 1 x107 (DL5).
The primary endpoint of the trial is to identify the maximum tolerated dose of FSH-CER T cells. Secondary endpoints will include duration of response, duration of disease stability, and overall survival with this approach. Additionally, the researchers plan to track T-cell persistence to better understand its effectiveness, according to Conejo-Garcia. Additionally, the effect of CER-T on pre-existing antitumor immunity will also be explored.
“By reducing tumor burden and inducing antigen spread, we hoped that pre-existing polyclonal responses [already] operating in the [patient] would be boosted,” Conejo-Garcia explained. “This would provide stronger anti-tumor immunity that would more effectively control tumor growth.”
It has also been hypothesized that CER-T may positively impact other solid tumors that overexpress FSH, as CAR T-cell therapies have not yet made progress in these patients.
“This could have a major impact on the field of gynecological malignancies. We have preliminary evidence that FSHR may be expressed in other tumors [types], namely kidney cancer,” Conejo-Garcia said. “[This is] for reasons we don’t understand. We are investigating. We hope this can be extended to other patients, if successful and safe.”
The trial will be led by Principal Investigator Robert Wenham, MD, MS, FACOG, FACS, who is the chair of the Department of Gynecologic Oncology at Moffitt Cancer Center.
In March 2021, Anixa filed an Investigational New Drug Application with the FDA for the CER-T approach. However, the application was put on clinical hold in April 2021 after the regulator requested additional information regarding the agent.3 The company provided this data to the FDA in May 2021,4 and so, in August 2021, the clinical trial for CER-T in ovarian cancer was cleared to start.5
- Anixa Biosciences announces the initiation of its Phase 1 CAR-T trial in ovarian cancer at Moffitt Cancer Center. Press release. Anixa Biosciences, Inc. May 30, 2022. Accessed April 28, 2022. https://prn.to/3x3CpFL
- Infusion of autologous T cells designed to target the FSH receptor in recurrent ovarian cancer. ClinicalTrials.gov. Updated April 7, 2022. Accessed April 28, 2022. https://clinicaltrials.gov/ct2/show/NCT05316129
- Anixa Biosciences and the Moffitt Cancer Center report a request for additional information from the US FDA regarding CAR-T therapy. Press release. Anixa Biosciences, Inc. April 19, 2021. Accessed April 28, 2022. https://bit.ly/3r1PETy
- Anixa Biosciences and Moffitt Cancer Center receive a request for additional information from the United States FDA for the CAR-T IND application. Press release. Anixa Biosciences, Inc. May 20, 2021. Accessed April 28, 2022. https://prn.to/3uRrGeZ
- Anixa Biosciences and the Moffitt Cancer Center Announce FDA Clearance to Initiate Clinical Trial of CAR-T Immunotherapy for Ovarian Cancer. Press release. Anixa Biosciences, Inc. August 30, 2021. Accessed April 28, 2022. https://prn.to/3NNplu7