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New CAR-T Technology Being Explored in Phase 1 for Solid Tumors

Several CAR T-cell therapies have proved to be efficacious in hematological malignancies; however, developing a safe and effective CAR T-cell approach for solid tumors has remained a challenge.

This article originally appeared on our sister site, OncLive.

Investigators at Moffitt Cancer Center are exploring a new follicle-stimulating hormone receptor (FSHR)–mediated CAR T-cell technology (CER-T) in patients with recurrent ovarian cancer as part of a phase 1 clinical trial (NCT05316129).1

“All the evidence that we have indicates that [this CER-T approach] behaves exactly as CAR T-cell [therapy], with the only difference that the targeted motif is different. We are selecting 4-1BB as the stimulatory domain,” Jose Conejo-Garcia, MD, PhD, chair of the Department of Immunology at Moffitt Cancer Center, said in an interview with OncLive®. “Other CAR T-cell [therapies] use CD28 [as a stimulatory domain, which] can be more sensitive. However, what we have [learned] from patients who have received CAR T cells is that 4-1BB–based CAR [T-cell therapies] appear to be more persistent. We decided to go for persistence to prevent further recurrence, as opposed to enhancing cytotoxic activity in the short term, which is what CD28-based [therapies] appear to provide.”

Several CAR T-cell therapies have proved to be efficacious in hematological cancers; however, developing a safe, effective CAR T-cell approach for solid tumors has remained a challenge. The autologous cell therapy is composed of engineered T cells that target the FSHR, which is detected at immunological levels exclusively on the granulosa cells of the ovaries.

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 that expresses the FSHR antigen.2 To be eligible for enrollment, patients need to have an ECOG performance status of 2 or better, a life expectancy of at least 3 months, and acceptable bone marrow, renal, and hepatic function. Patients also must have received 1 prior platinum-based chemotherapy regimen and be considered refractory to treatment. Patients also need to have measurable disease.

Those with a known germline or somatic BRCA pathogenic mutation should have previously received a PARP inhibitor and subsequently experienced disease progression. Patients can, but are not required to, receive 6 additional previous chemotherapy treatment regimens. Conejo-Garcia added that the trial is aiming to include a patient population that is devoid of available treatment options.

The estimated enrollment for the trial is 48 participants, who will intraperitoneally or intravenously receive 1 infusion of FSHR T cells at the following dose levels (DL): 1 x 105 (DL1), 3 x 105 (DL2), 1 x 106 (DL3), 3 x 106 (DL4), and 1 x107 (DL5).

The primary end point of the trial is to identify the maximum tolerated dose of the FSH-CER T cells. Secondary end points will include duration of response, duration of stable disease, and overall survival with this approach. Additionally, investigators plan to track the persistence of T cells 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 spreading, we hoped that pre-existing polyclonal responses [already] operating in the [patient] would get boosted,” Conejo-Garcia explained. “That would provide stronger antitumor immunity that would control tumor growth more effectively.”

It has also been hypothesized that CER-T could have a positive impact in other solid tumors that overexpress FSH, since CAR T-cell therapies have not yet made any headway in those patients.

“This could have a major impact on the field of gynecologic malignancies. We have preliminary evidence that the FSHR could be expressed in other tumor [types], namely kidney cancer,” Conejo-Garcia said. “[This is] for reasons we do not understand. We are investigating. We hope that this could be extended to other patients, if successful and safe."

The trial will be piloted by lead investigator Robert Wenham, MD, MS, FACOG, FACS, who is the chair of the Department of Gynecologic Oncology at Moffitt Cancer Center.

In March of 2021, Anixa filed an investigational new drug application with the FDA for the CER-T approach. However, the application was placed on clinical hold in April 2021 after the regulatory agency requested additional information regarding the agent.3 The company provided that data to the FDA in May 2021,4 and so, in August 2021, the clinical trial investigating CER-T in ovarian cancer was cleared for initiation.5

References
  1. Anixa Biosciences announces the initiation of its ovarian cancer CAR-T phase 1 trial at Moffitt Cancer Center. News Release. Anixa Biosciences, Inc. May 30, 2022. Accessed April 28, 2022. https://prn.to/3x3CpFL
  2. Infusion of autologous T cells engineered to target FSH receptor in recurrent ovarian cancer. ClinicalTrials.gov. Updated April 7, 2022. Accessed April 28, 2022. https://clinicaltrials.gov/ct2/show/NCT05316129
  3. Anixa Biosciences and Moffitt Cancer Center report US FDA request of additional information for CAR-T Therapy. News release. Anixa Biosciences, Inc. April 19, 2021. Accessed April 28, 2022. https://bit.ly/3r1PETy
  4. Anixa Biosciences and Moffitt Cancer Center receive additional information request from US FDA for CAR-T IND application. News release. Anixa Biosciences, Inc. May 20, 2021. Accessed April 28, 2022. https://prn.to/3uRrGeZ
  5. Anixa Biosciences and Moffitt Cancer Center announce FDA clearance to initiate clinical trial of ovarian cancer CAR-T immunotherapy. News release. Anixa Biosciences, Inc. August 30, 2021. Accessed April 28, 2022. https://prn.to/3NNplu7