CTX130 Allogeneic CAR T-cell Therapy Shows Tolerability, Intriguing Activity in Advanced RCC

Article

CTX130, an investigational allogeneic, CRISP/Cas9 gene-edited, anti-CD70 CAR T-cell therapy, was found to be safe with early signs of clinical activity in patients with advanced clear cell renal cell carcinoma, according to findings from the phase 1 COBALT-RCC trial.

Sumanta K. Pal, MD

Sumanta K. Pal, MD

CTX130, an investigational allogeneic, CRISP/Cas9 gene-edited, anti-CD70 CAR T-cell therapy, was found to be safe with early signs of clinical activity in patients with advanced clear cell renal cell carcinoma (RCC), according to findings from the phase 1 COBALT-RCC trial (NCT04438083) that were presented during the 2022 SITC Annual Meeting.

Results showed that, of 13 evaluable patients, the objective response rate was 8%, the stable disease (SD) rate was 69%, and the disease control rate was 77%. The 1 response was a partial response that deepened to a complete response (CR) by 3 months with a maintained CR at 18 months. At 4 months, 4 patients were in SD.

The therapy had an acceptable safety profile across all dose levels with no dose-limiting toxicities (DLTs). Of the 14 patients on the study, 50% had grade 1/2 cytokine release syndrome (CRS), 3 of which were related to CTX130. The median time to CRS onset was 1 day with a median duration of 2 days. Three patients had serious adverse events (AEs) that were infections, all of which were unrelated to CTX130. There was 1 death of pneumonia with grade 4 dyspnea, which was not related to treatment.

“This first-in-human clinical trial exploring CD70 CAR T-cell therapy in clear cell renal cell carcinoma showed a tolerable safety profile with no unexpected on-target off-tumor toxicities and encouraging antitumor activity,” lead study author Sumanta K. Pal, MD, a professor in the Department of Medical Oncology and Therapeutics Research, and codirector of the Kidney Cancer Program at City of Hope in Duarte, California, said in a presentation during the meeting. “To our knowledge, this durable complete response is the first to be achieved with allogeneic CAR T-cell therapy in patients with relapsed/refractory solid tumors.”

CD70 is a CD27 ligand that has transient expression on activated lymphocytes and is found to be highly expressed in clear cell RCC tumor samples. CTX130 is a first-in-class, CD70-targeting allogeneic CAR T-cell therapy that is being evaluated in patients with advanced clear cell RCC. The therapy has targeted disruption of the T-cell receptor α constant (TRAC), β2 microglobulin, and CD70 loci. With the use of an adeno-associated virus vector, an anti-CD70 CAR cassette is inserted into the TRAC locus by homology-directed repair.

The CAR T-cell therapy is manufactured from healthy donor T cells that are then selected and edited prior to expansion and cryopreservation for off-the-shelf use. Preclinical data demonstrated encouraging signals in an RCC xenograft model, Pal noted.

In the open-label, multicenter, international, single-arm COBALT-RCC trial, investigators sought to evaluate the safety and efficacy of CTX130 in patients with advanced clear cell RCC. The study had 2 parts: a dose-escalation portion (part A) and a cohort expansion portion (part B).

Patients underwent lymphodepletion with fludarabine at 30 mg/m2 plus 500 mg/m2 of cyclophosphamide for 3 days on days -5, -4, and -3. CTX130 infusion began on day +1 with the dose-escalation design: 3 x 107 (dose level 1), 1 x 108 (dose level 2), 3 x 108 (dose level 3), and 9 x 108 (dose level 4).

To be eligible for enrollment, patients with unresectable or metastatic RCC with clear cell differentiation had to be at least 18 years old and have a body weight of 42 kg or higher. Prior exposure to a checkpoint inhibitor and VEGF inhibitor was required; patients also had to have a Karnofsky performance status of at least 80%, as well as adequate renal, liver, cardiac, and pulmonary organ function.

Those who had prior treatment with anti-CD70 therapy or CAR T cells or any other modified T or natural killer cells were excluded from enrollment, as well as those with a history of central nervous system, cardiac, or pulmonary conditions; and prior solid organ transplantation or bone marrow transplant.

The primary end point of part A of the trial was incidence of adverse events via DLTs; in part B, the primary end point was ORR per RECIST v1.1 criteria. Secondary end points were best overall response, progression-free survival, and overall survival.

The median age was 64.5 years (range, 54-77) and 85.7% of patients were male. All patients had stage IV metastatic disease and previously received systemic therapy; 64.3% and 92.9% of patients received prior radiotherapy and surgery, respectively.

A total 57.1% of patients had International Metastatic Renal Cell Carcinoma Database Consortium intermediate-risk disease while 42.9% of patients had high-risk disease. Estimated glomerular filtration rate <60 mL/min/1.73 m2 were reported in 42.9% of patients. The median time from diagnosis was 4.9 years (range, 0.7-24.0), and the sum of diameters for target lesions was 64 mm (range, 12-141).

The data cutoff date was May 2, 2022.

Pal added that the typical pharmacokinetics were seen with peak time to expansion at a median of day 10 and peak concentration of approximately 3500 copies/µg.

Reference

Pal SK, Tran B, Hannen JB, et al. CTX130 allogeneic CRISPR-Cas9–engineered chimeric antigen receptor (CAR) T cells in patients with advanced clear cell renal cell carcinoma: results from the Phase 1 COBALT-RCC study. Presented at: 2022 SITC Annual Meeting; November 8-12, 2022; Boston, MA. Abstract 558.

Related Videos
Samer A. Srour, MB ChB, MS
Samer A. Srour, MB ChB, MS
Petros Grivas, MD, PhD, professor, Clinical Research Division, Fred Hutchinson Cancer Center; professor, Division of Hematology and Oncology, University of Washington (UW) School of Medicine; clinical director, Genitourinary Cancers Program, UW Medicine
Francesco Di Meo, PhD
A panel of 5 experts on renal cell carcinoma
Chandler H. Park, MD, an expert on renal cell carcinoma
Pasi A. Jänne, MD, PhD, discusses an exploratory analysis from the FLAURA2 trial of osimertinib plus chemotherapy in treatment-naive, EGFR-mutant NSCLC.
Eric S. Christenson, MD
Benjamin Garmezy, MD
Samer A. Srour, MB ChB, MS